Angiogenesis is crucial to facilitate tendon healing, such as delivering oxygen and nutrients, removing waste products, and controlling immune responses. Vascular endothelial growth factor (VEGF) is one of the most vital angiogenic factors that regulate blood vessel formation in tendon healing. Recently, biological therapies, including the application of exogenous VEGF, have been attracting increasing attention. However, at present, the effect of the application of exogenous VEGF in tendon healing is controversial, as the role of endogenous VEGF in tendons has also not been fully elucidated. This article will summarize the role of both endogenous and exogenous VEGF in tendon healing and discuss possible reasons for the controversy. The present review shows that tendon repair is facilitated only by proper angiogenesis and VEGF at the early stage, whereas the persistent high VEGF expression and prolonged presence of blood vessels may impair tendon repair at a later stage. Tendon is a specialized connective tissue that efficiently transfers muscle strength to the bone. Tendon injury is one of the most common reasons for presenting to a medical practitioner, accounting for 30% of all presentations for musculoskeletal complaints . The heaTendon healing can be separated into three overlapping phases: inflammation, proliferation, and remodeling. Both intrinsic tenocytes from the tendon itself and extrinsic peripheral fibroblasts work together to accomplish it . Intrinsin vivo, promoting vascular wall permeability and the growth and proliferation of vascular endothelial cells and perivascular cells, the latter of which are self-renewing and regenerative . VEGF becomes active just after tendon injury and continues to influence the functions of various processes . Immedianerative . In addinerative .The VEGF family of proteins includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, Placental Growth Factor (PlGF), virus-encoded VEGF-E, and the snake venom-derived VEGF-F. Among them, VEGF-A is a characteristic family member that is the most potent stimulator during angiogenesis (both endogenous and exogenous VEGF mentioned below are of this type) . FurtherHowever, at present, the role of application of exogenous VEGF is controversial, because the role of endogenous VEGF in tendons has also not been fully elucidated. This article will summarize the role of both endogenous and exogenous VEGF in tendon healing and discuss possible reasons for the controversy. This will ultimately contribute to a better understanding of the role of VEGF in health and disease, as well as future drug discovery efforts targeting tendon healing.Vascular endothelial growth factor is completely negligible in healthy tendons due to limited metabolic demands and its mechanical function . It is ein situ freezing model, Searching the literature on alterations in endogenous VEGF content after tendon injury, we summarized the variation trend of gross VEGF concentration after tendon injury in various tendon injury models . After aTendon healing time varies due to different modeling methods (surgery and graft reconstruction) or species . Although different peak periods of VEGF were monitored, their trends all increased first at the early stage in their proliferative phase of tendon repair and then decreased afterward. Moreover, this expression pattern of VEGF concentrations is consistent with the number of new blood vessels observed in the tendon repair site .The reason why VEGF changes after tendon injury is discussed both in acute and chronic tendon injury. There are four factors that are able to upregulate VEGF expression: hypoxia, inflammatory cytokines, nerve signals and mechanical load . At firsvia nerve-derived VEGF in tendons harbor more perivascular cells , which are the source of tendon stem/progenitor cells (TSPCs) that exhibit mesenchymal stem cell-like characteristics, including self-renewal and regeneration, mediating tendon injury healing  because the tendon is almost avascular . Besides healing . Next, a healing .Due to the regular changes of VEGF after tendon injury, some studies have proposed that VEGF and neovascularization are considered as observational indexes and predictors of clinical efficacy in patients with tendon injury before and after treatment . AccordiDespite the various benefits of VEGF in promoting angiogenesis for tendons, there is still some literature suggesting that VEGF impairs tendon healing, such as mechanical properties and pain. For chronic tendon injury, hypervascularity and high levels of VEGF were demonstrated in degenerated human and rabbit Achilles tendons or chronic tendon tendinopathy compared to native tendons . AlthougThe negative effect may be attributed to the fact that VEGF also has the potential to stimulate the expression of matrix metalloproteinases (MMPs) and inhibit the expression of tissue inhibitors of metalloproteinases (TIMPs) in endothelial cells and fibroblasts . They coDue to the necessity of angiogenesis for tendon repair, some scholars have explored the effect of using the delivery of exogenous VEGF on tendon healing as endogenous VEGF may not be sufficient to enhance early revascularization . HoweverMoreover, the advantage of exogenous VEGF delivery was also found by Different from others, By local injecting of VEGF or anti-VEGF antibody (B20.4-1-1) once daily in the early (day 0–2) and late (day 4–6) post-injury period, Finally, although a combined effect of both VEGF164 and FGF2 was evaluated, Altogether, these studies support the positive effect of exogenous VEGF by promoting angiogenesis on tendon repair, such as enhancing type I collagen synthesis and increasing the mechanical properties of tendons in the early stage of tendon healing.Although VEGF and neovascularization may play a key role in the tendon healing process, the negative role of VEGF on ECM disruption cannot be ignored to some extent (as mentioned above for endogenous VEGF).via bone marrow derived mesenchymal stem cells (BMSCs) in VEGF-only cells, forming new blood vessels and disrupting the collagen network, which led to the deterioration of tendon properties.In sharp contrast to the results above, the findings of Based on the above, some scholars have proposed that anti-angiogenic treatments may be beneficial for tendon healing, as anti-angiogenic treatment is commonly evaluated for cancer research or retinopathy treatments . Anti-anAccording to the findings of At present, the role of angiogenesis with endogenous VEGF expression in tendon healing has not been fully elucidated. We found that VEGF may have different effects during different tendon healing periods.For acute tendon healing, increased vascularization of the injured tendon is considered crucial because VEGF promotes angiogenesis and increases vascular permeability as an endogenous stimulator . Lack ofHowever, for chronic tendon disease, vascularization is thought to be directly negatively correlated to biomechanical properties of tendons as a persistent high expression of VEGF could induce sustained ECM degeneration by stimulation of MMPs and inhibition of TIMPs. However, so far, there is a lack of longitudinal studies illustrating whether poor vascularization and low-level expression of VEGF are the cause of poor healing or merely the sign of poor healing in degenerative tendons .We cannot deny the importance of early neovascularization for nutrition at the injury site, and therefore, we can identify VEGF-mediated ECM degradation as a negative side-effect accompanied by neovascularization during the remodeling phase . But wheWhen a tendon lesion is fully healed, newly formed blood vessels usually regress, and the prolonged presence of blood vessels is thought to result in an adverse healing microenvironment. If high levels of VEGF persist during the remodeling phase, this side effect may be more pronounced, leading to persistent pain and decreased biomechanical properties . In addiTherefore, it is not difficult for us to understand why the role of exogenous VEGF delivery is controversial. Tendon healing is likely to require balancing angiogenesis in damaged tendon tissue . Up- or First and foremost is the current biological state of the injured tissue, including the type of tendon disorders, the stage of tendon healing and the inflammation status. Administration of exogenous VEGF at the early period of acute tendon injury may promote angiogenesis and increase biomechanical properties of the tendon . As RiggSecondly, different dosages and splicing isoforms of VEGF may also influence the tendon healing capacity. As shown in in vivo and its biological role is easily lost. The half-life of VEGF under normal conditions is almost 30-45 min. The most common way of exogenous VEGF delivery is direct local injection. Sodium hyaluronate, a good carrier of VEGF, could prolong the mean residence time to better play the biological role of VEGF (Finally, the delivery method of exogenous VEGF may also impact the repair of tendons. Because of the short half-life of exogenous VEGF, it is easily decomposed  of VEGF . Further of VEGF . DiffereTherefore, the biological state, dosages, splicing isoforms of VEGF and delivery method of the exogenous VEGF are the most important factors for determining whether exogenous VEGF is beneficial for tendon healing. In the future, more basic and clinical research should be performed to clarify the role of VEGF in tendon healing and to clearly determine the conditions under which VEGF is beneficial for tendon injury, with factors to be considered being the tendon disorder type, stage of tendon healing and inflammation status. In addition, the dosages, splicing isoforms and delivery method of VEGF need to be further clearly explored which is the best.Altogether, while angiogenesis caused by VEGF is required for tendon healing, prolonged hypervascularization after tendon injury may be detrimental. To balance the manipulation of the angiogenic response in the injured tendon, pro- and anti-angiogenic therapy with exogenous VEGF or anti-VEGF can be applied. Whether it is exogenous VEGF or anti-VEGF is applied depends on the biological state of the injured tissue and its surrounding microenvironment. In this paper, we propose that tendon repair is facilitated only by proper angiogenesis and VEGF at an early stage, whereas the persistent high VEGF expression and prolonged presence of blood vessels may impair tendon repair at a later stage.XuL and XiL designed the present manuscript. XuL drawn the manuscript. BZ, YL, SG, and CW performed a literature search and selected the studies to be performed. XuL, DW, and SL revised including the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Globally, approximately 11% of all infants are born preterm, prior to 37 weeks’ gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP encompasses numerous types of preterm birth-related brain abnormalities and injuries, and can culminate in a diverse array of neurodevelopmental impairments. Of note, posthemorrhagic hydrocephalus of prematurity (PHHP) can be conceptualized as a severe manifestation of EoP. PHHP impacts the immature neonatal brain at a crucial timepoint during neurodevelopment, and can result in permanent, detrimental consequences to not only cerebrospinal fluid (CSF) dynamics, but also to white and gray matter development. In this review, the relevant literature related to the diverse mechanisms of cell death in the setting of PHHP will be thoroughly discussed. Loss of the epithelial cells of the choroid plexus, ependymal cells and their motile cilia, and cellular structures within the glymphatic system are of particular interest. Greater insights into the injuries, initiating targets, and downstream signaling pathways involved in excess cell death shed light on promising areas for therapeutic intervention. This will bolster current efforts to prevent, mitigate, and reverse the consequential brain remodeling that occurs as a result of hydrocephalus and other components of EoP. During infancy, hydrocephalus is characterized by the accumulation of cerebrospinal fluid (CSF) in the brain, progressive macrocephaly, ventriculomegaly, and increased intracranial pressure (ICP) ,2,3. InfAffecting nearly 1 of every 1000 live births, hydrocephalus presents a complex variety of both etiology and pathogenesis . SpanninGlobally, preterm birth is one of the leading causes of neonatal death, with approximately 15 million infants born preterm each year ,18. ThesEncephalopathy of prematurity is a broad, overarching classification which encompasses a great multitude of distinct neurological injuries and illnesses that develop during the critical perinatal developmental period ,25. WhilChorioamnionitis (CHORIO) is a major cause of preterm birth ,30,31,32CHORIO refers to acute intrauterine infection or inflammation (or both) involving the chorioamnionic membranes of the placenta and the umbilical cord during pregnancy . CHORIO CHORIO is considered a common complication of pregnancy, and can have extensive consequences, both for mother and fetus . The intPosthemorrhagic hydrocephalus of prematurity is the most prevalent form of hydrocephalus among preterm infants, and refers to the development of hydrocephalus following an intraventricular hemorrhage (IVH) in a preterm neonate ,42. In vWhile the transition from a post-hemorrhagic state to hydrocephalus is still an area of active and robust investigation, hypoxic-ischemic conditions have been implicated in activating a cascade of neuroinflammation that results in bidirectional activation of the neonatal immune system ,46. Of nIn addition to PHHP, there are other diverse forms of hydrocephalus prevalent in neonates and young children. Primary congenital hydrocephalus is highly dependent on a combination of genetic factors and abnormal structural development in the central nervous system (CNS) . One exaUnder the umbrella of brain injuries that contribute to encephalopathy of prematurity, the vast majority involve hypoxic, ischemic, and inflammatory conditions . For theSuspended within the cerebral ventricles, the choroid plexus is made up of a single layer of cuboidal epithelial cells aligned in a highly organized fashion, surrounding stroma containing clustered fenestrated capillaries . Early iThe choroid plexus exhibits upregulated activity in the setting of inflammation ,93,94. IFollowing IVH and related ventricular dilation in a preterm rabbit pup model of IVH, upregulation of several inflammatory mRNAs has been reported in choroid plexus cells, at both 24 and 72 h post-hemorrhage  100]. T. T100]. Further, choroid plexus cell death was also found to result from exposure to CSF contaminated by hemorrhage-related components, including factors resulting from hemoglobin breakdown . This inThe ependyma is a single-celled lining present along the interior surface of the cerebral ventricular system ,104. ThiOf great significance, the ependymal cells which line the cerebral ventricles are multiciliated . EpendymIn relation to infantile hydrocephalus, the synchronous beating of ependymal motile cilia is imperative to assure proper CSF circulation and prevent excess CSF accumulation under pressure . ConditiThe importance of healthy and fully functional ependymal cells with their motile cilia during the embryonic and postnatal periods cannot be understated. While a loss of ependymal cells or destruction of the ependymal layer is well recognized, very few reports have investigated the path to depletion of ependymal cells. Here, the limited existing literature will be reviewed as a starting point for further investigation.Ependymal cell death could ensue via two distinct paths in PHHP: (1) as a causative force, or (2) as an exacerbating manifestation. First, ependymal cell loss, and the concomitant loss of ependymal motile cilia, could hinder normal CSF circulation through the ventricular system, and therefore act as an initiating contributor to the onset of hydrocephalus ,124. SecEpendymal denudation, or the process in which ependymal cells of the ventricular epithelium vacate their position on the ventricular surface, has been widely reported in cases of hydrocephalus both in model systems and in pediatric patients  145,146,148. WhiThere is a substantial body of research which supports the concept that ependymal death precipitates hydrocephalus, via loss of ciliary propulsion resulting in excess CSF accumulation ,143,149.On a molecular level, vascular endothelial growth factor (VEGF) is present in the CSF of humans with hydrocephalus, and causes ventriculomegaly and ependymal changes in rats . In modeEpendymal cell death via necrosis has also been reported in relation to hydrocephalus. It was found that deletion of the selective protease UBP43 in mice results in spontaneous necrosis of ependymal cells, the collapse of the cerebral aqueduct, and subsequent development of hydrocephalus . In thishyh hydrocephalic mutant mice was found be nearly completed prior to induction of hydrocephalus [Providing more evidence for ependymal death contribution to hydrocephalus, sorting nexus family member 27 (SNX27)-deficient mice were found to have ependymal layer defects in the form of reduced ciliary and ependymal cell density on the ventricular surface, which led to the evolution of severe postnatal hydrocephalus . Similarcephalus .Ependymal cells are highly sensitive to infection by a variety of viral vectors . This ouIn some cases, rather than ependymal cell death serving as the primary driver of hydrocephalus, ependymal cells undergo cell death within a broader pathological process. For example, a study characterizing a lysophosphatidic acid (LPA)-induced model of fetal-onset hydrocephalus found evidence of ependymal cell death, phagocytosis, and denudation . FollowiEpendymal cells are generally susceptible to inflammation ,169,170.Ependymal cell loss is greater in neonates who experience both IVH and hydrocephalus, compared to those who recover from IVH without progression to hydrocephalus . FlattenIn sum, the ependymal layer normally serves a multitude of roles ,176. DesA critical concept to consider when evaluating the multi-fold impact of ependymal cell death includes the differentiation between cell loss resulting in damage and death, and loss resulting in consequences of impaired development. As a result of the age of onset of hydrocephalus, repercussions occur at critically sensitive timepoints in neurogenesis and neurodevelopment . TherefoMost directly, ependymal cell death eliminates the multi-ciliated surface of the ependyma. As discussed earlier, loss of these crucial cilia and their synchronous beating pattern results in uncoordinated, unpropelled movement of CSF through the ventricular system, and excess CSF accumulation. Stagnant CSF flow may promote hydrocephalus ,135. WhiIn addition to losing cilia and inhibiting CSF pulsatility, loss of the ependyma results in the migration of reactive glia into locations previously occupied by ependymal cells ,181,182.Additionally, the fetal ependyma is thought to act as a secretory structure during neurodevelopment and plays a role in the proliferation of nearby neural progenitors . EpendymFurthermore, it has been found clinically that ependymal cell loss disrupts several underlying periventricular regions critical for advancing neurogenesis . The gerThe glymphatic system, which has recently gained wider recognition, is a waste clearance system for the CNS . The CNSFunctionally, this diverse collection of cell types and unique structural architecture provide for the flow of CSF from the subarachnoid Virchow–Robin spaces down to the AQP4 channels of the astrocytic endfeet . FacilitIn a healthy CNS, the glymphatic system clears waste and assists with fluid circulation and distribution . The glyThe glymphatic system provides a critical avenue of fluid interchange and transport in CSF dynamics and serves as a potential region for intervention for hydrocephalus. Death of the astrocytes, pericytes, and endothelial cells which comprise the neurovascular units of the glymphatic system are reviewed in the context of hydrocephalus early in life, and the impact of such loss on disease progression and subsequent neurodevelopment will be discussed .Pericytes are a type of capillary-associated mural cell which wrap around the vessel-forming endothelial cells throughout the body, with the highest proportion found within the CNS ,204,205.Within the neurovascular unit of the glymphatic system, astrocytes, pericytes, and endothelial cells all produce and secrete unique isoforms of laminin in formation of the basal lamina ,211. SpeSpontaneous excess pericyte death is highly unlikely to occur without stimuli. In PHHP, IVH could fill this role as a precipitating factor in inducing pericytic cell death ,213,214.In addition to the direct impact that the loss of pericytes has on the BBB and cerebral vasculature, pericytic death has also been found to have significant impacts on the function of astrocytes, another key element of the neurovascular units which make up the glymphatic system . Astrocytes are the most ubiquitous cell type in the CNS . Like epi-coupled Ro1 and double transgenic mice found that activating specific astrocytic G-protein-coupled receptor (GPCR) signaling pathways could initiate hydrocephalus [Astrocytes are implicated in hydrocephalus in a myriad of ways, in alignment with their multi-functionality in the CNS. There is some evidence that altered astrocyte functionality may be implicated in hydrocephalus pathophysiology, although the direct pathways have yet to be completely elucidated. One study involving Gcephalus . On the cephalus . Gliosiscephalus . In the cephalus . This recephalus . These mcephalus ,231. AckMost existing reports of astrocytic cell death emphasize an ischemic environment as a critical, inciting factor ,233,234.After a CNS insult, in addition to astrocytic population shifts, aquaporin-4 channels are also lost. A reduction in AQP4 reduces rates of water diffusion in the CNS ,239. AqpWithout the ability to self-correct in this way, a glymphatic system lacking appropriate astrocytes is unable to drain CSF and ISF as necessary, and has been implicated in the progression of hydrocephalus. Further, astrocytic death will also have negative impacts on the structure of the extracellular matrix itself. Without astrocytic-produced laminin, the basement membrane responsible for the BBB is weakened . AdditioEndothelial cells constitute the cerebral vasculature and are responsible for physically forming the first layer of the BBB . Joined As with the other cellular components of the glymphatic neurovascular unit, hemorrhage and trauma can create a toxic microenvironment and cause endothelial cell death . FurtherSuch a sizeable loss of endothelial cells affects the glymphatic system as a whole. Endothelial laminin, laminin-alpha4, is essential in the embryonic and neonatal stages of development . In the Hemoglobin (Hgb) is a carrier molecule found in blood circulation which transports both oxygen and carbon dioxide to sustain respiration . StructuAberrant levels of iron in the body can have significant effects on normal physiology and function . FerroptExperimentally, intraventricular injection of iron results in damage to the ependyma and ventricular enlargement, as does injection of lysed red blood cells . IVH in A great majority of the literature describing ferroptosis in PHHP is focused on ferroptosis-driven neuronal and white matter cell death ,279. FerWhite matter in the CNS refers to the myelin-coated axonal projections which are found in the deeper, subcortical tissues of the brain ,282. MyeSimilar to white matter, cell death in other neural components within the developing nervous system occurs. Of note, transient neonatal neuronal populations, specifically the GABAergic neurons, are particularly vulnerable to the toxic microenvironmental conditions which can be induced following IVH . These lThe physiological structures, tissue organization, and causative mechanisms discussed in this review summarize the literature on cell death in the setting of PHHP. Inflammation and iron-related metabolites likely contribute to alterations of CSF dynamics via the choroid plexus, ependyma, and glymphatic system.In addition to further refining initiating causes of CSF overproduction by the choroid plexus, cell death in this important organ should also be investigated to elucidate downstream consequences, both in the initiation and progression of hydrocephalus, as well as possible lifelong impacts resulting from loss of choroid plexus tissue. The choroid plexus secretes multiple trophic factors critical for both neurodevelopment and maintenance of the healthy mature CNS ,294. With respect to the ependyma, deeper investigation into ependymal cell death is necessary. A more comprehensive understanding of the mechanisms involved in the denudation of the ventricular wall could lead to prevention of ependymal cell and associated motile cilia loss. Preservation of proper, coordinated ciliary movement could pave the way towards the rescue of abnormal CSF flow patterns and promotion of CSF drainage, helping to halt the evolution of hydrocephalic pathology after neural injury or inflammation. Changes in the glymphatic system after injury require extensive investigation. Improved understanding of fluid exchange pathways and signaling involved in regulation is needed. Additionally, mechanisms of cell death occurring in each component of the neurovascular unit—pericytes, astrocytes, and endothelial cells—require further characterization to identify new targets for intervention. Another key line of investigation is to identify changes that may be prompted simply by excess CSF pressure, rather than by the precipitating insult. It is quite likely that alterations in glymphatic function may play a pathophysiological role in numerous neurodevelopmental and neurological diseases and disorders as a result of the eminent roles of the blood–brain and CSF–blood interfaces in fluid and signaling homeostasis ,296,297.Finally, investigation into elucidating the critical signaling pathways associated with ferroptosis as a mechanism of cell death are of paramount importance. Ferroptosis likely contributes not only to white matter injury and neuronal loss in the cortex and deep gray matter, but also to loss of neural cells which regulate CSF dynamics, including microglia, astrocytes, and the specialized cells that comprise the choroid plexus, ependyma, and glymphatic system.As research on hydrocephalus advances, developing an improved, more comprehensive understanding of cell death as an exacerbating factor in pathogenesis is imperative. This review focuses on the context of PHHP, however many of the pathways and factors discussed are also plausible in other forms of infantile hydrocephalus as well. As such, we propose that there exists unifying pathophysiology of both inflammation-related and iron-related cell death across many forms of infantile hydrocephalus, independent of the initiating insult.Cell death represents a permanent, and often irreversible, loss of vital components within a rapidly developing neurological system. As an effect of hydrocephalus, systemic inflammation and loss of integral cellular components of the CNS serve as pivotally destructive insults in neonates. On a broader scale, continued studies to achieve a better understanding of all diseases falling under the umbrella of encephalopathy of prematurity are of paramount importance in the mission to reverse, and even prevent, perinatal brain injury in millions of infants around the globe.


Some professional associations have issued guidelines recommending measures involving patient flow and IVF practices. This study presents a review and considerations for the resumption of activities in IVF laboratories and clinics in Brazil during the COVID-19 pandemic, according to the guidelines and statements from professional organizations and societies in reproductive medicine.COVID-19 has caused radical effects on the daily lives of millions of people. The causal agent of the current pandemic is SARS-CoV-2, a virus that causes symptoms related to the respiratory system, leading to severe complications. In the  The COVID-19 pandemic has caused radical effects on the daily lives of millions of people. It emerged in December 2019 in Wuhan, China . Figure COVID-19 is an infectious disease caused by the new coronavirus associated with severe acute respiratory syndrome (SARS-CoV-2) (SARS-CoV-2 shows approximately 79% genetic similarity to SARS-CoV and ~50% similarity to Middle East respiratory syndrome coronavirus (MERS-CoV) . The prein vitro fertilization (IVF) procedures. This study presents a review and considerations for the resumption of activities of IVF laboratories and clinics in Brazil during the COVID-19 pandemic era, according to the guidelines and statements from professional organizations and societies in reproductive medicine.According to these facts, many human reproduction societies issued recommendations on how to deal with the pandemic and The American Society for Reproductive Medicine (ASRM) and the European Society for Reproduction and Embryology (ESHRE) have recommended cancelling fertility treatments, except in poor responders, who can still undergo treatment, although this may lead to additional stress for couples who badly want to have a child (The Brazilian Society for Assisted Human Reproduction (SBRA), the Brazilian Society for Human Reproduction (SBRH), and the Latin American Assisted Reproduction Network (REDLARA) have stated that individual cases must be discussed with a physician, because there are unique situations, in which postponing the treatment could reduce the likelihood of successful pregnancy . On JuneAs reported by the WHO, health facilities have to implement internal policies to ensure that all necessary preventive and protective measures are taken to minimize occupational safety and health risks. The clinical director or managers must provide information, instruction, and training on Occupational Safety and Health (OSH). The training includes information on how to wear Personal Protective Equipment (PPE), and the handling and disposal of infectious waste . The estCoronavirus spreads primarily through droplets generated by infected individuals during coughing, sneezing, or speaking . All medPrimary transmission is believed to occur through respiratory droplets from coughing and sneezing, and contagion requires proximity (less than 6 feet distance) between individuals . SubdiviRegarding patient flow, ASRM has recommended limiting the number of visitors to a single support person or encouraging alternative participation methods, such as by phone or video. When urgent procedures must be performed, minimize the time the patient is waiting in the reception area or waiting room . PRONUCLBefore the consultation:When scheduling procedures, receptionists must provide patients with information: masks are necessary and avoid accompanying persons.Instruct patients with respiratory infection symptoms  to postpone the procedure. However, if postponing the appointment is impossible, instruct them to report respiratory infection symptoms as soon as they arrive at the clinic.The procedures must be scheduled at intervals that allow the cleaning of the rooms.During the consultation:The patients must complete the Health Status Questionnaire (QSS) daily.Minimize contact with the patient to what is strictly necessary during the procedure, always maintaining a distance of at least 1 meter.For so-called asymptomatic patients, we recommended the patient should wear a mask.In cases of symptomatic patients, inform the entire team involved in the procedure in advance.During the patient’s presence at the service, whether characterized as asymptomatic or proven to be infected, avoid sharing items such as pens, clipboards, computers, phones, and others. Establish a hygiene protocol between procedures with the appropriate teams involved.If possible and, according to ANVISA rules, obtain consent documents electronically to minimize the patient’s time in the unit where the procedure is performed.According to Telemedicine should be used for all treatment steps that do not require the physical presence of patients at the clinic, to reduce unnecessary visits and staff-patient contact . ASRM haOn 18 March 2020, ANVISA established extraordinary and temporary rules to speed up the evaluation of new products by prioritizing the testing needed to detect the new coronavirus. This measure is part of the strategic actions to make products that can be used to face the COVID-19 pandemic more quickly, and maintain the safety and effectiveness criteria. Since the entire genetic sequence of the SARS-CoV-2 virus was uploaded to the Global Initiative on Sharing All Influenza Data (GISAID) platform on 10 January 2020, companies and research groups have developed many diagnostic kits for COVID-19. The availability of sequence data has facilitated the design of primers and probes needed for the development of SARS-CoV-2-specific testing . In Brazil, tests for COVID-19 consist of mostly immunoassays to detect antibodies or antigens, and molecular biology assays to detect RNA from the virus.This kind of laboratory test is designed to be used directly at the site of patient care, which may comprise physicians’ offices, outpatient clinics, intensive-care units, emergency rooms, hospital laboratories, and even patients’ homes . Their eRegarding the tests approved for antibody detection, all of them require a blood sample. A small sample of the patient’s blood is taken from a vein or a finger-prick device and dropped onto a spongy pad within the testing device. Few drops of a buffer are added to help the blood sample flow across the device. As the sample moves through the device, antibodies against SARS-CoV-2 present in the sample will attach to chemicals in the device, capturing the antibodies on the test and the control lines. This capturing and binding process results in a color change along the test and control lines, producing one, two, or three lines, depending on the type of antibodies present (IgM or IgG). An Enzyme-Linked Immunosorbent Assay (ELISA) is a microwell, plate-based assay technique designed to detect and quantify substances such as peptides, proteins, antibodies, and hormones. They can be qualitative or quantitative, and it takes 1-5 hours to get the results  also detects IgG and IgM antibodies. The DZ-Lite SARS-CoV-2 test was developed by Diazyme, USA, which, based on the chemiluminescent assay principle, can analyze 50 samples in one hour. Another company, Snibe, China, with the MAGLUMIA CLIA test based on the same principle, can detect antibodies in a patient sample in 30 minutes. The automated chemiluminescence test can detect the antibodies generated against the pathogen, and, compared to the POC test; this methodology has a very high yield of samples that can be analyzed, and the ability to perform other tests  is of great interest today for SARS CoV-2 detection due to its benefits as a specific and easy qualitative assay  revealed that both IgM and IgA had early responses, while IgG showed up later, so they suggest IgA should be included in a serological test, which may provide higher diagnostic accuracy for COVID-19.When the pathogen invades the host, the body produces large amounts of immunoglobulin (Ig) by the immune system and releases them into the blood stream, including IgG, IgM, and IgA. IgM is usually the first antibody produced in response to the virus invasion . IgG is Based on current data, the In the IVF universe, there are recommendations and protocols for infection control and laboratory safety , but it Laboratories should have the minimum number of personnel required to perform all quality control activities to ensure gamete safety and performance of urgent cases . It is rTo restrict access for the accompanying person(s) .Embryologists who have returned to their activities for at least 14 days should take their temperature daily; those who have a temperature above 37.3ºC and present any symptom related to COVID-19 must report to the clinic’s human resources department and remain socially distant .Embryologists should wear the necessary PPE, gloves, cap, and surgical mask. For procedures that generate aerosols , N95 mask, surgical mask, and facial shield or protection glasses .For the andrologist, the necessary PPE are gloves, cap, surgical mask, face shield, or glasses in specific activities that generate droplets and aerosol  and use long-sleeved aprons .Review of emergency action plans, if an embryologist and andrologist are unable to perform an activity, qualified personnel  should rOther employees, such as doctors or nurses, should be trained on the procedures for refilling liquid nitrogen in storage tanks , with products certified as to their effectiveness and tests recommended in the Standard Operating Procedure . DisinfeAll the necessary products for the laboratory use, after being received, must be disinfected with alcohol 70%, await evaporation of the product and stored in its appropriate location . Strict The laboratory must be subjected to maximum air filtration, through HEPA filters (high-efficiency particulate air) and control Volatile Organic Compounds (VOC) .All bodily fluids must be considered infectious . Their manipulation must be quick and effective. Handled on the Class II safety booth or vertical laminar flow using N95 masks to prevent aerosol contamination. .ESHRE has made some recommendations for oocyte retrieval based on triage results , and it It is essential to mention that other measures should be adopted to reduce the risks of transmission to staff members, as follows:The patient must wear a surgical mask, being removed only during the anesthetic process .All the teams must wear PPEs .Disinfection of operating theatre after the procedure .Follicular fluid must be handled in a laminar flow cabinet . If a laPRONUCLEO has advised that the embryologist of the andrology laboratory should adopt the use of universal standard precautions when handling samples. They suggest following GLP as recommended by the WHO and by the Centers for Disease Control and Prevention Center (CDC), which includes training all personnel in the use of PPE .The collection room must be equipped with disinfection material, such as water, neutral soap, and 70% alcohol gel , and theASRM has advised in the pandemic period the cancellation of all embryo transfers, whether fresh or frozen . ESHRE hCurrently, there is no proven evidence of the presence of infectious agents (viruses) in diseases transmissible to cryopreserved gametes or embryos of patients infected in culture medium or liquid nitrogen .Still, the possibility of cross-contamination of a liquid nitrogen container cannot be ruled out . TherefoThe use of cryogenic gloves and masks as PPE for embryologists .The possibility of using sample storage tanks in the nitrogen vapor phase to freeze positive samples for the SARS-CoV-2 virus . High-seFor patients who tested positive for SARS-CoV-2, their samples should be kept in storage tanks separate from the tanks used in the laboratory routine .All topics presented in this review were prepared based on all current scientific knowledge aiming to minimize the risks of SARS-CoV-2 transmission as much as possible. In summary, the resumption of activities at IVF laboratories and clinics in Brazil depends on the strict incorporation of all protection measures by the staff and patients. There is still little information regarding the impact of SARS-CoV-2 on fertility, pregnancy, and IVF, but treatments must be carried out safely as we know asymptomatic people transmit the virus.


In the process of exercise, human tissues are impacted, making cells suffer damage. Growth factor can accelerate the repair of damaged cells and regulate the synthesis of protein, so biological preparations of growth factors can be added to traditional therapies. A combination of growth factor biologics and conventional therapies may improve the efficiency of injury repair, but growth factor biologics may not produce any results. The feasibility of growth factor biologics in the treatment of motor injury was discussed. The research have shown that: 1) GF biological agent therapy is a very promising treatment for motor injury, which is based on the power of autologous growth factor (GFs) to accelerate tissue healing, promote muscle regeneration, increase angiogenesis, reduce fibrosis, and make the muscle injury rapid recovery. 2) There are various methods for delivering the higher dose of GF to the injured tissue, but most of them depend on the platelet release of GF. At the site of injury, there are several ways to deliver higher doses of GF to the injured tissue. 3) At present, the inhibition of GF is mainly through signal transduction inhibitors and inhibition of transcription factor production. 4) Pattern of GF during wound repair: GF directly regulates many key steps of normal wound repair, including inflammatory cell chemotaxis, division and proliferation of fibroblasts, keratinocytes and vascular endothelial cells, formation of new blood vessels, and synthesis and degradation of intercellular substances. 5) When GF promotes chronic wound healing, in most cases, certain GF can be used targeted only when  Growth factors, which are cytokines with activity of stimulating cell growth, are composed of polypeptides and protein and are used to regulate cell growth and other cell functions. They are found in platelets, various adult and embryonic tissues, and most cultured cells . It can GF formulations have described a number of fascinating results in sports medicine , howeverBone morphogenetic protein-2 and PDGF are the barrier membranes of osteogenic growth factors, and they have studied the loading and release kinetics of growth factors more through soaking in GF solution and culturing the membrane followed by freeze-drying, or mixing with polymer before evaporation to incorporate GF into the membrane . MembranStudies have shown that there are several methods for delivering higher doses of GF to injured tissues, but most rely on platelet release of GF. The alpha particles of platelets contain GF ,etc. Platelet-rich plasma is usually analyzed for peripheral blood using different types of centrifugation, and different separation methods result in different distributions of platelet and leukocyte counts . A standPlasma (PRGF) therapy, direct injection and hydrogel incorporation can be realized at the injury site as can be seen in In terms of the effect of activator on promoting the use of GF, some studies have found that the activator used in combination with PRP is effective for promoting the concentration of GF. Such as the effect of activator calcium chloride on the concentration of GF, activated and inactive calcium chloride prepared by PRP under each condition, activated with calcium chloride resulted in significant increases in PDGF antibody and IGF-1 concentrations, and calcium chloride activated PRP resulted in the release of platelet-differentiated GF . The useGF is the key to regulate cell signaling pathway. Currently, the inhibition of GF is exerted through signal transduction inhibitors. It can interfere with the process of protein-protein interaction between GF and its receptor by targeting the extracellular protein-binding domain of GF receptor. Such as the signal transduction inhibitor compound CJJ300, inhibits tgf-beta signals by disrupting the process of formation of signal complexes that transform gf-beta (tgf-beta) . The comIn addition, there is a method for producing an inhibitory effect on GF by inhibition of a transcription factor. Mechanical GF (MGF) can significantly promote the migration of chondrocytes from growth plates, accompanied by YAP activation. YAP is a transcription regulator that modulate cell proliferation, survival, and differentiation, in order to control organ development and tissue regeneration . KnockinWith the development of GF biological agents, many studies began to study GF inhibitors to achieve the purpose of inhibiting GF and controlling its action mechanism.Pattern of GF in the process of wound repair: GF directly regulates many key steps of normal wound repair, including inflammatory cell tropism, division and proliferation of fibroblasts, keratinocytes and vascular endothelial cells, formation of new blood vessels, and synthesis and degradation of intercellular substance . The preWhen being applied to the repair of articular cartilage injury and meniscus injury, the patients can move more smoothly when being injected with the GF, and the discomfort is obviously relieved ; and theIt has more obvious effect when being used for the treatment of “heel pain” of plantar fasciitis compared with the “local sealing treatment”. Local injection of exogenous insulin-like growth factor-1 (IGF-1) can stimulate the proliferation of myoblasts and accelerate the process of repair . It can in vivo regulation still cannot meet the need for repair, such as some hard-to-heal injuries, can certain GF be used pointedly. For example, local application of IGF-1 in human body has been proved to rapidly stimulate tendon collagen synthesis. Then can IGF-1 injection enhance tendon synthesis and tissue structure in patients with patellar tendon disease? Although clinical responses were small and rapid with IGF-1 injection in combination with training, no additional long-term effects of intratendon IGF-1 on structure and clinical outcome were observed in patients with patellar tendon disease (1) The surrounding environment of wound healing contains protein GF. Its content changes during the whole release process. When the effect of GF is inhibited, wound repair will encounter obstacles . 2) The  disease . As anot disease .Therefore, GF may not always be a hopeful tool for repairing damage, which is related to the site of sports injury, the design of treatment, the number and type of growth factor injections, and further research is needed to clarify the ineffective mechanism.Muscle damage is a common cause of long-term severe pain and limb disability. Recovery from muscle damage caused directly or indirectly by exercise is a complex but well-defined process that includes degeneration, inflammation, regeneration, and fibrosis. Biological agents, such as IGF-1, MGF, PDGF, and TGF-β have been discussed in clinical treatment. They have the potential not only to treat athletic injuries but also to be a centre of interest for stimulant abusers as biotechnologies that achieve good athletic performance but are not yet fully understood.in vivo regulation still cannot meet the need for repair.The research have shown that: 1) GF biological agent therapy is a very promising treatment for motor injury, which is based on the power of autologous growth factor (GFs) to accelerate tissue healing, promote muscle regeneration, increase angiogenesis, reduce fibrosis, and make the muscle injury rapid recovery. 2) There are various methods for delivering the higher dose of GF to the injured tissue, but most of them depend on the platelet release of GF. At the site of injury, there are several ways to deliver higher doses of GF to the injured tissue. 3) At present, the inhibition of GF is mainly through signal transduction inhibitors and inhibition of transcription factor production. 4) Pattern of GF during wound repair: GF directly regulates many key steps of normal wound repair, including inflammatory cell chemotaxis, division and proliferation of fibroblasts, keratinocytes and vascular endothelial cells, formation of new blood vessels, and synthesis and degradation of intercellular substances. 5) When GF promotes chronic wound healing, in most cases, certain GF can be used targeted only when To date, most treatments for muscle injury with GF biologics have been due to limited experimental and clinical data or only empirical trials. Therefore, we need more experimental studies, including the specific GFs to quantify the release of PRP, angiogenesis, myogenesis and functional recovery data, as well as other mechanisms of GF repair, to finally verify the repair hypothesis of GF biological agents in the treatment of muscle injury and open a new journey for its wide clinical application. Currently, there is a large amount of data on the pathophysiology of muscle injury in the relevant studies.


Partially different to the Swedish contribution, this paper analyses the relationships between perceived housing, life course transitions and wellbeing among community-dwelling older adults in Germany. Based on 15 qualitative interviews with persons aged 60-75 years, the contribution focuses on the experience of interrelationships between different life course transitions and perceived housing, and how they contribute to wellbeing in later life. First findings indicate a concourse of different transitions around the retirement age  and a temporal as well as causal relationship between the two transitions relocation and retirement . The entanglement of life course transitions, in turn, shapes the person-place-relationships and perceived housing in different ways, which will be exemplified and interpreted in the presentation. However, further research is needed to consider the effects of social inequalities in these processes.


The clinical implementation of pharmacogenomics (PGx) in the context of inpatient and outpatient medical care represents a feasible and likely influential enhancement to the therapeutic management of medications. Specifically, the utilization of genetics to identify efficacy and tolerability issues has been shown to impact economic, clinical, and humanistic outcomes that are realized by patients, healthcare providers, and payers. These positively influence healthcare’s Quadruple Aim of enhancing patient experience, improving patient outcomes, reducing costs, and improving clinician experience. The understanding of the genetic impact on pharmacokinetics and pharmacodynamics provides the foundation for the clinical utility of PGx. Layered on top are the technical, regulatory, and implementation challenges associated with providing real-world clinical decision support for personalized prescribing based on genomic data. While the recent years have delivered improvements, policy changes, and learnings from implementations of pharmacogenomics, we are now living in a unique time where technology, regulatory policy, payer policy, and medically relevant and clinically actionable science are aligned to support rational healthcare implementations. To ensure that patients are provided the opportunity to benefit from these technologies, feedback loops between molecular mechanisms, patient outcomes, and clinical implementations must be created. This Research Topic brings together seven articles focusing on PGx, affording readers the opportunity to learn about the intricacies of specific gene variants on clinical outcomes; to study the challenges, enablers, and impacts of clinical PGx implementations; to consider how to communicate often esoteric details to expand the research, clinical, and economic benefits of PGx to all stakeholders; and to contemplate the immediate and future impact of these findings.CYP3A4*22 variant remain unclear. To address this knowledge gap, Mulder and colleagues reviewed the clinical evidence for the *22 variant’s association with the pharmacokinetics, tolerability, and efficacy of 23 drugs used to treat infectious, psychiatric, and cardiovascular diseases as well as pain and cancer . They reported that the clinical evidence supporting CYP3A4*22 based dosing is limited for most drugs but did find strong evidence supporting an association between CYP3A4*22 and the pharmacokinetics of four drugs . However, evidence linking CYP3A4*22 genotyping to tolerability and efficacy of these four drugs was limited, suggesting further investigation is required to establish clinical utility.The use of PGx testing in the clinic is primarily focused on genes that encode drug metabolizing enzymes in the cytochrome P450 family. Interestingly, one the most important enzymes in this family, CYP3A4, has received minimal attention and is not included within current PGx-based guidelines . DespiteBuchner et al.). The validated TaqMan assay methodology for efficient detection of HLA haplotypes HLA-B*15:02 and HLA-A*31:01 could be readily replicated for other genotyping technologies that have the potential to identify haplotypes using single nucleotide variants.There are a few drugs, such as carbamazepine and oxcarbazepine, whose prescription can be guided by human leukocyte antigen (HLA) haplotypes to prevent severe adverse drug reactions. Buchner and co-workers investigated the analytical validity of TaqMan HLA assays for “tag” single nucleotide variants, using reference samples from diverse ancestral backgrounds . Among the barriers highlighted, cost of testing was the most frequently cited followed by physician knowledge of the evidence, and processes for integration of test result into current clinical workflows. While the most frequently cited enablers were positive perceptions of PGx testing’s role in precision prescribing, physician interest in using PGx testing, and beliefs that testing will become standard of care. As the authors aptly conclude, successful implementation of PGx testing in the mental health care setting will require thoughtful consideration of the barriers but also appropriate leveraging of enablers.Despite the availability of PGx dosing guidelines and drug labels with PGx information, the clinical uptake of PGx testing has been slow. This has been particularly the case in mental health care settings, where our understanding of the barriers as well as the enablers that contribute to the low clinical uptake are evolving. In a systematic review by Jameson and associates, nine barriers and eight enablers to the implementation of PGx testing in mental health care settings were identified and discussed  report. The authors emphasize a highly collaborative approach that managed the challenges and systemic barriers to implementation by coordinating the unique expertise of all local stakeholders. Education, review committees, scientific and clinical validation, and expert feedback at every point drove the success of the program and underscores the value of the bench to bedside and back paradigm highlighted in this Research Topic.Clinical uptake and implementation of PGx information has been similarly challenging in academic health systems. In a methods article, Koufaki et al.). Particularly, these authors outlined the available marketing theories and innovations that are applied to personalized medicine interventions, which could catalyze the adoption of PGx testing in clinical practice. These authors also presented the current ethical and legal framework about genomic data and proposed ways to tackle the main concerns mentioned in the literature and to improve the marketing perspective of PGx.The slow adoption of pharmacogenomics in clinical settings is also experienced by many healthcare systems in low- or middle-income countries. These settings have unique challenges related to operational and economical resources, expertise, and legal, ethical, as well as local evidence-base standards that may result in initial variation in implementation of PGx in practice. However, the slow adoption of PGx in the clinic is often attributed to modest levels of PGx awareness among healthcare specialists and minimal efforts to promote PGx testing among interested stakeholders, such as healthcare professionals and biomedical scientists. In their article, Koufaki and co-workers provided a marketing perspective for the adoption of PGx in the clinic . The authors compared hospitalization rates and medication changes amongst PGx tested patients with patients receiving treatment-as-usual. These authors concluded that not only have medication changes occurred significantly more frequently in cases with PGx-guided treatment but also hospitalizations were significantly lower, highlighting the positive impact of PGx-guided drug prescription towards patients’ benefit and the opportunities and evidence gaps that are important when considering the introduction of PGx into health systems.Despite the challenges with clinical uptake of PGx testing, there are examples of how PGx testing can impact important clinical outcomes. In their article, David and co-workers examined the current evidence on the impact PGx testing has on hospital admissions and whether it can effectively advise towards medication changes (Haga). Examples of PGx-specific genes that could also impact disease risk or phenotype highlight the need for these considerations—they are neither new, nor rare. In fact, Haga points out that, like adapting to the growing ACMG gene list, the healthcare system must be ready to deal with the ramifications of PGx testing and the incidental findings; and not just regarding host genetics. Haga suggests a logical list of steps including establishing a consensus list of secondary findings of pharmacogenes, developing patient educational materials, educating healthcare providers, and making available re-analysis and re-interpretation of variant data to reflect new evidence as it becomes available.As clinical uptake of PGx testing grows, it is prudent to consider the pleiotropic effects of pharmacogenes and the wide-reaching implications of PGx assay results and clinical reports. In a perspective article, Susanne B. Haga challenges readers to consider the identification and management of PGx secondary  findings especially in the context of both targeted and broad genetic tests like whole genome sequencing (Recent rapid advances on multiple fronts, as demonstrated in the articles in this Research Topic, have transitioned pharmacogenomics from a niche specialist research domain to a realizable, crucial, and routine component of healthcare delivery.


Gut microbiota is regarded as the second human genome and forgotten organ, which is symbiotic with the human host and cannot live and exist alone. The gut microbiota performs multiple physiological functions and plays a pivotal role in host health and intestinal homeostasis. However, the gut microbiota can always be affected by various factors and among them, it is radiotherapy that results in gut microbiota  These microorganisms are commensal with human host, 90% of the symbiotic microorganisms in the digestive tract . Intracellular symbionts  continue to increase after irradiation, indicating that they are potential biomarkers of intestinal damage. The abundance of Prevotella, Lactobacillus, Clostridium XIVa, Oscillibacter and Elusimicrobium/Treponema is significantly related to the radiation intensity  and rhesus macaques in acute radiation syndrome. They have found that although GMP and rhesus macaques have different intestinal microflora distributions, radiation had a similar effect at the phylum level, resulting in a decrease in ntensity . They haadiation . Lavrinies ratio . Liu et abolites .Clostridium IV, Roseburia, and Phascolarctobacterium counts were significantly associated with radiation enteropathy(RE). In radiation-induced bowel disease, homeostatic intestinal mucosal cytokines associated with intestinal flora regulation and intestinal wall maintenance are significantly reduced  is enough to induce a higher susceptibility to intestinal inflammation, indicating that the reduction of bacterial diversity may lead to a short-term and long-term risk of enteropathy in patients  that the gut microbiota changes dramatically after irradiation, which tends to the decrease of normal gut microbiota and shifts towards the increase of opportunistic pathogenic bacteria, causing intestinal microecological imbalance. In addition, this study has also suggested that the change of the gut microbiota induces the change in microbial metabolism and metabolic function. This shows the relationship between gut microbiota and its metabolites after radiation  . A reseaGammaproteobacteria, Bacilli and Negativicutes which are common in intestinal malnutrition, intestinal inflammation and radiation-induced intestinal injury , especially propionate caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses, which is mediated by the attenuation of DNA damage and the release of reactive oxygen species in hematopoietic and gastrointestinal tissues . PreoperMetabolites are often considered to function primarily as a “fuel” or energy source, or as the basis of a metabolic pathway. However, key metabolites (SCFAs are one of them) can also be regarded as extracellular signaling molecules, as they bind to receptors to activate a second messenger, thereby promoting downstream signal transduction .With regDue to rapid epithelial turnover, both the small and large intestine cause acute or chronic radiation damage to the intestine, especially when exposed to 45 Gy or higher doses of radiation . Radiatiin vitro, and the effect of SCFAs on EMT and intestinal fibrosis may be partly attributed to its regulatory role as an HDAC inhibitor , the trend of patients is that the production capacity of SCFA is higher but the dynamic decline, and the level of steady-state rectal mucosal cytokines involved in the maintenance of mucosal barrier is significantly reduced, which will be supported by the regulation of microbiota. Recently, FMT has been regarded as a successful treatment of immunotherapy induced colitis  has been considered to affect microbial community due to radiation. Ding Xiao et al. have reported for the first time that it is safe and effective that FMT might improve intestinal symptoms and mucosal injury in patients with CRE for a period of time . FMT canalancing . Althoug colitis .in vivo and in vitro. Valeric acid may play a role in AML1/KRT1 signaling through transporters or CPCRs , is effective for the treatment for acute radiation proctitis . In the or CPCRs . Moreoveor CPCRs . Debeb eor CPCRs . Chen etor CPCRs .Lactobacilli, Bifidobacteria, and butyrate-producing bacteria such as Roseburia and Coprococcus. In addition, n-3 PUFA reduces the proportion of LPS production and mucolytic bacteria in the intestine, which can reduce inflammation and oxidative stress. Importantly, n-3 PUFA also plays an anti-cancer role in colorectal cancer , and lactic acid treatment promotes intestinal stem cell-mediated epithelial regeneration in a Gpr81-dependent manner. In addition, feeding lactic acid-producing bacterial symbionts or lactic acid can protect mice from severe intestinal damage caused by radiation exposure and chemotherapy treatment. Similarly, they also confirmed that lactate and the receptor Gpr81 stimulate the Wnt/β-catenin signaling pathway in Paneth and intestinal stromal cells to promote intestinal stem cell-mediated epithelial regeneration (Omega-3 (n-3) polyunsaturated fatty acids (PUFA) can reverse intestinal microbial disease by increasing the number of beneficial bacterial species including l cancer . Lee et neration .Bacteroidetes and Firmicutes counts, which disrupts intestinal homeostasis and thereby promoting the occurrence and development of various diseases. Therefore, it has attracted more and more attention to reveal the pathogenesis of the disease from the perspective of gut microbiota. In addition, due to the different radiation sensitivity of different species, the alterations in gut microbiota caused by ionizing radiation are also different. Most importantly, the gut microbiota metabolites such as SCFAs play a pivotal role in health and disease. Radiation-induced gut microbiota dysbiosis causes changes in SCFAs accordingly and the reason can be attributed to the fact that radiotherapy has led to changes in the SCFAs-producing bacteria such as Bacteroidetes, Firmicutes and Roseburia etc. which in turn led to a decrease in the production of SCFAs. Furthermore, many studies have confirmed the correlation between the alterations of SCFAs and radiation-induced intestinal injury. The crosstalk between the alterations of SCFAs and radiation-induced intestinal injury can be traced from upstream to the decrease of the diversity of gut microbiota that produces SCFAs, and the downstream SCFAs can affect the occurrence and development of radiation-induced intestinal injury through different mechanisms. In this review, we focused on the progressive relationship among ionizing radiation, gut microbiota, SCFAs and radiation-induced intestinal injury, as shown in An increasing number of evidence demonstrated that radiotherapy can lead to gut microbiota dysbiosis and cause the alterations in the gut microbial communities such as the alterations of In conclusion, we believe that radiotherapy can cause changes in the gut microbiota, including the SCFAs-producing bacteria, which in turn leads to a decrease in SCFAs production. Less production of SCFAs is likely to be the pathogenic mechanism of radiation-induced intestinal injury and supplementing SCFAs can alleviate radiation intestinal injury, which can provide a new reference for the pathogenesis and treatment of radiation-induced intestine injury. In short, in this review, we highlight the correlation among gut microbiota, SCFAs and radiation-induced intestinal injury exposed to ionizing radiation. We also elaborate this relevance and have a better understanding of the pathophysiological basis of gut microbiota and SCFAs associated with radiation-induced intestinal injury so as to provide a reference for accurate treatment in the future.YQL and LYZ provide guidance on ideas and directions as well as the revision of the article. JPH and ND are responsible for the guidance of methodology. YYL and YMZ are responsible for the writing of the article. Others are responsible for collecting materials and participating in the revision of the article. All authors contributed to the article and approved the submitted version.This project was supported by the National Natural Science Foundation of China , China Postdoctoral Science Foundation Project (grant numbers 2021M693794), The Open Fund Project of Key Laboratory of Dunhuang Medicine and Translational Education Ministry (grant numbers DHYX19-13).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.


With the development of genomics, the update of modern imaging technology and the advent of artificial intelligence and big data, the surgical treatment of gastric cancer has gradually stepped into precision medicine. Precision surgery treatment of gastric cancer is based on accurate molecular typing and staging using modern molecular diagnostic technology and imaging, and the formulation of precise and individualized surgical treatment plans, with the concept of minimally invasive and accelerated rehabilitation surgery running through it. For intermediate-stage gastric cancer, we have adopted a comprehensive treatment approach including traditional radiotherapy and chemotherapy, targeted therapy and immunotherapy. Utilize artificial intelligence and big data technology to improve the standardization and interconnectivity of specialty data and realize the transformation of evidence-based medicine. Promoting the standardization, standardization and individualization of gastric cancer surgical treatment, providing patients with precise diagnosis and treatment, and further improving patients' prognosis are the opportunities and challenges in the development of gastric cancer surgery. Gastric cancer ranks second among all malignant tumors in terms of morbidity and mortality globally Figure .Gastric cancer can be classified into Borrmann's classification and Siewert's classification according to anatomical origin, WHO classification and Lauren's classification according to histological structure, and early stage and late stage according to disease severity The first attempt at gastric cancer typing was made by researchers in Singapore in 2013  Table .TCGA is a landmark study that combines data from different platforms to comprehensively report the genetic variability associated with gastric cancer, and fully demonstrates the unique genomic characteristics of each molecular subtype, opening a new era of molecular typing of gastric cancer. This kind of molecular data spectrum-based typing can provide more accurate efficacy and prediction information than the traditional tissue system classification, making it possible to provide precise targeted therapy for gastric cancerThe Asian Cancer Research Group (ACRG) in 2015 also proposed a new molecular typing of gastric cancer as microsatellite stable/epithelial-mesenchymal transformation (MSS/EMT) type, microsatellite unstable (MSI) type, microsatellite stable/tumor protein 53 active (MSS/TP53+) type and microsatellite stable/tumor protein 53 inactive (MSS/TP53-) type  Figure .Among all the clinical treatments currently available for gastric cancer patients, surgery is the only treatment that can completely eradicate gastric cancer, and is also the foundation of gastric cancer treatment As a class of highly heterogeneous tumors, different subtypes often show differentiated biological behaviors. The proliferation and metastasis of gastric cancer involve many molecular pathways: heterogeneity in cell proliferation, vascular metastasis in metastasis, and EMT pathway. With the development of molecular biology technology, we provide molecular typing and individualized molecular and immunotherapy for gastric cancer. Resectable gastric cancer preoperative refined imaging evaluation and artificial intelligence pathological diagnosis application; minimally invasive and surgical robots, precise operation of intraoperative fluorescent navigation and sophisticated perioperative management guided by the concept of accelerated rehabilitation is the direction of gastric cancer treatment in era of precision medicine.Accurate preoperative staging and resectability assessment of gastric cancer is the key to successful surgery. Traditional gastrointestinal imaging, CT abdominal enhancement and general gastroscopy can clarify the nature and location of lesions and the presence of distant metastasis, but it is difficult to assess the depth of primary lesion infiltration (T stage) and the degree of regional lymph node metastasis (N stage) and evaluate the efficacy of neoadjuvant or translational therapy.The problem of morphologic target lesions. Among endoscopy methods, endoscopic ultrasound has the advantage of evaluating T stage and perigastric lymph node metastasis, while magnified endoscopy can accurately determine the extent and nature of early lesion involvement, playing an important role in endoscopic treatment and preoperative lesion localization With the development of modern imaging and endoscopic equipment, including multislice spiral CT (MSCT), energy CT, MRI, PET-CT, and endoscopic ultrasound, pigmented endoscopy, and magnified endoscopy in the preoperative evaluation of gastric cancer, the accuracy of clinical staging of gastric cancer has been greatly improved With the development of minimally invasive technology and the introduction of precision medicine, the changes in the concept of gastric cancer surgery are mainly reflected in the following: on the basis of ensuring complete removal of tumor tissues, rational selection of surgical technique and scope of resection, preserving the function of the digestive tract as much as possible, reducing damage to the body and alleviating patients' pain. As medical technology continues to progress, it also pays more attention to the subjective needs of patients, hoping to cure the disease and minimize the trauma to the body at the same time th edition of the Japanese guidelines for gastric cancer treatment published in 2018 In the 5The da Vinci robotic surgical system is capable of presenting a clear three-dimensional field of view, applying more flexible artificial joints and automatic tremor removal, etc. In 2000, the U.S. Food and Drug Administration (FDA) approved the da Vinci Surgical System (DVSS) for clinical use, but due to its expensive equipment and high technical requirements, the clinical rollout has been slow and robotic gastrectomy. The use of robotic gastrectomy (RG) for the treatment of gastric cancer has been studied for more than a decade, and there is a lack of evidence that it can be used as a standard of care Throughout the development of gastric cancer surgery, the scope of surgery for gastric cancer has gone through the process of “from small to large, and then from large to small”. In the early stage of understanding, how to completely remove the tumor has become a misunderstanding in clinical practice that the surgery is always “bigger”, and lymph node dissection has been carried out from D1 to D2, then from D2 to D3, and even combined with multi-organ resection The earliest definition of lymph nodes in gastric cancer was made by the Japanese Gastric Cancer Association, which was the first to define 3 stations of lymph nodes, and defined the corresponding surgical names according to the differences in the extent of lymph node dissection during surgery As research progresses, in 2011, the Japanese Society of Gastric Cancer has redefined the scope of lymph node dissection in radical gastric cancer surgery, and believes that the scope of lymph node dissection should be determined according to the extent of gastrectomy, which improves the convenience of the surgery Adoption. From surgical gastrectomy to precise endoscopic resection of lesions, the reduction in the scope of gastrectomy has brought about the preservation of complete gastric function. At the same time, based on the in-depth study of the characteristics of EGC lymph node metastasis, the emergence of sentinel node navigation surgery (SNNS) and other techniques has made it possible for the future EGC lymph node dissection to shift from regional dissection to more precise targeted dissection The development and evolution of the treatment of early gastric cancer (EGC) more fully embodies the concept of precision surgery. Along with the continuous improvement of endoscopic techniques and innovation of operating instruments and energy devices, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have become the most popular methods for EGC treatment About minimally invasive surgery for early gastric cancer. With the continuous improvement in gastric cancer detection technology, more and more gastric cancer patients can be identified at an early stage. In order to maximize the quality of life of gastric cancer patients after surgery, whether patients with early gastric cancer need to undergo lymph node dissection at the beginning of diagnosis has become a hot topic of discussion. Related scholars have conducted linkage studies from other malignant tumor cases with the intention of determining whether sentinel lymph nodes exist in gastric cancer and whether lymph node metastasis in gastric cancer patients can be determined by detecting sentinel lymph nodes. If sentinel lymph nodes are present in gastric cancer patients, and then sentinel lymph node technology can be used in gastric cancer treatment, it will continue to promote the development of more individualized and precise treatment for early gastric cancer. Nanocarbon and ICG intraoperative lymph node visualization for precise dissection Accelerated rehabilitation surgery is the use of a series of evidence-based perioperative optimization measures to reduce patient stress, promote rapid recovery, reduce patient length of stay, and reduce hospital costs. The concept of accelerated rehabilitation was elaborated by Danish scholar Kehlet in 1997 Figure .For patients with gastric cancer, surgery is basically the only possibility of cure at this stage; however, since gastric cancer is insidious and lacks specific symptoms, most patients are already in advanced stages at the time of initial diagnosis, and adjuvant therapy improves the survival of operable gastric cancer patients In 2017, a study by Al-Batran et al demonstrated that the use of a more effective chemotherapeutic agent in the chemotherapy regimen  may improve patient outcomes, making FLOT the appropriate new standard of care for perioperative chemotherapy in patients with resectable gastric cancer, which is listed as a recommended regimen in international guidelines Gastric cancer has a high degree of intra- and inter-tumor heterogeneity, and at the same time, intra-tumor heterogeneity has both temporal and spatial heterogeneity, which leads to a diversity of molecular variants, so precise molecular typing is a prerequisite for realizing molecularly targeted drug therapy HER2-positive advanced gastric cancer and also established the star role of HER2 in gastric cancer, although subsequent studies of several targeted HER2 agents such as patumumumab, lapatinib, and T-DM1 in gastric cancer have all failed HER2 has not stopped.The ToGA study established the role of trastuzumab in the first-line treatment of patients with VEGFR-2, c-kit, etc. Apatinib can significantly prolong the survival of patients with advanced gastric cancer when used in third-line or higher therapy, and based on this, CFDA has approved the use of apatinib for gastric cancer indication The first antiangiogenic drug evaluated in gastric cancer, bevacizumab, failed, but other drugs in this class still show promise in gastric cancer and exploration continues. Apatinib is a small-molecule multi-targeted tyrosine kinase inhibitor developed in China, and its targets include MET is a transmembrane tyrosine kinase receptor that binds to HGF and triggers a downstream cascade reaction. Both antibodies targeting MET and small-molecule inhibitors have failed in studies of MET-positive gastric cancer, and the lack of uniform standards for detecting MET expression in gastric cancer has resulted in different rates of positive MET expression in different studies The phase III GOLD study in gastric cancer failed because the endpoint was not reached, but the subgroup analysis showed that olaparib could significantly benefit some patients and has some therapeutic potential in gastric cancer, but it is necessary to define the benefit groups, platinum-sensitive tumors and DNA HER2 is the star molecule in gastric cancer. Since trastuzumab was first approved for use in breast cancer studies, most of the trastuzumab resistance mechanism studies have come from breast cancer studies and a few from gastric cancer studies. There is evidence that membrane receptors other than HER2 can cause secondary resistance to targeted HER2 therapy, such as overexpression of MET and its ligand HGF decreases trastuzumab sensitivity, upregulation of the membrane receptor IGF-1R is also associated with trastuzumab resistance, upregulation of EphA2 expression triggers trastuzumab resistance, and activation of HER4 by its ligand NRG1 is involved in trastuzumab resistance. Downstream of HER2, PI3K/AKT pathway activation causes secondary drug resistance.Targeted therapy in gastric cancer is relatively backward, and trastuzumab remains the only first-line targeted therapy, while In recent years, the study of the immune microenvironment has become a hotspot, especially the relationship between tumor immune escape and the surrounding immune environment has shifted from basic to clinical, and immunotherapy represented by PD-1/PD-L1 inhibitors has achieved breakthroughs in the treatment of many tumors Currently, there is no gold standard therapeutic adjunct, but neoadjuvant chemoradiotherapy plus surgery plus adjuvant chemoradiotherapy can be applied to the appropriate population. In the future, risk stratification based on PET, R1 status, lymph node metastasis, and microsatellite instability (MSI) may help to individualize treatment choices for the greatest benefit of the patient The earliest work on artificial intelligence (AI) in medicine dates back to 1970, and the broad concept of AI was first published at a Dartmouth College conference in 1956. As a part of artificial neural networks, deep learning is one of the rapidly growing fields in artificial intelligence, but its practical utility in the real world will depend on joint applications in multiple environments that allow the integration of medical knowledge-based tools with other applications, including medical record systems, outcome reporting systems, electronic prescribing systems, and, in the biological context, tools for genomic/proteomic data management and analysis. Artificial intelligence has been increasingly involved in disease diagnosis, treatment, and drug development, etc. In the era of artificial intelligence and big data, the application of precision medicine in gastric cancer surgery is still based on standardized diagnosis and treatment. Artificial intelligence and big data are indispensable in the data collection, processing and application of precision medicine in gastric cancer surgery, such as data processing of cases and case specimens, interpretation of heterogeneous data and specific treatment of specific cases. Based on the clinical data of more than 10,000 cases in the international arena, the analysis of the above data has led to the emergence of norms that are applicable to the treatment in China and even internationally Many medical behaviors require the emotional participation of doctors; it is difficult for artificial intelligence to transmit the temperature of the doctor's face-to-face consultation in a short period of time for intelligent medical treatment. Establishment of large databases involves amount of important information, the protection of patient privacy faces unprecedented threats and challenges.In the era of precision medicine, along with the rise of artificial intelligence and big data, the diagnosis and treatment strategies of gastric cancer surgery have become more and more refined. Through accurate assessment of preoperative gastric cancer type and stage, precise, standardized, minimally invasive and individualized surgical treatments should be chosen. For patients with intermediate and advanced gastric cancer, interventions such as targeted therapy or immunotherapy combined with molecular targets are the key steps to realize the precision surgical treatment of gastric cancer. The author believes that in the near future, on the basis of integrating individual genomic information of gastric cancer patients with clinical, imaging and pathological data, the multidisciplinary diagnosis and treatment team of gastric cancer will be able to better realize individualized interpretation of the disease and provide patients with tailor-made and comprehensive treatment, which will truly reflect the precision of gastric cancer treatment.