Malignant tumors are the second leading cause of death worldwide. This is a public health concern that negatively impacts human health and poses a threat to the safety of life. Although there are several treatment approaches for malignant tumors, surgical resection remains the primary and direct treatment for malignant solid tumors. Anesthesia is an integral part of the operation process. Different anesthesia techniques and drugs have different effects on the operation and the postoperative prognosis. Propofol is an intravenous anesthetic that is commonly used in surgery. A substantial number of studies have shown that propofol participates in the pathophysiological process related to malignant tumors and affects the occurrence and development of malignant tumors, including anti-tumor effect, pro-tumor effect, and regulation of drug resistance. Propofol can also reshape the tumor microenvironment, including anti-angiogenesis, regulation of immunity, reduction of inflammation and remodeling of the extracellular matrix. Furthermore, most clinical studies have also indicated that propofol may contribute to a better postoperative outcome in some malignant tumor surgeries. Therefore, the author reviewed the chemical properties, pharmacokinetics, clinical application and limitations, mechanism of influencing the biological characteristics of malignant tumors and reshaping the tumor microenvironment, studies of propofol in animal tumor models and its relationship with postoperative prognosis of propofol in combination with the relevant literature in recent years, to lay a foundation for further study on the correlation between propofol and malignant tumor and provide theoretical guidance for the selection of anesthetics in malignant tumor surgery. Malignant tumor is one of the diseases that seriously affect the human quality of life . Accordiversus inhalation anesthesia, highlighting the need for large, multi-center, and prospective randomized controlled trials in the future.The influence of perioperative anesthesia management on the postoperative prognosis of malignant tumors has increasingly come to light in the recent years. Studies have found that different anesthesia techniques and drugs can affect tumor recurrence and metastasis, resulting in different postoperative prognoses. Propofol exerts sedative-hypnotic effects by the means of chloride transport and γ-aminobutyric acid (GABA) receptors and is commonly used in terms of the induction and maintenance of general anesthesia, with the characteristics of rapid induction, rapid recovery, and few adverse effects . It is wHere we conducted a narrative literature review on propofol regarding its chemical properties, pharmacokinetics, clinical application and limitations, studies in animal tumor models as well as effects on the biological characteristics of malignant tumors, reshaping of the tumor microenvironment and postoperative prognosis, intending to lay a theoretical foundation for future large-scale prospective multi-center clinical trials and provide potential guidance for the precise selection of surgical anesthetics .in vivo and in vitro studies have also shown that propofol can act as an antioxidant by rapidly and stably scavenging free radicals and inhibiting the process of lipid peroxidation , propofol can rapidly produce a slightly hypnotic effect. It is estimated that the half-life of blood-brain balance is about one to 3 min, which is probably the reason for the rapid induction of anesthesia . PropofoPropofol is mainly metabolized in the liver . It is rThrough the in-depth study of the pharmacokinetics of propofol, we can understand the absorption, distribution, and elimination process of propofol in the human body and the target organs where it exerts its pharmacological effects, which will further indicate the target organs and directions for the study of propofol. Propofol is highly lipophilic and protein-binding and is widely distributed in the liver, brain, gastrointestinal tract, and adipose tissue, so propofol tends to act in these organs. From a review of the literature, we found that propofol exerted a greater effect on liver cancer, gastric cancer, colorectal cancer and breast cancer, which is more consistent with the pharmacokinetic characteristics of propofol. Therefore, an in-depth understanding of the pharmacokinetics of propofol in the human body is of great significance for the rational use of drugs, the prediction of efficacy and toxicity, and the study of pharmacological effects.Propofol is a short-acting intravenous anesthetic with the advantages of rapid onset, short duration of action, rapid elimination and low incidence of post-operative nausea and vomiting. It can depress the central nervous system and produce sedative and hypnotic effects, and is commonly used for induction and maintenance of anesthesia as well as sedation and analgesia. It is now commonly used for the induction and maintenance of general anesthesia (GA) and total intravenous anesthesia (TIVA), as well as for sedation during anesthesia, after surgery and in the intensive care unit (ICU).The most common types of general anesthesia are propofol-based total intravenous anesthesia (TIVA) and volatile drug-based inhalation anesthesia. Of course, in many cases a combination of intravenous and inhalation anaesthesia is also used. Total intravenous anesthesia is a method of administering anesthesia to patients using intravenous anesthetics and its auxiliary agents with the advantages of rapid induction, smooth anesthesia, no contamination and quicker awakening . PropofoAt present, sedation and analgesia has become one of the important treatment methods in ICU, which can reduce stress, reduce the body oxygen consumption, make the patient in a comfortable state, reduce the accident of extubation and is conducive to prevent accidents and the recovery of the patients. Propofol is a fast-acting, short-acting, fast-recovery intravenous anesthetic. It can achieve good sedative effect under the premise of analgesia and is suitable for short-term sedation in ICU .In recent years, with the continuous development of endoscopic techniques and the increased demand for painless endoscopy, propofol is also being used for various outpatient endoscopic surgeries such as painless gastrointestinal endoscopy and tracheoscopy. Propofol is becoming increasingly popular in sedation for gastrointestinal endoscopy due to its unique pharmacokinetic properties, predictable recovery process and rapid recovery .etc.Currently, propofol is commonly used clinically as a fat emulsion formulation, and a number of problems remain in its clinical application. Apart from producing pharmacological adverse effects such as dose-related blood pressure drop, heart rate decreases and apnea, others are mainly associated with propofol in fat emulsion formulations, such as injection site pain, thrombophlebitis, hypertriglyceridemia, potentially fatal bacterial infections, rupture and blockage of the infusion line during prolonged infusion, propofol infusion syndrome (PRIS) and allergic reactions, Propofol has a cardiovascular depressant effect and causes hypotension associated with reduced peripheral vascular resistance, reduced cardiac preload, reduced sympathetic activity and myocardial contractility . StudiesIn clinical use, propofol is highly likely to cause respiratory depression. Even the induced dose of propofol can cause slower respiration, reduced tidal volume and even greater degree and frequency of apnea than other intravenous anesthetics of the same type .Injection site pain can occur in both adults and children, this pain can be immediate or delayed. This pain is due to the activation of the plasma pancreatic Vaso peptide system by propofol and the subsequent production of bradykinin, which is not the only factor causing the pain . Pain caPropofol is mainly given as an emulsion, and prolonged infusion is accompanied by elevated lipid levels. The long-chain triglycerides in the emulsion are the main factor causing elevated lipid levels . In addiPRIS is a dangerous adverse reaction in the use of propofol and its treatment success rate is low. It was found that when propofol dose > 4 mg/(kg h) and infusion time >48 h may lead to PRIS. The main manifestations are unexplained cardiac arrhythmias, metabolic acidosis, hyperkalemia and cardiomyocyte lysis, which eventually develop into severe heart failure and even lead to the death . TriggerSurgical resection is the primary treatment for solid malignancies. Numerous studies have demonstrated that the choice of anesthetic is closely associated with the postoperative prognosis of tumor patients. As a commonly used anesthetic, propofol not only has an anesthetic effect but also may act on tumor cells directly, which affects the biological characteristics of tumor cells, including anti-tumor effect, pro-tumor effect, and regulation of drug resistance.in vitro and in vivo. It has been shown that the anti-tumor effects of propofol are mainly through the regulation of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) expression to target multiple signaling pathways, oncogenes and functional proteins  is a kind of functional RNA molecule that cannot be translated into protein. They have mRNA-like structures and complex mechanisms of action. Numerous studies have demonstrated that lncRNAs play an important role in tumorigenesis and development by regulating epigenetic transmission, cell cycle and cell differentiation. Propofol can target various signaling pathways by regulating lncRNA expressions in tumor cells, such as the Wnt pathway, JAK2/STAT3 pathway, and Akt/mTOR pathway . Shen etIt is worth noting that both lncRNAs and miRNAs are non-coding functional RNAs with epigenetic regulation, which are closely related to the malignant biological characteristics of tumor cells. LncRNAs can bind to miRNAs and affect their functions, while miRNAs can regulate the stability of LncRNAs. Numerous studies have indicated that propofol could exert its anti-tumor activity by modulating the interaction between lncRNAs and miRNAs. Among which, lncRNA HOXA11-AS is currently more widely reported. in vitro via the PD-L1/Nanog pathway, thereby inhibiting cancer cell recurrence and metastasis. Another study showed that propofol inhibited the expression of circNOLC1 to attenuate tumor stem cell function via miR-365a-3p/STAT3 signaling pathway in breast cancer.Tumor stem cells are cells in tumors that have the ability to self-renew and generate heterogeneous tumor cells, which play an important role in tumor survival, proliferation, metastasis and recurrence, and are also a cause of drug resistance . Recent 2+ flux, has recently been found to be associated with propofol-induced inhibition of glycolysis. Qi et al. found that , very large VLDL free cholesterol content (XL_VLDL_FC), and very large HDL triglyceride content, and slightly increased serum total triglyceride levels  can be described as a highly complex system, which is composed of tumor cells, interstitial cells around tumor cells , extracellular matrix (ECM), and signal molecules (such as cytokines and chemokines). The two-way interaction between tumor cells and TME affects the tumorigenesis and progression at multiple levels. Tumor cells can change TME to produce a suitable living environment, and TME can in turn affect the behavior of tumor cells . With thin vitro and in vivo, possibly by inhibiting the NMDA receptor. Hypoxia is an important feature of the tumor microenvironment and is an important cause of tumor neovascularization. When the oxygen partial pressure of the tumor microenvironment is reduced, hypoxia-inducible factors (HIF) are activated to regulate primary transcriptional adaptation to the hypoxic microenvironment  on immunosuppression in renal cancer also showed that propofol was not effective in improving the immunosuppressive state of the tumor microenvironment  is a well-conserved, highly adhesive nuclear protein involved in maintaining the nucleosome integrity and facilitating gene transcription, which is now considered to be an important late-stage inflammatory factor and is of greater clinical importance than early-onset rapid inflammatory factors such as TNF and IL-1 . TargetiCyclooxygenase (COX), also known as prostaglandin endooxygenase reductase, is the key enzyme that catalyzes the conversion of arachidonic acid to prostaglandins . It consIn conclusion, propofol can reduce inflammation in the tissue microenvironment by inhibiting the production and release of pro-inflammatory cytokines and targeting multiple inflammation-related proteins, which will lay a theoretical foundation for propofol to inhibit tumorigenesis by improving the tumor inflammatory microenvironment.The extracellular matrix (ECM) is a macromolecular substance that is synthesized and secreted by cells and distributed on the surface of cells or between cells, consisting of the basement membrane (BM) and the intercellular matrix. The ECM is linked to the inside and outside of the cell by membrane integrins, which involve cell survival, cell shape determination, cell differentiation modulation and cell migration control .Metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade almost all protein components of the extracellular matrix and disrupt the histological barrier. They are closely associated with tumor invasion and metastasis, and are an important biological marker for tumor invasion and metastasis . Xu et aThe disintegrin and metalloprotease (ADAM) family are multifunctional proteins, consisting of eight structural domains including the metalloproteinase domain and deintegrin domain, which can be divided into membrane-anchored and secreted types . ADAM isin vivo and clinical research. Propofol can not only affect the biological characteristics of tumor cells in vitro, but also play a role in animal tumor models. In hepatocellular carcinoma, Advances in biomedical research often rely on the use of animal models as the basis for both experimental and clinical hypotheses. Animal studies can fill the gap between Perioperative factors such as inflammatory stimulation and metabolic changes can affect the prognosis of a tumor patient. In recent years, more and more attention has been paid to intraoperative anesthesia management, indicating that the different methods of anesthesia and drugs used have a significant impact on the prognosis of the tumor after surgery. Studies have shown that the use of propofol during operation is closely related to the disease-free survival rate and overall survival rate of various types of tumor patients. Therefore, the author combs and summarizes the clinical studies in the recent 5 years, hoping to lay a foundation for further study on the effect of propofol on postoperative prognosis .Several retrospective clinical researches have shown that the use of propofol in anesthesia in tumor surgery can significantly improve the prognosis of patients. Propofol may improve the survival rate and reduce the recurrence and metastasis of patients with digestive tumors. In gastric cancer, However, some studies have found that intravenous anesthesia with propofol does not improve the postoperative prognosis of tumor patients compared with other volatile anesthesia. In breast cancer, At present, the clinical research on the effect of propofol on the postoperative prognosis of tumors is mainly focused on retrospective analysis, which covers a wide range of tumor types, especially breast cancer. However, due to the limited sample size, the defects of retrospective study analysis, and the heterogeneity of clinical samples, the view that propofol can improve the postoperative prognosis and reduce recurrence and metastasis is worth further exploration and research. The conclusion is not yet consistent. We hope that in the future there will be more multi-center, large-scale prospective clinical trials with large samples to provide more theoretical evidence on whether propofol affects the postoperative prognosis of tumor patients and more precise guidance on the choice of anesthetic drugs in clinical practice.In vitro and in vivo studies have shown that propofol exerts anti-tumor effects through mechanisms of action such as regulation of microRNA, lncRNA, stem cell function, and metabolic reprogramming. For some specific types of tumors or conditions, propofol can promote malignant biological behavior of tumors through a variety of mechanisms. Chemotherapy is an important treatment for malignant tumors, and chemo-resistance is one of the difficulties in oncology research and poor prognosis. Propofol regulates resistance to many common chemotherapeutic agents such as cisplatin, paclitaxel, and 5-fluorouracil, which provides a new strategy for reversing drug resistance. For the reshaping of the tumor microenvironment, propofol can act through anti-angiogenesis, regulation of immunity, reduction of inflammation, and remodeling of the ECM.Propofol is a commonly used clinical agent for total intravenous anesthesia. In this review, the chemical properties, pharmacokinetics, clinical application and limitations and studies in animal tumor models of propofol were summarized, as well as the effects on the biological characteristics of tumors and the reshaping of the tumor microenvironment were discussed in detail. However, at present, the interaction between propofol and tumors is contradictory, and the conclusion is not yet consistent. Most studies found that propofol could suppress tumor proliferation, differentiation, metastases and promote apoptosis, and it is related to good postoperative prognosis. Nevertheless, some studies have demonstrated that propofol could promote the proliferation and migration of certain types of tumor cells, and it does not significantly improve the postoperative prognosis. Therefore, it is very important to clarify the mechanism of propofol on the occurrence and development of a malignant tumor and the relationship between propofol and postoperative prognosis. Meanwhile, we hope that there will be more large-scale prospective clinical trials with the multi-center, multi-sample, and multi-level to further explore the internal relationship between propofol and malignant tumors and guide more accurate intraoperative anesthesia management. Finally, it is worth emphasizing that this is a narrative review and the studies listed are not exhaustive, such as miRNA and lncRNA studies.


Conclusion: As for the implication of our study, special actions by urban authorities such as increasing mixed-use and creating attractive places will be required to enhance the walkability of the neighborhoods. Moreover, notifying the adults regarding the benefits of physical activity is much more needed.Objective: To augment the international scientific approach to raising public mental health through active lifestyle among adults, we added the evidence of the association between physical activity and subjective wellbeing in the Middle East and North Africa region by emphasizing the mediator—COVID-19. This study aimed to identify the correlations between active mobility and subjective wellbeing during the COVID-19 pandemic in a sample from Tabriz, Iran, which has not yet been tackled in previous study. Methods: We finalized an online survey (N = 603) from adults between 5 June and 15 July 2021. This group reported their individual and socio-economic characteristics and their perception features and location  during COVID-19. The paper developed three ordinal logistic regression (OLR) models to examine the association between active mobility types such as commute, non-commute, frequency of active travel to parks and services per week, and different subjective wellbeing including: 1- life satisfaction, 2- feeling energetic, and 3- peaceful mind while controlling for socio-economic variables  and objective commute distance. We also incorporated the most relevant objective  and subjective  factors. Results: Positive response relationships between four types of physical activity levels and subjective wellbeing scores were demonstrated in all of the three developed models  with appropriate model fits, which confirmed the existing literature. However, these relationships showed different patterns (varied significant levels) for each type of subjective wellbeing. In addition, the factors including street length ( The COVID-19 pandemic has infected and harmed a large number of individuals around the world . BecauseIt has been said that such a lifestyle  resulting from the pandemic has caused various detrimental impacts on human health and wellbeing. For example, sleep difficulties and an increase in comfort eating are believed to have resulted during the pandemic, leading to a loss of weight control . Accordihttps://keydifferences.com/difference-between-developed-countries-and-developing-countries.html (accessed on 17 April 2020))” ones due to insufficient health data, infrastructures, and relevant studies.The existing literature evaluated the relationship between active transport  and subjective wellbeing. The previous words provide evidence for positive correlations between active transport and subjective wellbeing ,25. The Hence, examining the association between different kinds of physical activity and wellbeing during the pandemic may promote measures which target increasing active modes of transport, which ultimately will lead to a growth in wellbeing and health among individuals. As a matter of fact, this research will make an essence for better understanding of the association among active mobility and subjective wellbeing in a large city of MENA countries for scholars, urban authorities, and individuals in a comprehensive manner which finally will contribute to the increase in health and wellbeing. This article has taken four modes of active travel, including commute, non-commute, and active travel frequencies to service and parks, as independent variables whose impact will be assessed on the three dependent variables of subjective wellbeing, including life satisfaction, feeling energetic, and peaceful mind. All of these measures will result in three output models. This approach will aid planners and authorities to have a comprehensive and accurate understanding of the active lifestyle impact on subjective wellbeing in large cities of developing countries. Thus, objectives of the study are: 1—to recognize the effects of active transport behavior of adults on the subjective wellbeing in the large cities of developing countries during COVID-19; 2—to compare the output models driven from the impact of active modes of walking on different dependent variables of subjective wellbeing during COVID-19.The following units make up the rest of the article. The connection between active transport and physical and mental health has been investigated by many researchers ,32. MostResearchers have tried to understand the nature, determinants, and consequences of subjective wellbeing with the rise of new courses such as hedonic psychology, positive psychology, and happiness economics ,36. SubjYet, there remain critical gaps in the evidence regarding the associations between active commuting and wellbeing . In mostThis study aims to examine these associations by considering the mediator of the COVID-19 outbreak. There are even apparent knowledge gaps in understanding the role of the pandemic on the associations between various types of active travel and subjective wellbeing.To cope with the pandemic’s physiological impact and restore homeostasis, self-care has been highlighted as increasingly important , and phyDuring the COVID-19 crisis, evidence regarding the link between physical activity and mental health is still being gathered. Despite this research, it has yet to be empirically studied whether different types of active travel, such as daily commutes to work or leisure active travel, contribute to effective wellbeing in different ways during the pandemic. No study has holistically investigated the relationship between active travel and various domains of subjective wellbeing during confinement, such as the quarantine caused by COVID-19. Thus, information on the effect of lockdown strategies from multiple global regions may help governments improve future lockdown strategies to minimize or mitigate adverse physical and mental health effects. Accordingly, we aim to explore the relationship between different types of active travel  and various dimensions of subjective wellbeing  among adults during the COVID-19 pandemic. It may help the community members to improve their subjective wellbeing through active travel in the face of a future pandemic or potential waves/relapses.In contextual studies, inconsistencies are observed between developing and developed nations. Active travel’s health impacts vary slightly across industrialized and poor countries. Developed countries have a more elevated economic level, and more individuals engage in physical activity . FurtherThere are fundamental research gaps in contextual fields concerning the relationship between active lifestyle and emotional health. As a result, in a rapidly urbanizing region such as MENA and a country such as Iran, individuals’ living circumstances, physical exercise habits, and mental health are changing. Furthermore, earlier research has demonstrated a relationship between walking (not cycling nor a combined factor) and mental health . However(1).What associations exist among the various types of active mobility/physical activity and different domains of subjective wellbeing during COVID-19 in the large cities of the MENA region?(2).What similarities and differences exist among the three patterns resulting from the impact of active lifestyle on the different variables of subjective wellbeing?This paper intends to address the following questions to predict the subjective wellbeing through active mobility habits in the understudied context of MENA:We hypothesize the existence of positive correlations between all kinds of active lifestyle  and subjective wellbeing  during the COVID-19 pandemic. However, we hypothesize that distinct patterns do exist resulting from the impact of various variables of active lifestyle on different measures of subjective wellbeing. Moreover, this paper assumes that the street length as a mediating factor has a positive role in predicting the association between active lifestyle and subjective wellbeing. However, the factor of population density as another mediating variable negatively correlates with subjective wellbeing during COVID-19 in the metropolitan cities of the MENA region.Due to the high similarities in socio-cultural features and urban form  affecting attitudes toward the travel behavior of inhabitants in large cities of the MENA region , the finding can potentially be generalized , Thus, TTabriz is a metropolitan city which is located in northwest Iran with approximately 1.6 million citizens (2022). This town is considered as one of the modern industrialized Iranian cities. Similar to any other large city in Iran, this town has witnessed swift transformation during the last few years. Moreover, renovations in urbanization after the appearance of modernism in planning have demolished the conventional elements and constructions of the city.Furthermore, the organic system and functional diversity of cities and urban communities have been supplanted by functional zoning. As a result, walkable neighborhoods have changed, and the city’s overall walkability has declined substantially. To put it another way, the bus rapid transit (BRT) system was established roughly 15 years ago to alleviate the high traffic on the city’s major boulevards, and one of the metro routes recently began servicing inhabitants. However, this city suffers from a scarcity of public transport systems, shifting many citizens to use their cars on their journeys. Additionally, non-supportive environmental factors, including lack of perceived social support, poor political and legal support, climate conditions, air pollution, seasonal limitations, and recent restrictions of the COVID-19 pandemic, are the most substantial barriers to physical activity in Tabriz . DespiteThis research is based on secondary data from geographic information system (GIS) layers and data from an online questionnaire survey conducted between 5 June and mid-July 2021. This time coincided with general restrictions imposed by Iran’s government , and the sampling was performed by asking about the current situation of the respondents. Considering the interdisciplinary nature of this study, two different types of questionnaires  for neighborhood walkability, and PGWBI  for subjective wellbeing) were used. The selection of respondents was based on an online random sampling method among the citizens of Tabriz (with diverse socioeconomic background from different urban contexts). The information regarding the respondents was given by the respondents about their socio-economics, their perceptions of distance to land uses and services and their neighborhood walkability, mobility mode choice for commute and non-commute trips, physical activity , and their subjective wellbeing . Only 670 of the 1091 citizens who began responding to the questionnaires completed enough questions to be used in the analyses. Due to item non-response, some samples were removed from the modeling procedure (603 remained). According to Cochran, the total sample size was 603 and is representative of Tabriz (1963). This report is simply an exploratory study aimed at identifying the link between active mobility, physical activity, and residents’ subjective well-being during the COVID-19 outbreak in large Iranian cities as a model for large MENA cities.The employed indicators including individual features, travel mode choice, respondents’ perception regarding neighborhood walkability, subjective wellbeing, and built environment  indicators are depicted in p-value, insignificant variables were removed from the OLR models. For the first, second, and third models, this process was repeated 24, 25, and 22 times, respectively, until suitable models based on significant variables and a better value of Nagelkerke’s R2 were reached. The models were built using both highly significant  and marginally significant  variables. Finally, to test the OLR assumptions, we used both proportional odds and multicollinearity for each model and variables. The proportional odds assumption means that for each variable and item that exists in the model, the ‘slope’ estimate among each pair of results across two response levels are assumed to be the same regardless of which partition we consider )). This test is an important validation step, and its rate should not be significant (less than 0.05). Multicollinearity occurs when independent variables in the model are highly associated to each other. It makes it hard to interpret the model and also creates an overfitting problem (Available online: https://towardsdatascience.com (accessed on 28 June 2022)). The obtained amount for each variable in VIF should not exceed 10.Three ordinal logistic regression (OLR) models were generated. For this aim, these models were obtained using SPSS. 26 software package. Accordingly, the variables such as mobility mode choices , socio-economic (control factors), and subjective and objective walkability were employed as the independent variables to measure the status of subjective wellbeing as the dependent variable. Next, we developed three OLR regression models for three sub-criteria of subjective wellbeing  during the outbreak of COVID-19. The obtained models showed how active lifestyle affects the subjective wellbeing of residents during the pandemic. Through the three models, the status of citizens’ subjective wellbeing was analyzed based on their mobility type and their built environment and the residents’ subjective perceptions (objective). As independent variables, the first set of OL models used 26 variables employing backward approach. Unlike the forward approach, the backward approach avoids producing so-called suppressor effects. (These suppressor effects occur when predictors are only significant when another predictor is held constant). Based on the highest A total of 603 Tabriz residents took part in the poll. In terms of gender, women made up 59.2 percent of responses , while men made up 40.8 percent . Despite coming from a variety of age categories, the 18-year-olds were the least represented, with the bulk of respondents being between the ages of 28 and 40 at the time of the poll. The average age of respondents was 36.7 years old.Based on It is apparent that the use of non-active modes for commute and non-commute purposes are considerably widespread in Tabriz, which shows the dominance of motorized travels, especially private cars. In terms of physical activity in parks, it is likely that the majority of respondents adopted the sedentary lifestyle during COVID-19.Three OLR models were developed for this study. In the following, the ultimate models are indicated after the exclusion of insignificant factors.p-value of less than 0.05) and marginally significant  variables. Accordingly, apart from the control factors  which were kept in the model, other factors including walking places2 , perceived facilities attractiveness, population density, street length, active mobility (commute and non-commute trips), and physical activity  indicate significant relationships with life satisfaction. On this point, active mobility (commute and non-commute trip) and physical activity  have a positive and highly significant  correlation with life satisfaction. This can explain that active lifestyle can significantly increase the levels of life satisfaction regardless of the type of physical activity. It is likely that active travel satisfaction levels have differences to the satisfaction with travelling with motorized trips. On the other hand, the high life satisfaction levels can be interpreted by relatively positive attitudes toward active transport in short trips. The most influential factor among these is the frequency of walking to the services followed by non-commute trip which show the highest amounts with estimate rates of 0.931 and 0.798, respectively. Both walking places 2  and facilities attractiveness show significant but weak correlations with association rates of 0.149 and 0.191, respectively. By indicating a considerable positive significance (33.432 association rate), street length demonstrates its importance in enhancing life satisfaction due to placing multiple features such as walkable sidewalks, beautiful designs, attractive monuments, pavement cafes, etc. which can hugely affect life satisfaction feelings. As a matter of fact, when the length of a street rises, the concept of the land-use mix can easily appear, provoking citizen’s positive feelings regarding their lives. The goodness-of-fit test has generated a deviance value divided by degrees of freedom proportion of 0.487 which showed a valid model because it is less than 1. The outputs of the Omnibus )) This test also showed validity (p < 0.001). The obtained rate of proportional odds for this model is 0.251 which shows good validity. In addition, the multicollinearity (VIF) test for each variable is ranged between 1.044 and 1.661 which again indicates the acceptability. The detailed results are depicted in In this stage, after running 24 models, the best model for the identification of the correlation between active mobility and the life satisfaction was developed using the following highly significant  and marginally significant  variables: control factors , walking places1 , walking places2 , distance to shopping malls, population density, street length, active mobility (commute and non-commute trips), and physical activity . In this regard, the classification of the independent variables for starting our first run was exactly as the variables in the first model, while the dependent variable was the second sub-criteria of subjective wellbeing, namely the feeling of being energetic. On this point, again active mobility (commute and non-commute trip) and physical activity  have a positive and highly significant  correlation with the feeling of being energetic. It is likely that during COVID-19, using active travel modes to move toward different purposes had a prominent role in enhancing the power of mind of the individuals. Such similar trends between different travel purposes showed similar trends. Surprisingly, the pandemic-oriented restrictions and necessity of social distancing indicated many advantages to those who used walking or cycling for their journeys. In this respect, such benefits could be interpreted by a release of dopamine during physical activity which can improve mood and reduce stress. For commute travels, it is likely that respondents choose active travel for closer destinations, while by increasing the distance, the tendency to employ active modes decreases. Among these variables, commute trips along with the frequency of walking to services had the highest impacts on the feeling energetic with estimate rates of 1.348 and 1.119, respectively. Apart from walking places1 , walking places2  and street length also have a positive association with the feeling of being energetic which means by increasing the existence of sidewalks, green spaces between streets and sidewalks, and street length, the feeling of being energetic also rises. This increase could also be due to the increase in walking which resulted from the growth in the above-mentioned variables. Meanwhile, the relation between the perceived distance to shopping malls and feeling of being energetic is significantly negative. This highly negative association can be interpreted to mean that as distance to shopping malls increases mentally, the likelihood of the feeling of being energetic decreases dramatically. This refers to declining the perceived energy of individuals when perceived distances of shopping centers (or job places as mentioned above) become more far, which makes the individuals less inclined to use active travel. The same results are seen for population density as well. It is likely that individuals living in densely populated areas show lesser rates of energies. The goodness-of-fit test has produced a deviance value divided by degrees of freedom proportion of 0.491 which showed a valid model. The obtained results of the Omnibus Test also showed validity for this model (p < 0.001). The obtained rate for proportional odds is 0.149 which shows a good validity. The multicollinearity (VIF) test for each variable is ranged between 1.060 and 1.678 indicating the acceptability of the model. The detailed results can be seen in In this stage, after running 24 models, the optimum pattern for the recognition of the relationship between active lifestyle and the feeling of being energetic was developed using the following highly significant  and commute distance.The ordinal logistic model for identifying the association between mobility mode choice, physical activity, and peaceful mind was completed after running 22 models, and the ultimate model was generated after omitting the non-significant indicators with higher As can be understood from All things considered, the existing models demonstrated similar patterns despite having minor differences which indicate that active mobility in all modes have positive impacts on the subjective wellbeing of individuals during COVID-19. In this regard, the role of urban features such as green spaces and sidewalk designs are directly and indirectly promising in the subjective wellbeing of citizens. In addition, in the COVID-19 era, it is likely that individuals inevitably are inclined to use active types of travel for short distances.The current study analyzes the associations among different modes of active lifestyle  and wellbeing  during the COVID-19 pandemic in Tabriz. In this paper, we controlled both socio-economic and commute distance variables. Along with the mentioned variables used in this study, we utilized some relevant objective and subjective variables to enhance and enrich the model fit. We developed three separate models considering the number of dependent variables for this aim. In each model, we incorporated any above-mentioned types of active transport simultaneously to explore the associations.A large body of literature emphasizes the association of non-commute walking with SWB ,57. Simi1 and non-commute 2), physical activity , and life satisfaction, any of the four mentioned variables indicated significant correlations with life satisfaction while controlling for factors including commute distance and individual-level factors such as age, gender, education, job, and income. The overall outcome is in line with some studies before [In our first model which explored the associations between active mobility  and the subjective factor of feeling energetic. Similar to the first model’s pattern, any of the four active travel types expressed significant associations with the characteristic of feeling energetic. However, these correlations are strong. This result is in line with these studies before and during COVID-19 ,80,81,82Our third and final model addressed the associations between different types of physical activity  and the subjective factor of peaceful mind (as the third component of wellbeing in this study). Like the two former models, all active modes of travel were correlated with peaceful mind  ,92,93,94Overall, we found that active commute, non-commute, and frequency of physical activity in parks and services have significant positive impacts on subjective wellbeing dimensions, including life satisfaction, feeling energetic, and a peaceful mind. Hence, these findings indicate that staying physically active over the pandemic is important, regardless of the physical activity domain. However, this effect differs following the various types of physical activity. Accordingly, different patterns have appeared. In other words, multiple types of physical activity have different estimations and predictions on the variety of self-assessed mental wellbeing in Tabriz, an indicator of a developing country’s metropolitan area. The finding also supports the debate that active commuters and non-active individuals have taken different lifestyles and environments, and thus, various factors must be controlled to avoid biased results . GeneralThe timeline of the survey during the COVID-19 period, the collection of retrospective data to capture the period during the pandemic, and the use of standardized self-reported subjective wellbeing measures were all strengths of this study, in addition to the use of different types of active lifestyle targets in subjective wellbeing. Some limits, however, were mentioned. The information was acquired during the pandemic, which necessitated an internet sampling of 603 respondents. With a larger sample size, more credible data for modeling the relationships between various forms of active lifestyles and subjective wellbeing might be collected. Young adults from middle-income families made up the majority of the sample. In addition, in this study, we focused on Iran citizens, and it might be biased to generalize the outputs for the whole cities located in MENA region; however, the results can be an indicator of large cities of MENA due to the similarities which were mentioned already.The current research aimed to identify the associations between different types of the active lifestyle , subjective wellbeing  during the COVID-19 pandemic. It was carried out among the adults in one of Iran’s metropolitan areas  as an example of a developing country site. To conclude, multiple lessons are obvious from this research. In closing, our results further support the importance of engaging in an active lifestyle, as this is correlated with maintaining subjective wellbeing.First, the volume of studies evaluating the mentioned relationship is considerably rare in the universal context. These studies predominantly have been conducted in developed countries of North America and Europe, limiting our findings generalization to other contexts . Such scSecond, although based on the literature and finding of this study there is a positive association between increased physical activity/active lifestyle and improved subjective wellbeing, further longitudinal studies in city or neighborhood scales are needed to achieve more accurate, reliable, and robust findings. This need is also more demanded during COVID-19. The impact of the COVID-19 outbreak on subjective wellbeing may be continuous and long-term ,99. ThusThird, despite achieving similar results which conformed to the significant and positive impact of different active lifestyles on subjective wellbeing, the estimation patterns are different in the provided models. For example, this amount in commute trips ranges from 0.480 in life satisfaction to 1.348 in feeling energetic. Thus, a unit increase in active lifestyles would lead to different raise outcomes in the dependent variable of subjective wellbeing, which should be considered in planning and policymaking.First model: perceived separation of the street from the sidewalk by green spaces, perceived facilities attractiveness, population density, and street length.Second model: perceived existence of sidewalks, perceived separation of street from the sidewalk by green spaces, perceived distance to shopping malls, population density, and street length.Third model: perceived existence of sidewalks, perceived separation of the street from the sidewalk by green spaces, perceived distance to parks, and population density.Fourth, besides the existence of significant relationships between various kinds of active lifestyles and different variables of subjective wellbeing, the rest of the significant indicators (without taking into consideration the controlling factors) which affect subjective wellbeing are:Overall, the obtained results from this study holistically add new evidence to the existing COVID-19 literature and have made an important contribution to enabling subjective wellbeing, with an outcome of various kinds of activities and neighborhoods that have been largely neglected. In addition, the obtained results provide a chance to suggest some intervention policies and implications to similar towns in MENA or other developing nations to encourage individuals toward the active lifestyle. Consequently, there is a significant requirement for a more integrated COVID-19 study in all nations and countries that enables scientists and academicians to analyze and help stakeholders and policymakers have accurate plans to spread out healthy communities.


Dystonia diagnosis is based on clinical examination performed by a neurologist with expertise in movement disorders. Clues that indicate the diagnosis of a movement disorder such as dystonia are dystonic movements, dystonic postures, and three additional physical signs . Despite advances in research, there is no diagnostic test with a high level of accuracy for the dystonia diagnosis. Clinical neurophysiology and genetics might support the clinician in the diagnostic process. Neurophysiology played a role in untangling dystonia pathophysiology, demonstrating characteristic reduction in inhibition of central motor circuits and alterations in the somatosensory system. The neurophysiologic measure with the greatest evidence in identifying patients affected by dystonia is the somatosensory temporal discrimination threshold (STDT). Other parameters need further confirmations and more solid evidence to be considered as support for the dystonia diagnosis. Genetic testing should be guided by characteristics such as age at onset, body distribution, associated features, and coexistence of other movement disorders . The aim of the present review is to summarize the state of the art regarding dystonia diagnosis focusing on the role of neurophysiology and genetic testing. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both.Dystonic movements are typically patterned, twisting, and may be tremulous.Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.Dystonia is a term used to identify hyperkinetic movement disorders in which dystonia is the prominent feature. However, dystonia can also be present in other conditions. According to the etiology, dystonia can be distinguished as acquired, inherited, or idiopathic. The diagnosis of dystonia is based on clinical examination conducted by physicians with expertise in movement disorders through a careful examination of the phenomenology of the condition that allows for a classification of dystonia. For the diagnosis of dystonia syndrome, the examiner should follow the definition of dystonia approved in the last expert consensus , articulThe examiner should focus on the classic five physical signs of dystonia syndromes: two main physical signs (dystonic movements and dystonic posture) and three additional physical signs  ,3.The role of laboratory analysis, neuroimaging studies, neurophysiology, and genetic tests is to support the etiology definition of the disease, according to the Axis II of Dystonia classification ,4. The aim of the present review is to summarize the state of the art regarding dystonia diagnosis focusing on the role of neurophysiology and genetic testing.Clinical neurophysiology techniques such as EMG mapping ,5 allow Since the early 1980s, neurophysiology has been used to characterize dystonia pathophysiology. Most studies were performed in focal hand dystonia (FHD) . At firsThe electromyographic (EMG) pattern observed in dystonia patients records simultaneous activation of agonist and antagonist muscles (co-contraction), prolonged duration of EMG bursts, and involuntary overflow activation of muscles not directly involved in the movement ,23.The most relevant neurophysiological feature shared by all dystonia subtypes is the reduced inhibition of central motor circuits . This isIn recent years, the relevance of the cerebellum in dystonia’s pathophysiology has been investigated . The eyeTraditionally, dystonia was referred to as a motor disorder; however, several recent studies have provided evidence on the role of the somatosensory system in dystonia pathogenesis. Several studies suggested that abnormalities in the somatosensory system are present in almost all dystonic patients, and several neurophysiology tests investigated these findings. The most relevant discovery is the abnormality in the somatosensory temporal discrimination threshold (STDT) . STDT reFinally, another possible contribution to dystonic pathophysiology is represented by maladaptive plasticity. Abnormal sensory-motor plasticity was demonstrated using a paradigm termed paired associative stimulation (PAS) In this TMS protocol, cortical stimulation is paired with peripheral nerve stimulation at an interstimulus interval of 25 ms resulting in long-term potentiation-like phenomenon (LTP). This form of LTP is pathologically enhanced in FHD . MaladapAlthough all this evidence suggests that dystonia is a complex network disorder involving the brainstem, the basal ganglia, the thalamus, the cortex, and the cerebellum , originaThe study of oscillatory activities in neurological disorders  revealedDystonia genetics is a wide field with continuous updates. After the first description of DYT-TOR1A, several other genes have been proposed as linked with the dystonia phenotype . As in oThe classic DYT nomenclature is based on locus symbols  and has been used for several years. It is still used in literature and clinical practice . HoweverMoreover, in the proposed nomenclature and in the last consensus update on dystonia, the term complex dystonia is used, referring to conditions in which dystonia predominates the clinical phenotype but occurs in the context of a complex disease including symptoms other than movement disorders ,69. For Combined dystonia is characterized by the coexistence of another movement disorder in addition to dystonia. The association of dystonia with parkinsonism defines dystonia–parkinsonism. The monogenic forms of dystonia–parkinsonism are DYT/PARK-GCH1, DYT/PARK-TH, DYT/PARK-TAF1, and DYT/PARK-ATP1A3 . ContrarDYT/PARK TAF1 differs from the previous mentioned strains for the age of onset, body distribution of dystonia, and neuroimaging. This form of combined dystonia begins in early to late adulthood and, contrary to DYT/PARK-GCH1 that begins with foot dystonia and then progress cranially, DYT/PARK TAF1 involves mainly the upper body, with characteristic jaw opening dystonia and bulbar involvement. Another difference with respect to the dopa-responsive dystonia is the absence of diurnal fluctuation. Brain imaging shows striatal atrophy and pallidum volume loss, considered an expression of the neurodegenerative nature of the disease. This form recognizes an X-linked transmission, hence is more frequent in males ,87,88,89Combined dystonia also encompasses dystonia associated with myoclonus and other hyperkinetic disorders. To date, two forms of dystonia–myoclonus have received confirmations: DYT-SGCE and DYT-KCTD17. These diseases have several features in common: age of onset is in the first or second decade of life, myoclonic jerks involve the upper body, and in DYT-SGCE also the neck may be involved. In both diseases, dystonia affects the upper part of the body, with involvement of upper limbs and the cranio-cervical region. If in DYT-SGCE myoclonic jerks dominates the clinical picture, in DYT-KCTD17 dystonia seems to be the prominent feature. Interestingly, DYT-SGCE myoclonic symptoms respond to alcohol, while in DYT-KCTD17 this response is absent ,92. Dystonia may coexist with other hyperkinetic disorders, such as chorea, as observed in several forms of complex dystonia. Marras et al.  also claAccording to the EFNS dystonia guidelines, genetic testing is not sufficient to make a diagnosis of dystonia in the absence of clinical features suggestive of dystonia . TherefoThe previously mentioned guidelines recommend, with a level B of evidence, the DYT-TOR1A testing for patients with limb-onset, primary dystonia with onset before age 30 , and in -Age at onset ,-Body distribution ,-Dystonia category .In clinical practice, genetic testing consists of of using predefined panels for dystonia. The whole-exome sequencing (WES) is also a resource to consider; however, it is expensive and requires a long time. Zech et al.  proposedSummary scores range from 0 to 5 and predict the diagnostic success rate of WES in individuals with dystonia. If the score is three, the sensitivity is 96% and the specificity is 62%; if the score is five, the sensitivity is 62% and the specificity is 86%. Hence, if the score is equal to or higher than three, whole-exome sequencing is recommended .An extensive discussion about genetic counseling goes beyond the scope of this review. The main concept to underscore is that genetic counseling depends largely on the determination of the mode of inheritance of a specific cause of an inherited dystonia in an individual . According to the inheritance, -DYT-SGCE dystonia has maternal imprinting of the gene, meaning that the dystonia-myoclonus only manifests when SGCE pathogenic variants are paternally inherited .-DYT-TOR1A has a reduced penetrance of the GAG deletion in TOR1A, from about 35% to 3% in individuals who also have a heterozygous NM_000113.2:646G>C (p.Asp216His) variant in TOR1A on the other allele .Moreover, penetrance must be considered because of the influence of the phenotypic expression of dystonia . For exaGenetic counseling should be offered to the patients and the family by qualified personnel and, according to the EFNS dystonia guideline, is recommended .The present review summarized the possible contribution of clinical neurophysiology and genetic testing to clinical examination for dystonia diagnosis .However, dystonia diagnosis is still based on clinical examination conducted by physicians with expertise in movement disorders. The clinical diagnosis should be based on the observations of two core characteristics and of adjunctive features . AccordiOnce dystonia has been clinically diagnosed, the definition of the etiology is needed . The etiConsidering the inheritance mode and the risk of transmission of the disease in the context of the same family, genetic counseling should be offered to the patients and a multidisciplinary approach involving geneticists, psychologist is desirable.


Lymphoepithelial cysts are rare in the oral cavity. Located mainly on the mouth floorA male, 71-year old patient was referred to us because of a painless intraoral lesion, perceived 6 months ago, with a granulomatous and ulcerated surface, firm to the touch, approximate size of 2cm and located in the anterior region of the mouth floor. Upon oral examination, we noticed another yellowish papular lesion measuring about 3mm; thus, the diagnostic hypotheses were of epidermoid carcinoma and granular cell tumor, respectively. We biopsied the lesion suggestive of malignant neoplasia and excised the other. After the pathology exam, the diagnosis was of epidermoid carcinoma  and lymphoepithelial cyst , followed by the posterior region of the tongue (13.7%). Nonetheless, in the present case, the lesion involved the tongue belly. Its development happens on the oral lymphoid tissue normally surrounded by areas of keratin from the coating epithelium%, followPereira et al. (2009)We stress the importance of a careful clinical exam for asymptomatic and small lesions, regardless of ulceration and ease of recognition, as well as the role of professionals who work with the oral cavity, namely dentists and ENTs, in the early diagnosis of malignant lesions.


Antimicrobial resistance (AMR) is a challenge to human wellbeing the world over and is one of the more serious public health concerns. AMR has the potential to emerge as a serious healthcare threat if left unchecked, and could put into motion another pandemic. This establishes the need for the establishment of global health solutions around AMR, taking into account microdata from different parts of the world. The positive influences in this regard could be establishing conducive social norms, charting individual and group behavior practices that favor global human health, and lastly, increasing collective awareness around the need for such action. Apart from being an emerging threat in the clinical space, AMR also increases treatment complexity, posing a real challenge to the existing guidelines around the management of antibiotic resistance. The attribute of resistance development has been linked to many genetic elements, some of which have complex transmission pathways between microbes. Beyond this, new mechanisms underlying the development of AMR are being discovered, making this field an important aspect of medical microbiology. Apart from the genetic aspects of AMR, other practices, including misdiagnosis, exposure to broad-spectrum antibiotics, and lack of rapid diagnosis, add to the creation of resistance. However, upgrades and innovations in DNA sequencing technologies with bioinformatics have revolutionized the diagnostic industry, aiding the real-time detection of causes of AMR and its elements, which are important to delineating control and prevention approaches to fight the threat. In the year 1928, Alexander Fleming discovered penicillin, which killed the staphylococcal bacteria he was examining. It soon became the key antibiotic for the treatment of key diseases caused by Gram-positive pathogens . Apart fMicrobial pathogens continue to evolve and develop resistance to emerging and traditional treatment methodologies; and this, combined with the extreme decline in antibiotic research has only increased the magnitude of AMR and its impacts on global healthcare costs and outcomes. The rampant upswing in use of antibiotics with over-the-counter options has only fueled AMR. This also adds to the risk of re-emergence of many diseases; the emergence of XDR-TB, extensively drug-resistant tuberculosis, is an example worth citing.Antibiotics are a pillar of modern medicine. Their use has reduced childhood mortality. Beyond that, they are crucial for invasive surgery and complex treatments such as chemotherapy. They are irreplaceable aids in the complex era of robotics-guided surgeries, and for the management of secondary infections during sickness with the common flu, and infections of the skin, gut, etc. However, infections by multidrug-resistant bacteria are on the rise globally, causing the specter of untreatable infections to become a reality. A 2017 World Health Organization  report confirmed that the entire world would will run out of antibiotics, as the existing drugs in clinical use were developed through modifications to the existing classes, and have shown to have short impact cycles . The Eur(i)developing an enhanced derivative from an existing antibiotic family;(ii)designing structurally superior anti-bacterial agents ;(iii)identifying the benefits of alternative classes of agents, including phages.Monitoring the use of available antibiotics has been popularly recommended to tackle rising incidences of antibiotic resistance, apart from the pressing need for identifying new target molecules and redesigning of the existent one to tackle the mounting adversity from MDR and XDR pathogens. Different aspects that can be included in development include:One of the key strands of red-tape is regulatory aspects around certification, which adds to the complexity in the pipeline of developing new antibiotics, making it less lucrative for pharmaceutical companies to invest time and effort. The current situation indicates that urgently adopting new ways to fight antibacterial resistance is necessary. One such widely discussed approach includes the principle of nanotechnology, and the use of “nano functionalization” to re-establish the antimicrobial activity of existing antibiotics. A report by Natan, M. and Banin, E. 2017) details the use of nanotechnology to combat MDR, wherein nanoparticles (NPs) in two functional categories were introduced  details . These fTracanna, V. et al. (2017), in a report discussing the diversity of functions of prokaryotic antimicrobial compounds, highlighted different mining strategies, including ribosomal synthesis and post translational modification of peptides, polyketides, etc . These sThroughout history, the development of antibiotic resistance has been documented to be a natural process to enable survival of the bacteria, but has been fueled by human activities, including over-prescription and inappropriate prescription, overuse, excessive use of antibiotics as growth supplements in livestock, and the availability of few new antibiotics . NumerouAntibiotic resistance occurs when the target microbe develops a physiological mechanism to overcome the drug’s impact. This may be due to a change in bacterial envelope structure or composition, production of enzymes that break down the target agent, etc. Other mechanisms include limiting drug influx and increasing efflux, or modification/inactivation of drug target . Apart fAMR, apart from adding to the challenge around disease management, also impacts the patient. It has been documented to compromise the human immune system, and increase complications and vulnerability after complicated surgeries involving cancer, knee replacement, dialysis, etc. Further, individuals with comorbid conditions have an increased risk of severe adverse outcomes with AMR. Conditions which necessitate the use of “last-resort” antibiotics also significantly increase treatment costs to the client, prolonging in-hospital time and admission rates ,17.The mounting evidence around antibiotic usage practice being a crucial risk towards AMR necessitates the need for inculcating habitual and appropriately guided clinical management practices. Knowledge around vaccinations, transmission, and prevention strategies are the key in public health education. Elaborate care practices for wounds and infections among patients with comorbid conditions can reduce the burden on hospital admission, and control infection spread.Communicating the need for antibiotics based on diagnosis and recommended clinical management protocol is also a crucial aspect in AMR. A lack of diagnostic tools and regulatory guidelines, and self-treatment with over-the-counter antibiotics for ailments such as the common cold and flu are common in developing countries, adding severely to the burden of AMR . FurtherApart from changes in antibacterial use and consumption patterns across different global economies, modern day travelling has also been a major contributor towards dissemination of new infections and antibiotic resistance across the world. The recent coronavirus disease (COVID-19) pandemic is the best example. One documented study among European travelers from India identified the presence of carbapenemase-producing Enterobacteriaceae (CPE), even among those with no contact with the Indian healthcare system during their stay ,21.Transmission of highly drug resistant microbes has been documented to occur inter- and intra-species. Identifying the reservoirs and best practices around causes for transmission will be fundamental to controlling future pandemics. Pandemics and epidemics involving COVID-19 are examples involving viruses which spread material between species. Any public healthcare measure that can control the dissemination and use of antibacterial agents is the first step in controlling AMR. High-quality global surveillance systems are needed to provide warnings associated with changes in antimicrobial use, and avoidance of the time lag in knowledge transmission is a key to preventing a global health crisis by AMR.Preventing infections and controlling transmission.Improving antibiotic use to slow the development of resistance through high quality surveillance and usage guidelines.Stopping the spread of resistant microbes when they do develop through antimicrobial stewardship programs.Antibiotic resistance development is a gradual process wherein the microbes in question develop resilience against agents targeted towards their destruction. Addressing this threat needs aggressive action towards:The science of the gut microbiome has presented ever-expanding opportunities to study the human—microbiome interaction, and provide an ecosystem to assess microbiome—antibiotic interactions. The impact of antibiotics on the human gut’s microbiome continues to be a key topic. Antibiotic exposure in early childhood has been linked to immunological, neurological, and gastrointestinal impacts; and antibiotic use at any age has been linked to negative impacts on the gut microflora leading to the emergence of antibiotic-resistant diarrhea . Apart fAntibiotic-induced microbiome depletion is a well-documented phenomenon due to antibiotic therapy and has been implicated in the alteration of metabolic homeostasis through gut signaling . StudiesClostridioides difficile infection (CDI), with which cure rates of up to 90% have been recorded. Other conditions include inflammatory bowel disease, with the respective clinical efficacy ranging between 25 and 50%. The differences in the impact of FMT have also been attributed to differences in microbiome composition between donors and recipients, due to changes in diet and environment at different time points . Though the panel is often predefined for a set of ARGs, the high confidence prediction makes it suitable for clinical use.The fundamental approach to identifying the presence of ARGs involves studying the whole genome sequencing data, for both the endogenous elements and plasmids. The data on presence/absence and abundance of vectors have been used for the development of machine learning models to predict the occurrence of AMR in samples. A report on prediction of AMR by WGS in lgorithm . Anotherlgorithm . PhyResSiagnosis . The tooiagnosis . The “MyE. coli. This study found acquisition of resistance to one drug changes susceptibility and resistance to others. Subsequent gene expression analysis led to the identification of dynamic compensatory mechanisms. Teixobactin, a new antimicrobial agent has documented activity against S. aureus and Enterococcus faecalis without resistance. A study which reported on the transcriptional response of E. faecalis to teixobactin levels identified development of intrinsic tolerance to high concentrations of the same (through deletion of croRS), and this is generally considered a precursor for the development of resistance [E. coli, and identification of differentially expressed transcripts, are further delayed by the need for functional annotation to decipher their role in AMR.Another approach to AMR prediction is through differences in gene expression of the isolate post exposure to the target drug. A report by Suzuki S et al. , detailssistance . BesidesM. tuberculosis and S. aureus as a powerful approach. This study highlighted the significance of genotyping with k-mers, and the benefits include being alignment-free and the ability to identify different categories of genetic variants, including single nucleotide insertions and deletions in the coding and non-coding regions. The study identified k-mers , which were further used in linear regression models for each tested antibody and found to have performance on par with Mykrobe [This approach elucidates AMR mechanisms based on global genomic comparisons with various susceptibility profiles of multiple strains. Another proof-of-concept study recorded the significance of stability selection to investigating the bacterial genotype–phenotype relationship in  Mykrobe .M. Tuberculosis to identify genetic signatures of antibiotic resistance. Subsequent mapping to available 3D structures of select proteins associated with AMR allowed the authors to pinpoint mutation clusters of certain proteins in the antibiotic response. This insight may help to better explain the AMR causality of alleles [Studies have highlighted the significance of machine learning with pan-genome structural analysis of  alleles . Another alleles .The pan-genome approach is funding intensive due to need for genomic sequencing technology and tools for a genome-wide comparison approach, although it holds great promise for clinical applications. An advantage is its ability to explore entire genomes instead of known AMR-related regions, to identify new mechanisms or regulatory elements. This is crucial to determining if the relation between a genomic signature and AMR is a statistical probability or causal. Furthermore, the need for large collections of strains is key to obtaining informative insights into AMR, which adds to the challenge.E. coli and simulated the corresponding metabolic status via genome-scale metabolic network model. The white-box machine learning approach yielded information on pathway mechanisms, facilitating the quantification of the relative contributions of each metabolic pathway towards tackling lethal mechanisms of each antibiotic. Further, profiling of over 500 intracellular and extracellular putative metabolites involving the 190 evolved populations highlighted carbon and energy metabolism to constrain the speed and mode of resistance acquisition. The study further identified multiple mechanisms employed by the E. coli strain to compensate for the pressure from different antibiotics, including mutations or expression of efflux pumps, which was further found to be influenced by the carbon source, and therefore, the metabolic state the organism is in [Studying metabolic profiling has also been widely studied as an approach orthogonal to the ones discussed previously. A report by Yang JH et al.  discussesm is in . This apResistance towards antibiotics is an inevitable part of microbial evolution. This emphasizes the need for surveillance of ARGs as the key aspect in future policy making. WGS and metagenomics, coupled with powerful bioinformatics tools and databases, have only furthered our knowledge in this regard. The reliability of results from these techniques foster encouragement for their execution in routine diagnostics. Use of antibiotics leads to dysbiosis of the gut microbiome, causing several side effects. In the monitoring of AMR in general and in the implementation of NGS technologies in particular, each domain has its own set of technical challenges, requirements, and realities. The only way forward is continuous education, surveillance, data analysis, and research to tackle the ever-emerging AMR crisis. A global public awareness campaign tackling the supply problem, control of antibiotic usage, and stimulus to the diagnostic market to initiate more rapid diagnostic tests, has been discussed as a key intervention with which to tackle AMR.The bioinformatics approach to AMR identification includes the aspects that focus on reliable insights of AMR that are replicable in clinical settings. This is focused towards underlining new genes of resistance, the regulatory mechanisms, or new antibiotic targets. Every approach has limitations which should be taken into consideration when building and training superior prediction models. The combination of advanced molecular technologies and powerful artificial intelligence and machine learning algorithms holds great promise for understanding AMR at the molecular level to generate clinically relevant predictions, leading towards selection of personalized antibiotics geared for favorable clinical outcomes.


Calcific tendinitis of the shoulder (CTS) is one of the pathological conditions that most often affects the shoulder and consists of a calcium deposit that settles within the tendon tissue of the rotator cuff. The scientific literature has long highlighted the impact of anxiety, stress, and depression on CTS. The goal of this case report is to highlight how the emotional state of patients and their neuro-psychomotor behavior induce a state of constant muscular tension which, through the physical phenomenon of piezoelectricity, causes calcium salts to precipitate and form calcifications. Therefore, stress, anxiety, and depression are likely factors underlying the etiopathogenesis of CTS. Consistent with this interpretation, this report presents five cases of CTS treated with three specific neurobiological stimulation treatments using the radioelectric asymmetric conveyer (REAC) technology, which has demonstrated its effectiveness on alterations in postural attitude intended as neuro-psychomotor behavior, anxiety, stress, and depression, as well as on autonomic and metabolic alterations of the tissues at a local level. The results presented suggest that this approach may be useful in the treatment and prevention of CTS. Calcific tendinitis of the shoulder (CTS) is one of the pathological conditions that most often affects the shoulder . AlthougVarious causes are hypothesized in the etiopathogenetic mechanism of the deterioration of the scapulohumeral joint, which represents the initial step of the CTS. The most common mechanisms invoked are aging, clothing lifestyle, sedentary life, and habitual movements but also factors such as hypertension, diabetes, alcoholism, smoking, and autoimmune pathologies for calcium dysmetabolism contribute to the weakening of the muscles and tendons because they reduce the blood supply . To dateNaturally, muscles must maintain their contraction for a sufficiently long time to determine the organization of the precipitated calcium salts in a calcific formation. The mechanism that can most easily determine this situation in an unconscious way is the postural attitude, which is a neuro-psychomotor behavior correlated to the subject’s emotional state . In the Case oneThe first case concerns a 60-year-old woman, a cook. During the first observation, in addition to complaining of local pain and functional impotence in the left shoulder, the patient complained of a state of strong anxiety and stress related to work overload. Clinical examination revealed shoulder calcific periarthritis of the left shoulder. This diagnosis was confirmed by the radiological examination performed before the REAC treatments, which showed minute multiple calcifications of the periarticular soft tissues Figure , Panel AOn a check-up three months after the end of the REAC treatments, the patient reported the disappearance of the local pain and restoration of the full functionality of the left shoulder. Moreover, the patient affirmed a clear improvement in the quality of life both in the workplace and in society, with a reduction in feelings of anxiety and stress. The radiological results showed the total disappearance of the calcifications after about three months from the previous X-rays Figure , Panel BCase twoA 48-year-old construction worker presented to us because all previous treatments had been ineffective in relieving pain and improving the functionality of his right shoulder. The patient reported having suffered from depressive episodes treated pharmacologically, but as the drugs used negatively affected his skills at work, they were taken inconsistently and for short periods. The reported symptoms of vivid pain and functional impotence suggested a diagnosis of FS.Before the REAC treatments, the X-rays showed important multiple calcifications of the supraspinatus, confirming FS Figure , Panel AOn check-up four months after the REAC treatments, it is interesting to highlight that the patient, while reporting a full recovery of work activity with the disappearance of the pain in the right shoulder, affirmed as the main improvement the positive change in mood and the way he faced daily adversities. The X-rays showed almost total disappearance of the calcifications previously reported, with a total recovery of shoulder function Figure , Panel BCase threeThe third case concerns a 53-year-old housewife. The patient reported that she had suffered for many years from pain and functional limitation in the right shoulder, which did not improve with any treatment, neither pharmacological nor rehabilitative. In addition, she reported widespread pain, so much so that she was diagnosed with suspected fibromyalgia. Previous X-rays showed a picture of major calcification of the cuff, particularly of the supraspinatus , steroid injections, and physical therapy. In case of failure of the previous treatments, therapeutic ultrasound, extracorporeal shockwave therapy, radial shockwave therapy, joint washing treatment with saline solution, intra-articular infiltrations with hyaluronic acid, and surgical treatment are also used. The treatments listed above are intended to reduce pain, inflammatory processes, and mechanically or chemically break down calcification, but none of these are intended to reduce the constant state of muscle tension induced by depression, anxiety, and stress, conditions reported by various authors in the field of CST ,10,13,16Based on the behavioral neuro-psychomotor approach, the constant muscular tension of the subject triggers a piezoelectric effect, which, in turn, determines and supports the formation and maintenance of calcification. Therefore, the first therapeutic goal is to act on the state of the behavioral neuro-psycho-physical tension of subjects, and consequently, on their state of constant muscle tension. Moreover, the altered behavioral state affects the autonomic response that conditions the microcirculation and metabolic processes at a local level. For these reasons, the remodeling of the autonomic components, capable of influencing the vascular, inflammatory, and immune response at the tissue level also represents further therapeutic support. The combination of REAC NPO, NPPO, and TO-B neurobiological stimulation treatments can represent a therapeutic arsenal useful in the prevention and treatment of CTS.The cases described in this study offer evidence of how useful the behavioral neuro-psychomotor approach can be as a key to understanding how CTS arises and which factors contribute to sustaining it. It would be opportune that the psychogenic/neuropsychic component be increasingly investigated in the context of orthopedic pathologies, analyzing how these components unconsciously condition the motor behavior patterns and determining osteoarticular pathologies over time.REAC NPO, NPPO, and TO-B neurobiological modulation techniques allow the therapist to deal with the psychogenic/neuropsychic components of osteoarticular pathologies.The REAC neurobiological modulation treatments used in this report allow for the optimization of the neuropsychic abilities and the autonomic response altered by psychogenic/neuropsychic states also at a local level, determining the reduction of the probably primary cause of joint damage.The findings described in this manuscript highlight how the REAC neurobiological stimulation treatments can constitute an effective therapeutic strategy in preventing and treating CTS cases.


Early-life adversity (ELA) is known to alter brain circuit maturation as well as increase vulnerability to cognitive and emotional disorders. However, the importance of examining sex as a biological variable when researching the effects of ELA has not been considered until recently. This perspective discusses the sex-specific behavioral outcomes of ELA in both humans and animal models, then proposes microglia-mediated mechanisms as a potential underlying cause. Recent work in rodent models suggests that ELA provokes cognitive deficits, anhedonia, and alcohol abuse primarily in males, whereas females exhibit greater risk-taking and opioid addiction-related behaviors. In addition, emerging evidence identifies microglia as a key target of ELA. For example, we have recently shown that ELA inhibits microglial synapse engulfment and process dynamics in male mice, leading to an increase in excitatory synapse number onto corticotrophin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) and aberrant stress responses later in life. However, ELA-induced synaptic rewiring of neural circuits differs in females during development, resulting in divergent behavioral outcomes. Thus, examining the role of microglia in the sex-specific mechanisms underlying ELA-induced neuropsychiatric disorders is an important topic for future research. Early-life adversity (ELA) is now well-known to alter the development of multiple brain circuits and increase long-term risk for cognitive and emotional disorders, including depression and substance abuse  axis as a major outcome  rodents , and this increase persisted into adulthood  to enable high-resolution functional imaging of microglia in humans. Importantly, many earlier studies excluded female subjects for simplification, due to the misconception that females presented more variability Shansky, . HoweverThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Institutional Animal Care and Use Committees of the University of California—Irvine and Georgia State University.MG and JB wrote and edited the article, performed the experiments and analyzed the data. JB created the figures for the data included in this Perspective article. All authors contributed to the article and approved the submitted version.This work was supported by National Institutes of Health (NIH) grant K99/R00 MH120327 (JB).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.


Normally occurring changes in sleep patterns can affect behavior, safety, and function in older individuals. In addition, altered sleep of one partner can affect the functioning of the other. We tested a novel intervention using an off the shelf, wrist-worn actigraph as a personal sleep monitoring device (PSMD) with dyads comprised of individuals who were 70 years old or older, and slept in the same house. Aims included: 1) Establish the feasibility of sleep self-monitoring using PSMDs, as a self-management strategy. 2) Establish the feasibility of PSMD data sharing among members of the dyad to improve sleep self-management and improve sleep quality; and 3) Evaluate the usability of PSMDs and data sharing for dyads of older individuals. Over the course of a five-week trial, we used a mixed methods approach. Data were comprised of daily sleep diaries, data from the PSMD, weekly questionnaires regarding sleep patterns and function, and qualitative interviews focused on sleep, self-management within the dyad, and the usability of the PSMD. Data were analyzed using qualitative or statistical methods. The use of the PSMD increased awareness of sleep patterns at the individual and dyadic levels, but the limitations of the PSMD were frustrating. Participants valued having a graphic image of how their daily activities affected their sleep patterns. The dyadic approach was effective in improving sleep patterns for older individuals, and using over the counter activity monitoring devices provide a relatively inexpensive way to assist older adults to improve their sleep self-management.


Due to the high clinical heterogeneity of neuronal intranuclear inclusion disease (NIID), it is easy to misdiagnose this condition and is considered to be a rare progressive neurodegenerative disease. More evidence demonstrates that NIID involves not only the central nervous system but also multiple systems of the body and shows a variety of symptoms, which makes a clinical diagnosis of NIID more difficult. This review summarizes the clinical symptoms in different systems and demonstrates that NIID is a multiple-system intranuclear inclusion disease. In addition, the core triad symptoms in the central nervous system, such as dementia, parkinsonism, and psychiatric symptoms, are proposed as an important clue for the clinical diagnosis of NIID. Recent studies have demonstrated that expanded GGC repeats in the 5′-untranslated region of the NOTCH2NLC gene are the cause of NIID. The genetic advances and possible underlying mechanisms of NIID  are briefly summarized in this review. Interestingly, inflammatory cell infiltration and inflammation were observed in the affected tissues of patients with NIID. As a downstream pathological process of NIID, inflammation could be a therapeutic target for NIID. Neuronal intranuclear inclusion disease (NIID) was first described in 1968 and is considered to be a rare neurodegenerative disease . With thRepeated GGC expansion in the 5′UTR of the NOTCH2NLC gene was identified as the causative mutation for NIID in Japan and China in 2019 . These fHundreds of NIID cases have been reported so far, and the most common feature of NIID is symptom heterogeneity; different families and individuals have different symptoms of NIID. In early clinical studies, the major clinical manifestations of previously described cases were cerebral cortical dysfunction and extrapyramidal symptoms, including cognitive dysfunction and dementia , PD-likeDementia was one of the main symptoms described in a patient with NIID in 1978 . Since tParkinson’s disease-like symptoms are regarded as another common and typical representative symptom in patients with NIID . PD-likeIt is worth noting that a significant proportion of patients with NIID have adverse changes in terms of mood and personality , but dueLimb weakness was found in many patients with NIID and is one of the key phenotypes of NIID . A previAlthough progressive symptoms, such as cognitive impairment and parkinsonism, are key features of NIID as a neurodegenerative disease, episodic attacks are also found in some patients with NIID, such as encephalitis-like, vestibular migraine-like attacks, or MELAS-like or epileptic episodes .Several ophthalmological manifestations have been reported in patients with NIID, such as abnormal pupillary functions, miosis, oculogyric crisis , reducedExcept for the nervous system, many studies have indicated that other systems are involved in the pathology of NIID . The nonA recent study showed that ubiquitin and p62-positive cells are found in the lung tissues of patients with NIID, indicating the presence of intranuclear inclusion bodies in the lung . By inteCardiomyopathy and coronary atherosclerosis are reported to be associated with circulatory symptoms in patients with NIID. In previous studies, intranuclear inclusions were found in the kidneys of patients with NIID , but uriDigestive system symptoms in patients with NIID commonly manifest as severe nausea and vomiting, which can occur alone, but in most cases, nausea and vomiting occur together. A case report showed that a patient with NIID repeatedly vomited for 7 years before the apparent abnormality in DWI was found, suggesting that periodic vomiting could be the only symptom of NIID in the early stages of NIID . GastroiThe patients with familial NIID were reported to have erectile dysfunction beginning in the first or second decade of life . Chen etAlthough different systems and organs are involved in NIID, the sequences of involvement in different systems may vary in individual patients according to previous case reports; for example, the existence of intranuclear inclusions and symptoms in systemic organs, such as the stomach and kidneys, precedes the onset of nervous system symptoms in NIID case reports . TherefoImaging examination is of great value in the clinical diagnosis of NIID. The earlier reported MRI findings were atrophy of the cerebellar hemispheres and no specific imaging for NIID . With thNeuronal nuclear inclusions (NIIs) in the skin or biopsy samples of other tissues are the characteristic histopathologic findings of NIID. NIIs are not limited to NIID, but are also present in a variety of multiple neurodegenerative diseases, such as fragile X-associated tremor/ataxia syndrome (FXTAS), distal ophthalmopharyngeal myopathy, and oropharyngeal myopathy, which have overlapping clinical symptoms and similar pathological outcomes, and even have some commonalities in genetic diagnosis . The exiThe NIID was defined as an intranuclear inclusion disease when it was first described in These inclusion bodies are circular, 1.5–10 μm in diameter, and are located near nucleoli, and ubiquitin/p62 staining, but not tau epitope, can be seen around NIIs . ElectroExcept for the NIIs in the different tissues, in the pathological examination of NIID tissues, diffuse inflammatory cell infiltration near the intranuclear inclusions, such as neutrophil monocytes and macrophages, was found in the affected tissues, including the brain, lung, bladder, and prostate gland , indicatIn 2019, studies reported GGC repeat expansion at the 5′ region of NOTCH2NLC as the genetic cause of NIID . NOTCH2NBased on a multiethnic cohort of gene-confirmed patients with NIID from Southeast Asia, it was suggested that the presence of GGA interruptions in the repeated expansion of GGC may play a role in modifying the disease in terms of age at symptom onset . Based oA previous study demonstrated that the NIIs in sporadic and familial NIID contained Sumo-1 and SUMOylation substrate PML and HDAC4 . Based oAlthough GGC repeat expansion in the NOTCH2NLC gene has been proven to be the cause of NIID, the molecular mechanisms underlying NIID remain unclear. Similar to FXTAS (GGC repeats in the FMR1 gene), Huntington’s disease (CAG repeats in the HTT gene), amyotrophic lateral sclerosis/FTD (GGGGCC repeats in the C9ORF72 gene), and myotonic dystrophy , NIID is one kind of nucleotide repeat expansion disorder or microsatellite repeat expansion disorder with expanded GGC repeats in the NOTCH2NLC gene. Therefore, NIID may share some similar mechanisms to these microsatellite repeat expansion disorders. Here, we briefly propose some possible mechanistic models of NIID at the DNA, RNA, and protein levels . For morUnconventional translation, named repeat-associated non-AUG translation (RAN), of expanded repeats in toxic proteins has been identified in a variety of microsatellite disorders . For exaPrevious studies have demonstrated that repeat expansion-containing RNAs from the non-coding regions of genes linked to diverse human diseases, such as myotonic dystrophy type 1 and FXTAS, can form intramolecular hairpin secondary structures, bind to many RNA-binding proteins, and form RNA-protein aggregates in the pathology of these neurodegenerative diseases, resulting in toxic gain-of-function of these mRNAs . NOTCH2NExtended GGC repeats may cause the pathology of neurodegenerative diseases not only at the protein level and the RNA level but also at the DNA level. A previous study indicated that GC enrichment in the extended GGC repeats of the FMR1 gene increases the propensity of the formation of RNA-DNA hybrid R-loops . These cIn early case reports, autopsy, rectal biopsy, and nerve biopsy were mostly used to diagnose patients with NIID . Sone etDue to the high heterogeneity and multisystem symptoms of this disease, it is difficult to reach the diagnosis of NIID in clinical practice. The diagnosis of NIID can be considered from typical MRI signals, clinical manifestations, pathology of NIIs, and genetic tests. DWI high-intensity signals in head MRI are the strong indicators for the diagnosis of NIID. If patients had no typical MRI changes, the triad of clinical manifestations such as dementia, PD-like behaviors, and personality changes is a good cue for the diagnosis of NIID. For patients without the triad of NIID and DWI high-intensity signals, NIIs in the pathological findings from skin or other tissues are also a cue to suspect the diagnosis of NIID. Once the diagnosis of NIID is suspected, a genetic test for GGC repeats in the NOTCH2NLC gene should be performed to confirm or rule out the diagnosis of NIID, as shown in Because NIID is a symptom-heterogeneous disease and shares similar imaging features with some diseases, NIID has many differential diagnoses from other diseases.Because FXTAS and NIID are both autosomal-dominant GGC trinucleotide repeat expansion diseases in different genes  , FXTAS iNeuronal intranuclear inclusion disease should be distinguished from Creutzfeldt–Jakob disease and some diseases with leukoencephalopathy or dementia. Creutzfeldt–Jakob disease has progressive cognitive impairment and myoclonus in the extremities, as well as characteristic lacy high-intensity signals in the cortex, caudate nucleus, or putamen on brain DWI. A recent study proposed that brain DWI is the key to differentiate from Creutzfeldt–Jakob disease and different leukoencephalopathy grades .Middle cerebellar peduncle lesions are considered to be a characteristic finding of NIID , but theCurrently, there is no treatment to cure or slow down the process of NIID, but medications that control symptoms, such as muscle weakness, impaired consciousness, abnormal behavior, and sensory impairment, can improve a patient’s quality of life . ClinicaRecently, different therapeutic strategies have been proposed for NIID, for example, antisense oligonucleotide therapy, RNA interference, small molecule RNA drugs, and CRISPR-based therapy . AlthougWith an increasing number of reported cases of NIID, the clinical manifestations of NIID are well characterized. Early studies showed that NIID mainly has neurological symptoms; the latest studies demonstrated that there are a variety of symptoms and signs in various systems, indicating the high heterogeneity of clinical symptoms and signs of NIID. This increases the difficulty in the clinical diagnosis of NIID. Although patients with NIID present heterogeneous symptoms, they also show some core symptoms, such as triad symptoms in the central nervous system . Before the NOTCH2NLC gene was linked to the etiology of NIID, tissues/skin biopsy and DWI high-intensity signals along the corticomedullary junction were strong clues for the diagnosis of NIID; now, genetic tests for expanded GGC repeats in the NOTCH2NLC gene have become the gold standard for NIID.Expanded GGC repeats in the NOTCH2NLC gene have been confirmed as the cause of NIID, but how expanded GGC repeats in the NOTCH2NLC gene cause pathological changes and the accumulation of NII in the nucleus remains unclear. As a nucleotide repeat expansion disorder, NIID may share similar mechanisms to other nucleotide repeat expansion disorders, such as expanded nucleotide repeat-induced DNA damage, RNA toxicity, and abnormal encoded protein toxicity. Although recent studies have demonstrated the presence of polyG-NOTCH2NLC protein in the animal models and tissues of patients with NIID, the mechanism by which the polyG-NOTCH2NLC protein causes toxicity still needs more investigation. RNA toxicity and DNA instability theory need to be identified in the mechanisms of NIID. How do expanded GGC repeats in the NOTCH2NLC gene induce the formation of NIIs? What are the components in expanded GGC repeat-induced RNA foci? Which RNA-binding proteins are involved in the pathogenesis of NIID? These questions await more investigation, and the answers to these questions will help to guide the treatment of NIID. To date, no effective treatment is available. Even though different gene therapies, such as antisense oligonucleotide therapy and RNA interference, have been proposed, many great challenges must be overcome, such as the specificity and out-of-target nature of RNA drugs. Recent findings have shown that inflammation is involved in the pathological changes of NIID and may be downstream of expanded GGC repeat-induced RNA/protein toxicity. Therefore, the role of inflammation should be further identified in the pathology of NIID, and anti-inflammation could be a promising therapeutic strategy for NIID.XX, MS, and BoW designed and revised the manuscript. YL and HL collected the literature and made the first draft. XL, BiW, HY, BoW, and MS discussed and interpreted the analysis. All authors contributed to the article and approved the submitted version.