Objective: To assess the effect of early implementation of and longer daily duration of rehabilitation on patients with acute ischemic stroke who require assistance with activities of daily living (ADL) before hospital admission.Design: Nationwide, cohort, observational study from April 2018 to March 2019.Setting: Acute care hospitals in Japan.Participants: The Japanese national Diagnosis Procedure Combination database was searched for the period between April 2018 and March 2019. Of the 330,672 patients with ischemic strokes identified, 53,523 met the inclusion criteria of being older than 20 years, having a prehospital modified Rankin Scale score of 3, 4, or 5, and having undergone rehabilitation .Interventions: Not applicable.Main Outcome Measures: Improvement in ADL from admission to discharge using the Barthel Index. The effects of the following 3 rehabilitation variables on ADL improvement were evaluated: (1) average daily duration of rehabilitation; (2) rehabilitation started within 3 days after admission (early rehabilitation); and (3) rehabilitation started 1 day after admission (very early rehabilitation).P≤.001). A longer duration of rehabilitation was also significantly associated with ADL improvement  compared with a ≤1 hour of rehabilitation .Results: Early rehabilitation was significantly associated with improvements in ADL (odds ratio, 1.19; 95% confidence interval, 1.10-1.28; Conclusions: Early implementation of rehabilitation and a longer duration of rehabilitation per day improved the ADL of patients who required assistance before the onset of cerebral infarction. The purpose of this study was, therefore, to investigate the effectiveness of rehabilitation for ADL improvement in patients with acute ischemic stroke who required assistance with ADL before admission.This was a nationwide, observational study based in Japan from April 2018 to March 2019 in a cohort of hospitalized patients.International Statistical Classification of Diseases, Tenth Revision codes were used for the identification of cerebral infarction (I63). Patients 20 years or older (Japanese adult standard), those with a prehospital modified Rankin Scale (mRS) score of 3, 4, or 5 , and those who underwent rehabilitation were included in the study.We extracted the data of inpatients who were diagnosed with cerebral infarction at the time of admission (April 2018 to March 2019) from the Japanese national Diagnosis Procedure Combination (DPC) database. The International Statistical Classification of Diseases, Tenth Revision.DPC is a national acute care inpatient database in Japan; it uses a fixed payment system per hospitalized day. This database covers 55% of hospitalized patients in Japan. The DPC system is mandatory for all university hospitals.,Age was divided into 5 groups: 59 or younger, 60-69, 70-79, 80-89, and 90 years or older, because the incidence of stroke increases after the age of 50 years and because we analyzed age distribution and decided to stratify it into 5 groups. We calculated the body mass index at admission from the recorded height and weight, assigned based on modified World Health Organization classifications.The average daily duration of rehabilitation, calculated as the total duration of rehabilitation during hospitalization divided by the number of dates of rehabilitation performed, was categorized into 3 groups: ≤1.0 hours, 1.1-2.0 hours, and ≥2.1 hours. Early rehabilitation was defined when rehabilitation was started within 3 days of admission, and the following categorical variables were created: early rehabilitation and usual rehabilitation early. Very early rehabilitation was defined as when rehabilitation was started within 1 day of admission.The primary outcome was ADL improvement from admission to discharge using the BI. We subtracted the BI score at discharge from that at admission and created categorical variables. Based on a previous study, the minimal clinically important difference of the BI was defined as 1.85 points.The basic characteristics were described, and categorical variables are expressed as the number of participants and percentage. Continuous variables are expressed as mean.We tested whether there were differences in the BI, LOS, and discharge destination in the very early and early rehabilitation groups and between the duration of rehabilitation per day groups. The outcome of this study was the difference between ADL at admission and discharge because ADL is affected by LOS and discharge destination.,For the main analysis, multivariable logistic regression models were constructed for early rehabilitation, duration of rehabilitation per day, and independent variables that were related to the outcome in prior studies.aIn the regression model, missing data of ADL were assigned using multiple imputation with the chained equations method.Study approval was obtained from the institutional review board of the Tokyo Medical and Dental University (M2000-788-27). Because of the anonymous nature of the data, the requirement for informed consent was waived.A total of 330,672 ischemic stroke cases were extracted from the database; 53,523 cases were eligible for analysis considering the eligibility criteria . Of thesP<.001; early rehabilitation [2.4±5.6] vs usual rehabilitation [1.7±6.1]; P<.001). Crude BI values decreased significantly as rehabilitation duration per day increased . The implementation of very early rehabilitation and early rehabilitation occurred at a higher rate than usual rehabilitation . The most common duration of rehabilitation per day was ≤1 hour . The median LOS was significantly longer in the usual rehabilitation groups, and it was increased as the duration of rehabilitation per day increased (P<.001). The discharge destination to the facility was a significantly higher rate in usual rehabilitation than very early and early rehabilitation (P<.001). The discharge destination to home was a significantly higher rate in the duration of rehabilitation per day in the >2.1 hours group (P<.001).P≤.001), and a longer duration of rehabilitation per day was also significantly associated with ADL improvement compared with a duration of rehabilitation ≤1 hour .P≤.001; mRS4, P=.002; mRS5, P=.689).,,This study was the first to reveal the effectiveness of acute stroke rehabilitation in patients who required assistance before hospitalization. In the early rehabilitation and very early rehabilitation group, the improvement in ADL from admission to discharge was better than in the usual rehabilitation group for mRS3 and mRS4 patients. Regarding the duration of rehabilitation per day, the degree of improvement in ADL was higher for those who received >1 hour of rehabilitation than for those with <1 hour of rehabilitation. The present results are generally consistent with those from previous observational and intervention studies.In our study population, the highest incidence of stroke was in patients aged 80-89 years. Compared with epidemiologic data on stroke in Japan,Early rehabilitation of patients with stroke who required assistance prior to admission was as effective in improving ADL as in patients with stroke who did not require assistance before admission.We found that very early rehabilitation was also effective in patients with stroke who required assistance before the onset of stroke. This result differed from the results of a previous study that investigated very early rehabilitation of patients with stroke who did not require assistance before the onset of stroke.This study showed that increasing the average rehabilitation duration per day for patients who required assistance before the onset of stroke led to improved ADL, similar to previous studies. Increasing the duration of rehabilitation after stroke reportedly affects physical function at discharge and ADL improvement after 3 months.In the analysis of the effects of rehabilitation on patients stratified by prehospital mRS, score early and very early rehabilitation did not result in ADL improvement in patients with an mRS score of 5 before hospital admission. In contrast, the duration of rehabilitation per day was associated with ADL improvement in all mRS strata. Previous studies on early rehabilitation are difficult to compare with this study because the participants had an mRS score ≥2 before admission. Herein, we found that the effect of early rehabilitation on the improvement of ADL differed depending on the care required before hospitalization. This suggests that it is necessary to consider long-term physical function in early rehabilitation intervention.This study has several limitations. First, it used medical administrative databases, which do not represent nearly half of patients in Japan. Second, the primary outcome had 20.8% missing data of the total population. We performed the analysis using multiple imputation for this missing data, which may be insufficient to control bias. However, the basic characteristics of the groups with and without missing values were balanced (0.1<standardized mean difference) except for the body mass index and emergency transport variables. In the analysis of rehabilitation for ADL improvement calculated with missing values, early rehabilitation, very early rehabilitation, and daily duration of rehabilitation each had the same direction of results as when missing values were imputed .Third, this study does not allow for discussions on the low-volume, high-frequency interventions of early rehabilitation discussed in A Very Early Rehabilitation Trial, because the database contains data on total rehabilitation hours per day; however, it does not contain information on how many interventions are performed in a day.Fourth, lack of information on the site of stroke onset and the location of the infarction plus lack of background factors for nutritional status may have resulted in insufficient adjustment for background factors and severity of the disease. Fifth, this study could not examine the long-term outcomes of rehabilitation because the data were obtained during hospitalization in an acute care hospital. The transition from acute hospitalization to a rehabilitation hospital and outpatient treatment differs from country to country. In Japan, the policy is to shorten the length of acute hospitalization and to transfer patients to rehabilitation hospitals as early as possible. This study focuses on the period from admission to discharge from acute care hospitals. The effect after transfer to a rehabilitation hospital is not clarified.Early implementation of rehabilitation and a longer duration of rehabilitation per day improved ADL for patients who required assistance before the onset of cerebral infarction. However, the indications for early rehabilitation need to be considered according to background factors such as the patient's physical status before admission. More information is needed from randomized trials to confirm the effects of early rehabilitation and the daily duration of rehabilitation on ADL recovery in patients with stroke who require preadmission assistance.a.R statistical software version 4.2.0; R Core Team.


Allergic rhinitis and nasal polyps are common otorhinolaryngological diseases. Small extracellular vesicles and microRNAs have recently become major research topics of interest due to their key regulatory roles in cancer, inflammation, and various diseases. Although very detailed and in-depth studies on the pathogenesis and pathophysiology of allergic rhinitis and nasal polyps have been conducted, few studies have assessed the regulatory effects of exosomes and microRNAs on allergic rhinitis and nasal polyps. This paper reviews the studies on small extracellular vesicles and microRNAs in allergic rhinitis and nasal polyps conducted in recent years and focuses on the regulation of small extracellular vesicles and microRNAs in allergic rhinitis and nasal polyps with the aim of providing insights for the future diagnosis and treatment of allergic rhinitis and nasal polyps. Allergic rhinitis (AR) is clinically defined in the 2008 Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines as “a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation” . EpidemiSmall extracellular vesicles (sEVs) are lipid bilayer vesicles with a maximum diameter of 150 nm that are secreted by a variety of cells through the processes of endocytosis, fusion, and exocytosis . SEVs armiRNAs are endogenous RNAs that regulate gene expression in a posttranscriptional manner; these RNAs are widely expressed in eukaryotic cells and play important roles in biological activities . miRNAs AR is a nasal mucosa type I IgE mediated allergic disease. Major histocompatibility complex class II (MHCII) molecules are expressed after allergens are taken up by dendritic cells (DCs). The allergen and MHCII molecules form a complex and are presented to T cells, which differentiate into T helper 2 (Th2) cells to produce Th2 cytokines , such asFang et al.  reportedThe miRNAs are endogenous RNAs that exert posttranscriptional regulation. A previous study found differences in the expression of miRNAs in AR patients; some miRNAs are significantly upregulated or downregulated in AR patients, which indicates that miRNAs are related to the occurrence of AR. Among these miRNAs, some exert positive effects on AR –59, wherChronic rhinosinusitis (CRS) is defined as chronic inflammation of the nasal cavity and paranasal sinuses that can be classified based on the presence of nasal polyps: with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) . CRS is Recent research has shown that nasal sEVs can promote the in vitro migration of several immune cells, including monocytes, neutrophils, and natural killer (NK) cells, which further contributes to mucosal immune defence . Nocera As mentioned above, NPs are caused by tissue oedema due to an increase in the vascular endothelial gap and plasma protein overflow. The increases in angiogenesis and vascular permeability are causative factors of NPs. Previous research has indicated that sEVs and both of these biological processes can promote NPs. Some scholars have isolated sEVs from nasal lavage fluid and analysed their effects on in vitro tube formation and vascular permeability. The results showed that nasal lavage fluid-derived sEVs from patients with NPs promote tube formation by human umbilical vein endothelial cells and increase vascular permeability compared with those from unaffected people. The main secreted substance detected in this experiment is a disintegrin and metalloproteinase-10 (ADAM-10) , which iSome scholars have detected high P-glycoprotein levels in nasal mucus sEVs from patients with NPs, and the secreted sEVs effectively transport P-glycoprotein and improve the functional P-glycoprotein levels in recipient cells. An increase in P-glycoprotein expression is the key to promoting Th2-type inflammation . The inhβ1, upregulate epithelial marker expression, and downregulate mesenchymal marker expression. Interestingly, Zhu et al. [miRNAs also have a considerable impact on NPs. Relevant studies have identified differences in miRNAs in the nasal mucosa between patients with NPs and unaffected patients, which suggests a close relationship between miRNAs and the occurrence of NPs –84. Amonu et al.  found thThe occurrence and development of AR and NPs are related to sEVs and miRNAs, which regulate the pathogenesis of these diseases by controlling intercellular communication.Many studies have revealed the effects of miRNAs and sEVs on AR, and in these studies, AR mice were used to evaluate the overall response to allergens after knockout of the corresponding miRNAs, such as the release of inflammatory factors, the serum IgE level, and the severity of allergic symptoms. However, these studies do not explain which specific processes of allergic inflammation are regulated by the miRNAs, such as antigen presentation by dendritic cells, the differentiation of naïve T cells, or the degranulation of mast cells, which are also the key points that should be analyses in future research.Previous studies have confirmed the differences in miRNAs expression in the nasal mucosa and mucus of patients with AR and genetic materials of sEVs, and the findings provide ideas for further experiments. However, based on the existing research on sEVs and miRNAs, they can be transmitted between cells, that is, through the blood, nasal mucosa, and nasal secretions. sEVs and miRNAs at the three positions can be transmitted to each other to regulate AR, but no studies have investigated these three positions simultaneously. Subsequently, nasal mucosa, nasal mucus, and even blood samples from patients with AR and NPs and the control group should be collected at the same time, and relevant miRNAs sequencing can be performed. The regulatory roles of miRNAs in AR and NPs may be further clarified by analysing the differences between the three groups. If some specific substances in an miRNAs or sEVs are specific or highly expressed in patients with AR or NPs, sEVs in nasal mucus can be effectively used in the diagnosis of AR and NPs as a noninvasive and quantitative index.If some studies clarify that the miRNAs or some sEV substances can treat AR or NPs, sEVs and miRNAs are expected to play a role in future targeted drug therapy due to their nanocarrier properties. AR and NPs can be effectively treated for a long time through sustained-release nanomaterials coated with the corresponding miRNA and sEVs. These ideas warrant clinical attention.


Augmented Reality (AR) and cyber-security technologies have existed for several decades, but their growth and progress in recent years have increased exponentially. The areas of application for these technologies are clearly heterogeneous, most especially in purchase and sales, production, tourism, education, as well as social interaction . Essentially, these technologies are recognized worldwide as some of the pillars of the new industrial revolution envisaged by the industry 4.0 international program, and are some of the leading technologies of the 21st century. The ability to provide users with required information about processes or procedures directly into the virtual environment is archetypally the fundamental factor in considering AR as an effective tool for different fields. However, the advancement in ICT has also brought about a variety of cybersecurity challenges, with a depth of evidence anticipating policy, architectural, design, and technical solutions in this very domain. The specific applications of AR and cybersecurity technologies have been described in detail in a variety of papers, which demonstrate their potential in diverse fields. In the context of smart cities, however, there is a dearth of sources describing their varied uses. Notably, a scholarly paper that consolidates research on AR and cybersecurity application in this context is markedly lacking. Therefore, this systematic review was designed to identify, describe, and synthesize research findings on the application of AR and cybersecurity for smart cities. The review study involves filtering information of their application in this setting from three key databases to answer the predefined research question. The keynote part of this paper provides an in-depth review of some of the most recent AR and cybersecurity applications for smart cities, emphasizing potential benefits, limitations, as well as open issues which could represent new challenges for the future. The main finding that we found is that there are five main categories of these applications for smart cities, which can be classified according to the main articles, such as tourism, monitoring, system management, education, and mobility. Compared with the general literature on smart cities, tourism, monitoring, and maintenance AR applications appear to attract more scholarly attention. Rapid technological advancement has taken place in the last decade, propelled by developments and advances in information and communication technologies (ICT). This has revolutionized the way people communicate, live, work, and travel, among other things. As a result, smart cities have emerged, evolving towards intelligent, dynamic infrastructures that serve civilizations while accomplishing the criteria of sustainability and energy efficiency . AccordiOne of the new technologies that are widely deployed and exploited within smart cities is Augmented Reality (AR), which, as noted by , can enhWith human perception regarding the environment increasingly changing with modern technology, AR becomes progressively prominent. Ref.  further The use of smart technologies such as AR, however, raises new issues and challenges. In smart cities, the vulnerable action of users and organizations can put the entire city at risk of cybercrimes. Ref.  notes thIn this work, an overview of AR applications in smart cities around the world is provided. The paper also investigates the topic of cyber-security for smart cities, demonstrating how specific aspects of smart cities give rise to cyber-security challenges in an augmented reality world. In other words, this article focuses on cyber-security risks that may affect data privacy and the outputs generated by the AR applications through the device, and how this could impact the implementation of AR technology in smart cities. The paper adopts a systematic literature review approach in order to achieve a comprehensive research synthesis on the basis of evaluation and analysis of literature under investigation in this study. In the end, it is believed that the findings of this study will have implications for academicians, practitioners, and societies at large. It also adds to the academic literature on the use of AR technology in the building of smart city infrastructure, where government officials and urban planners can use this technology to enhance cities’ environments, infrastructure, services, and the quality of life of urban dwellers.The study consists of six parts: Introduction, Smart City Concept, Methods, Results, Discussion, Conclusion and Future Work. The second chapter describes the concept, elements, and general structure of a smart city. The third chapter presents the methodology adopted in conducting the systematic literature review, including the search strategy and inclusion and exclusion criteria. The fourth chapter presents the results of the review, while the fifth presents the discussion. In the final chapter, the conclusion and future research are stated.As noted by researchers such as , smart cThe infrastructure of a smart city can create a unique collaborative system where citizens, educational institutions, industries, prosumers, and researchers can develop innovative products, services, and solutions. Contrary to traditional double-sided marketplaces, Ref.  argue thPresently, there are many existing urban projects that have been transformed to meet the aforementioned smart city criteria. Some projects have been developed from scratch, while others consist of the transition and modernization of existing cities into smart cities. As noted by , some ofIn order to achieve this study’s objectives, a Systematic Literature Review (SLR) methodology was followed. As pointed out by , the SLROne of the fundamental goals of this study was to be as inclusive as practically possible. However, the idea was also to obtain scholarly papers within the last decade to ensure that materials gathered were the latest, and coincided with the digital age and era of smart cities. As such, all papers published in journals and conferences between 2010 and 2021, which included the phrases ‘Augmented Reality for Smart Cities’ and ‘Cyber-security for Smart Cities’, and related user studies were considered. In the planning phase, some of the most utilized online scientific databases were used to search for peer-reviewed literature. Three relevant literature databases were selected, including Emerald Insight (EI), Science Direct (SD), and IEEE Xplore (IX). As research sources, these multidisciplinary databases were selected and recognized for their indexing and coverage. They were consulted, and subsequently, the results obtained were cross-checked. Furthermore, the databases used in these academic studies have met the protocol requirements and used protocol-specific parameters.The results from the search process were screened against pre-set inclusion and exclusion criteria, as mentioned in Among the exclusion criteria, this study excluded studies that only reported on AR and cyber-security initiatives in other contexts. Studies that did not mention AR or cyber-security in smart cities were also excluded. The same applied to studies that claim to report AR but referred to VR or mixed reality (MR) instead. Studies not considered as peer-reviewed journals, book chapters, or conference papers in the context of AR and cyber-security in smart cities were excluded.After performing the search based on the identified keywords, as shows in After further screening titles, abstracts, introductions, and conclusions, a further 105 studies were removed. Finally, following full-text reading and examination of each of 71 articles, a total of 31 studies met the criteria proposed and definition for inclusion in this review.This phase was a two-part process in which each individual article was analyzed to determine final inclusion into the SLR. To minimize bias, this process was conducted by two individuals, each screening articles independently. The initial part involved skimming through the title and abstracts, as well as introductions and conclusions, to determine whether the obtained articles were relevant in addressing this study’s research objective. The second stage involved skimming through and subsequently reading through full texts to obtain relevant data for SLR. In this stage, five QA criteria were developed to assess each study’s quality.Q1: what was the application area ?Q2: what was the type of data collected?Q3: what was the experimental design (methodology)?Q4: where was the research conducted (based)?Q5: what type of study was conducted ?In order to systematically and accurately record data based on these QAs, an excel spreadsheet was developed. During the review of the paper and data extraction, the researcher also flagged certain publications  for additional discussion and cross-referencing. The data extraction form only contained information relevant to this study for analysis and descriptive purposes (in the discussion chapter) later in the SLR.Since this SLR spans across a number of academic disciplines and fields, a thematic synthesis approach was adopted as the modulus of analysis. As discussed by , this apThe search process produced 31 studies that were included in the SLR. The ensuing sections in this chapter provide a summary of results according to the pre-stated data extraction criteria intended to fulfill this study’s research objectives. One of the findings is that most of the studies related to AR and cyber-security for smart cities contexts are mostly published in Science Direct (16) and IEEE Xplore (12). The third database for this investigation, Emerald Insight, only produced three results; two relating to AR and one to cybersecurity, under the researched contexts. The majority of included studies were published in 2019 (14). Of the rest, three were published in 2014, three in 2016, five in 2017, seven in 2018, and nine in 2020. Based on this SLR, the number of publications increased from 2014 to 2020. This drastic increase may have been caused by technological advances and the development of smart cities. Between 2018 and 2020, there is particularly a consistent number of publications related to AR and cybersecurity for smart cities. As highlighted in the subsequent sub-sections, AR and cybersecurity papers for smart cities are divided into various applications and relating aspects.Results under this segment indicate that the most discussed potential AR applications for smart cities are in various categories including, tourism, information dissemination, mobility, risk management, construction, education, energy management, and traffic monitoring. These application categories can be further grouped into five distinct classifications, including healthcare, robotics, public sector, tourism, (system) monitoring, (system) management, education, and mobility. Through this SLR, these categories have been critically compared based on aim, methodology, and chronological perspective. The results indicate that a number of AR application studies for smart cities focus on tourism and management/monitoring aspects comparing to other aspects.There is considerable consensus that AR allows for the simultaneous perception of the real environment and a virtual audio overlay. This is particularly vital in mobile applications, where users are continuously aware of their surroundings, such as in the case of urban smart and urban tourism, where travelers explore foreign sights and cities. Recent studies report that AR continues to become increasingly popular within the travel industry, especially because it enables attraction sites, hotels, and businesses operating in this industry to enhance physical environments while encouraging both local and international tourists to visit. As seen subsequently in the Discussion Chapter, previous studies in this area have shown that AR can be used in a variety of ways, including augmented reality gasification, beacon technology and push notifications, augmented reality destinations, and interactive hotel and attraction elements. However, AR application in tourism for smart cities is not well explored, and as such, publications relating to the same are limited. From database search, this study only obtained three studies: ,24,25.Ref. , in his Correspondingly, Ref.  believe In the third paper for AR application in tourism for smart cities in this study, Ref.  explore Performing monitoring and maintenance tasks in complex environments has long been shown to be challenging and difficult due to complexity, and possibly due to the use of multifaceted processes, heavy machinery, human factors, uneasy access, and underground facilities, among others. The underlying technology is often shown to be inefficient because of simultaneous supervision of people working together under extreme settings, missing multi-input interfaces, and significant delays in communication and data transmission. Recently, however, AR as a tool for information visualization is said to provide solutions to these issues, where real-time reports are essential for monitoring systems and aiding in decision making. This SLR identified two applications where this technology can be applied for smart cities. The first is the study of  that anaIn the second paper under this category, Ref.  explore This study identified four studies that examine how AR can be used in management systems in various areas, including rent management, emergency management, lighting system management, and energy management. In the first study under this set, Ref.  analyze Similarly, Ref.  illustraA wireless, AR-powered LED streetlight system with centralized and remote-control technology has also emerged as an innovative application for smart cities. In their study, Ref.  illustraThe search results also indicated that AR could be used in energy management for human-computer interaction in a smart city. Traditional energy management systems are often based on graphical and numerical values through monitor screens. Ref.  suggest The combination of educational content with AR technology to create a new type of automated applications and enhance the effectiveness and attractiveness of teaching, learning, and instruction has been explored widely in recent times. However, this exploration is yet to attract considerable attention under the smart city context. In fact, this study’s SLR only retrieved two studies from the selected databases that met the inclusion criteria. The first was that of  who atteIn the second paper under this category, Ref.  examine Mobility, although examined limitedly, is another area of application of AR in smart cities. This study only produced one study that explores this application in the smart city concept. Ref.  investigThe implementation of technologies such as AR and IoT in smart cities is normally hailed as the solution to numerous urban problems such as environmental protection, waste and energy management, and transportation. However, the implementation of these technologies is seen to be the source of numerous cybersecurity issues. Scholars agree that as smart cities become increasingly interconnected and the level of digital infrastructure becomes more complex, such cities will become more vulnerable to cyber-attacks. This SLR produces 17 publications that address the topic of cybersecurity for smart cities, with the majority of articles published in the Science Direct database. After reviewing the articles, the researcher classified the results under two main categories: challenges (issues) and opportunities (solutions).One of the key papers under this category is from the Oxford Analytica Daily Brief that analyses industrial , businesIn a systematic literature review, Ref.  also ideReference  provide Reference  also ideAlthough the exact shape that smart cities will finally take remains to be indeterminate, scholars agree that there needs to be a variety of precautions, interventions, and solutions to cyber threats to guarantee a smoother implementation process and, ultimately, more secure infrastructure. Some studies included in this SLR provide some solutions and applications that need to be implemented for smart cities to provide some form of security against cyber-criminal activities. For instance, Ref.  believe In their paper, Ref.  propose Reference  suggestsIn the context of smart city initiatives in different parts of the world, this SLR reveals that upcoming digital technologies such as AR play a fundamental role in the development of various systems and infrastructures. Indeed, several studies have already been conducted in this area with a keen focus on the application of AR in different areas, including tourism, management, monitoring, education, shopping, transportation, marketing, interior design, and smart parking. Although this exploration remains limited for smart cities, the study identified five main areas where recent scholars have investigated the application of AR for smart cities, including tourism, system monitoring, system management, education and instruction, as well as mobility (aid in movement). Under the tourism category, scholars such as ,24,25 hiFor example, in exploring the value of AR for tourism, Ref.  found fiThe SLR also discovered that AR could be effectively used for system management and monitoring. Studies included in this research, including ,28,29,30Education and training are other areas where AR can maximize the potential for smart cities. In this study’s SLR, Refs. ,31 highlThe last category, mobility, is also examined and reported by researchers studying the application of AR in differing frameworks. In the included study for this SLR, Ref.  revealedWhile technologies such as AR hold great promise for smart cities, the SLR also revealed great concern relating to cybersecurity. Included studies suggest that the interconnectedness of smart cities through advanced technologies gives room for cyber threats. It is suggested that lack of protection against these threats, poor understanding of social engineering, weaponized machine learning technologies by cyber-attackers, non-existent secure device onboarding services, poor encryption key management, as well as lack of cryptographic measures are some of the key issues that contribute to the intensification of cyber threats in smart city ecosystems. Studies included in the SLR, including ,36,37,38This SLR intended to address the study’s main topic: AR and cybersecurity for smart cities. In other words, it intended to investigate the application of AR in this context, and the cybersecurity issues that may arise as a result of the adoption of digital technologies. A review of the final 31 articles was then provided. Based on this review, the application of AR for smart cities can be categorized into five main classifications, including tourism, system monitoring, system management, education and instruction, and mobility (navigation). Tourism, monitoring, and maintenance AR application appear to attract more scholarly attention than education and mobility for smart cities, compared to the general literature on the topic. Regardless of attention, it is believed that a close connection between industry and academic fields is going to be connected. The adoption of these technologies and continued interconnectedness in smart cities is shown to give rise to a host of cybersecurity threats, with among them loss of privacy and confidentiality, physical threats, systems and applications vulnerability, malware injection attacks, denial of service (DoS), malicious insider threats, and data leakage. Solutions to these problems have been suggested by various researchers, but they remain inconsistent and widely unproven. Until now, the majority of studies have attempted to prove concepts rather than describe well-established analytical approaches. In the future, the need for more practical- and analytically based studies is emphasized in order to evaluate discussed hypotheses from this SLR in real smart city contexts.


Our analyses examined the extent to which the use of rehabilitation for patients with mental disorders decreased due to the COVID-19 pandemic in Germany.We used monthly cross-sectional administrative data on rehabilitation utilisation due to mental disorders in 2019 and 2020 and estimated a difference-in-differences model to determine the reduction in rehabilitation utilisation attributable to the pandemic.We included 151,775 rehabilitations in 2019 and 123,229 rehabilitations in 2020 in our analysis. The number of rehabilitations decreased from April to December by 14.2% due to the pandemic (March to December: 21.8%). The decline was more pronounced for women than for men and varied regionally. Temporal and regional differences in utilisation were moderately associated with the decrease in mobility in the pandemic year. In the first phase of the pandemic, i.e., March and April 2020, the decline was strongly associated with the regional incidence of SARS-CoV-2 infection.Due to the pandemic, significantly fewer rehabilitations due to mental disorders occurred in Germany in 2020 than in 2019. The likely increasing need for rehabilitation for people with mental disorders should be addressed by making rehabilitation access and delivery more flexible. The SARS-CoV-2 pandemic has posed major challenges to the care of people with mental disorders. Psychosocial and psychiatric care was reduced substantially around the world. Treatments were abruptly terminated, interrupted, or replaced by telemedicine care –3. ElectUnemployment and underemployment due to the pandemic, as well as financial worries, can also have a psychological impact . ExistinConsiderable restrictions on the care of people with mental disorders were observed in Germany. About half of the people with a current depressive episode reported constraints in medical care, including care by specialists and psychotherapists, during the first year of the pandemic . The inpIn addition to restrictions on primary care and outpatient and inpatient psychiatric treatment, potential effects on rehabilitation care and aftercare are relevant for people with mental disorders , 12. RehThe admission bans in many rehabilitation facilities introduced in spring 2020 had an immediate and direct impact on the utilisation of rehabilitation in Germany. However, the decline in utilisation of rehabilitation for mental disorders due to the pandemic has not been comprehensively described to date. Describing the decline is important for estimating unmet need during the pandemic and any additional treatment capacity that may be needed in the near future.We therefore compared the number of rehabilitations due to mental disorders performed in Germany in 2020 with the number performed in 2019, in order to clarify the extent to which utilisation of rehabilitations declined after the German Bundestag declared an epidemic situation of national concern on March 27, 2020. In addition, we analysed the differences in the decline in rehabilitation utilisation by gender and region. Furthermore, we examined possible correlations of the decline in rehabilitation utilisation with the observed mobility decline, the incidence of SARS-CoV-2 infections in Germany, and socioeconomic indicators.We used monthly cross-sectional data on rehabilitation of working aged people due to mental disorders performed in 2019 and 2020 for a difference-in-differences analysis , 15. PreIn Germany, rehabilitation of working aged people due to mental disorders is mainly provided by the pension insurance institutions. Rehabilitation is not prescribed by physicians or psychotherapists, but instead involves a request from the individual. Utilisation, therefore, depends on whether people with a need for rehabilitation decide in favour of or against an application , 17. TheComplete data on the use of rehabilitation due to mental disorders were provided by the German Pension Insurance, categorised by gender, state, and month of use, including rehabilitations starting and ending within 2019 and 2020. Regional population data were retrieved from the statistical information system of the Federal Statistical Office. We obtained the incidence of SARS-CoV-2 infections from the Robert Koch Institute reporting system. Mobility was captured through anonymised and aggregated mobile phone data. These data are also provided by the Federal Statistical Office, mapping the movements within a region based on switching between radio cells. Regional socioeconomic indicators (i.e. unemployment rates and net household income) were used from the statistical information system of the Federal Institute for Research on Building, Urban Affairs and Spatial Development.The rehabilitations provided were first presented descriptively by gender, state and month. Then, using a difference-in-differences model, we estimated the reduction in rehabilitation utilisation attributable to the pandemic , 20. TheIn addition to the difference-in-differences estimator for the total population, we also determined difference-in-differences estimators for men and women and for the different federal states. Regional differences in the decline in rehabilitations were presented using choropleth maps. For this purpose, the decline was categorised along quartiles. To test the association of decline in mobility and incidence of SARS-CoV-2 infections with rehabilitation utilisation decline, we calculated Spearman’s rho. To test associations of socioeconomic indicators with rehabilitation utilisation decline, we also calculated Spearman’s rho. We supplemented our analysis with a sensitivity analysis, for which we used a pre-observation period from January to February and a post-observation period from March to December. The two-sided probability of error was 5%. All analyses were performed using Stata/SE version 16.0.From January to December 2020, 126,512 rehabilitations were used due to mental disorders. In 2019, there were 154,427 rehabilitations. We excluded a total of 5,935 rehabilitations due to incomplete information on place of residence, place of residence abroad, or undetermined gender. Of the remaining 123,229 rehabilitations in 2020, 77,302 (62.7%) were for women. Of the remaining 151,775 rehabilitations in 2019, 96,127 (63.3%) were used by women.Compared with 2019, the nationwide decline in rehabilitations performed in the pandemic year 2020 peaked at 64.3% in April  for April to December . The monthly regional incidence of SARS-CoV-2 infections was associated with the decline in rehabilitations only in March and April .Regional unemployment rates in 2019 were not associated with the monthly decline in rehabilitations. However, a higher regional net household income in 2019 was associated with a stronger decline in rehabilitations in April 2020 .Our difference-in-differences analysis showed that the number of rehabilitations due to mental disorders decreased by 14.2% due to the pandemic for April to December. Our sensitivity analysis for March to December estimated a drop of 21.8%. The decline in utilisation was more pronounced for women. Temporal and regional differences in utilisation were moderately associated with the mobility decline in the pandemic year. We observed a strong association with regional incidence of SARS-CoV-2 infection in March and April.The decline in rehabilitations for patients with mental disorders that we describe, particularly in the spring of 2020, is consistent with the decline in inpatient and outpatient care observed in the United States , 24, FraIn addition, the general restrictions that have been gradually introduced in Germany to control the incidence of infections and individual concerns about infections are likely to have had an effect on postponing the visits to a physician that are required for a rehabilitation application. This is supported by the observation that a decline of a similar extent was noted for other care services for people with mental disorders . These aThe regional differences in rehabilitation decline, which we observed, were associated with mobility decline and the SARS-CoV-2 incidence. While we did not found associations with unemployment rates, our analyses demonstrated that a higher regional net household income was associated with a stronger decline in rehabilitations in April 2020. This finding reflects that the entry and spread of the virus in Germany began in the more prosperous western federal states of Germany (e.g. Bavaria and Hamburg). These states therefore responded earlier with constraints on public life explaining the initially greater decline in rehabilitations in these federal states.The results of the current analysis must be interpreted considering the following limitations. First, our analyses only describe the extent of the reduction. They do not enable us to explain why people decided to refrain from using rehabilitation. Temporal and regional differences in the decline in mobility and spread of infection could only partially explain the variance in the reduction in rehabilitation use. Second, the period we included in the analyses is limited to the first wave of the pandemic, the summer with very low infection rates, and the first part of the second wave. The extent to which the described decline continued during the second wave, over the turn of 2020/2021, and in 2021 can only be clarified with future data. Third, administrative data are not generated primarily for research purposes and are responsive to changes in administrative processes, for instance how an incident case is determined . Fourth,These limitations are balanced by the following strengths. First, we were able to use validated administrative and publicly available data on rehabilitation utilisation, incidence and mobility, and socioeconomics for our analyses. Underreporting, overreporting and misreporting of rehabilitation utilisation are unlikely because of the use of administrative data, except for the data used for December. Second, the difference-in-differences approach we chose allowed us to investigate declines due to the pandemic.For many people with a mental disorder in need of rehabilitation, not using rehabilitation increases the risk that their condition will persist or worsen. After the significant decline in rehabilitations in the spring of 2020, the number of rehabilitations increased again, but not to the extent that would be expected given unchanged disease burden or additional disease burden due to the pandemic. A rebound effect has not been observed so far. In view of the limited treatment capacities in rehabilitation centres for people with disorders, the increasing demand for people in need of rehabilitation due to postponement and abandonment, as well as new cases, is likely to lead initially to longer waiting times. Increasing the flexibility of treatment provision by making the duration of rehabilitation more flexible and expanding the digital treatment options developed and implemented during the pandemic could help to meet the expected increase in demand for rehabilitation for people with mental disorders. Future research should examine the gendered impact of the pandemic on access to health care and the long-term outcomes of unmet mental health care needs during the pandemic.


The feasibility of the proposed BCI-based RASRS was demonstrated through a use-case description with a timing diagram and meeting the crucial requirements for developing the proposed rehabilitation system. The use of a patient's intrinsic feedback mechanism will have significant implications for the development of human-in-the-loop stroke rehabilitation systems.Conventional rehabilitation systems typically execute a fixed set of programs that most motor-impaired stroke patients undergo. In these systems, the brain, which is embodied in the body, is often left out. Including the brains of stroke patients in the control loop of a rehabilitation system can be worthwhile as the system can be tailored to each participant and, thus, be more effective. Here, we propose a novel brain-computer interface (BCI)-based robot-assisted stroke rehabilitation system (RASRS), which takes inputs from the patient's intrinsic feedback mechanism to adapt the assistance level of the RASRS. The proposed system will utilize the patients' consciousness about their performance decoded through their error-related negativity signals. As a proof-of-concept, we experimented on 12 healthy people in which we recorded their electroencephalogram (EEG) signals while performing a standard rehabilitation exercise. We set the performance requirements beforehand and observed participants' neural responses when they failed/met the set requirements and found a statistically significant ( Thus, regaining control of the upper limb is significant for patients with quadriplegia   signal which elicits in the human brain, be it healthy people or motor-impaired stroke patients , would attempt to reach the target. Simultaneously, the EEG signals would be recorded from the patient's brain. If the patient fails to reach the defined target of the exercise, an ERN signal associated with the Training-ErrP signal will elicit in the patient's brain, which, from the patient perspective, would indicate that he/she has failed to complete the rehabilitation movement. Thus, on the ERN signal detection, the external assistance would be increased/triggered so that the patient can complete the rest of the rehabilitation exercise. In the trials of subsequent sessions, the exercise's difficulty level can be decreased through the exercise's target, or the fixed minimum assistance level can be increased, to adapt the rehabilitation system as per the patient's current motor impairment level.The control unit will process the EEG signals and the Kinect sensor's data in real-time, increase/decrease the assistance level of the rehabilitation robot, and adapt the exercise target level for every exercise trial, based on the detection of ERN signal and the past performances of the patient in performing rehabilitation exercises (tracked through the Kinect sensor).x in e1 in d1 in x+1 level  is decreased. In Trial 3, the patient further gets better in performing the rehabilitation exercise and performs almost the whole exercise with the minimum level of robotic assistance . The extent of the exercise completed is additionally verified with the Azure Kinect sensor's data. As a result, the ERN signal also elicits near the very end of the trial  age: 22.8 ± 3.2 years]. None of the participants had a BCI experience. The experiment was conducted at Shantou University, China. All participants voluntarily participated in the experiment and signed a written informed consent before the experiment started. The study was approved by the ethics committees of the 2nd Hospital of Jiaxing and the First Affiliated Hospital of Shantou University Medical College, China. The experiment was conducted by the declaration of Helsinki. One of the participants' data were not included in the analyses as the events information for his experiment went unrecorded due to a technical glitch in the EEG recording software.Participants sat on a chair facing a LED monitor with 1,920 × 1,080 resolution at a 60 Hz refresh rate. The experiment required participants to perform a standard Bobath's rehabilitation exercise involving shoulder flexion-extension while adjoining both hands. The experiment was conducted in a synchronous format, and the experiment instructions and cues were delivered using the LED monitor, in order, as shown in As shown in The duration given to the participants to complete the rehabilitation exercise varied from 2 to 15 s pseudo-randomly. Specifically, 2–4 s were given in 18 of the 48 trials, 9–10 s were given in four of the 48 trials, and 15 seconds were given in 26 of the 48 trials, to all participants to complete the rehabilitation exercise. These time-durations, together with the instructions given to participants on how to perform the exercise (described in the preceding paragraph), ensured that participants failed to complete the rehabilitation movement in the 2–4 s trials  and successfully completed it in 15 s trials . An exercise trial was marked as successful when a participant started performing the exercise on the onset of the screen as in The experiment procedure was explained to the participants, and sufficient time was given for practice before the experiment started. The experiment's visual stimuli were designed and delivered using the Presentation software .Thirty-two channels of EEG  were recorded using g.Nautilus  wireless EEG acquisition system, as per the international 10–20 system. Eight-pin g.SAHARA dry-active EEG electrodes mounted on a g.GAMMAcap were used for the EEG recording. All channels were referenced to the right mastoid and grounded to the AFz location. The EEG data were acquired at a 500 Hz sampling rate with a 50 Hz notch filter.The recorded raw EEG data were pre-processed offline before making any analysis. The MATLAB-based custom scripts and EEGLAB toolbox  was used for statistical analysis. Every participant's averaged ERN and CRA neural response was utilized for the statistical analysis, and it was tested if the amplitude of the ERN and CRA waveforms are significantly different from each other, or in other words, if the Training-ErrP signal is significantly different from zero. Based on previous knowledge, the ErrP signals have the highest activity around Fz and Cz electrodes; therefore, the statistical analysis was conducted on EEG signals at the Fz electrode location. The Monte Carlo cluster-based permutation test is widely used to address the multiple comparisons problem for electrophysiological data analysis , with radial basis function (RBF) kernel, was used to classify the ERN and CRA epochs. Before classification, the class weights of both classes were balanced based on the class frequencies in the input data. A 5-fold cross-validation was used to estimate the classification performance. In each fold, the parameters such as xDAWN spatial filter weight matrices and PCA weight matrices were calculated on the training data only, and the validation set was transformed using these weights. Accuracy, the area under the receiver operating characteristics curve (AUROC), and F1-score were used as performance evaluation metrics. A one-tailed Wilcoxon signed-rank test (exact method) was used to assess if the classification accuracy is significantly higher than the chance level accuracy calculated using the Zero Rule classifier. Zero Rule classifier always outputs the class that is in the majority in the training set, regardless of the input.ERN vs. CRA classification for classification. Therefore, the proposed ERN-RASRS requires detecting ERN signals against the background EEG activity in real-time and in a single trial. Here, the feature extraction steps followed were the same as the ones followed in ERN vs. CRA classification. The  ms interval relative to the error onset  was estimated. For bootstrapping, after selecting an epoch for validation, the training data epochs were randomly sampled with replacement from the rest of 179 epochs, which were repeated over 100 times.where M = −5.9, SD = 6.1), followed by a positive peak (peak-2) at 340 ms . Both the peaks were observed to be statistically significant (p < 0.05) after correcting for multiple comparisons , AUROC of 0.818 (SD = 0.029), and F1-score of 0.821 (SD = 0.025) were observed in ERN vs. CRA binary classification, using 5-fold cross-validation. The classification accuracy was significantly higher than the chance level accuracy , which was 0.604 and was obtained using the Zero Rule classifier. The row-normalized confusion matrix of the ERA vs. CRA binary classification is shown in A mean classification accuracy of 0.820 , voluntary physical efforts, and cognitive investment all play an important role in the rehabilitation but are rarely considered together. Rehabilitation therapies, such as constraint-induced movement therapy (CIMT), focus on voluntary physical efforts in a limited ROM (Abo et al., x and x+1 level, see x in On the other hand, ERN-RASRS promotes the balance between the ROM and the patients' voluntary movements with the impaired limb, and it can be utilized not only by patients with voluntary control of their impaired limb but also by patients with little to no voluntary movement. In ERN-RASRS, the balance between the ROM and the voluntary movements can be adapted to a patient by adjusting the level of external assistance (i.e., the The Training-ErrP signal observed in this study has a considerable difference from the ErrP signal observed in Kumar et al. , which cn to 2 or 3 has reduced the incorrect detection rate; however, the correct detection rate also dropped considerably, which reduced IDR. We explored various measures to increases the share of correctly classified trials, including the use of probability measures to increase the classifier's sensitivity toward the ERN class, which increased the number of correctly classified trials. However, the number of incorrectly classified trials also increased. A possible workaround for this issue is that, instead of relying on the raw timing of event d (i.e., when ERN signal is detected, see i in The classification approach used resulted in statistically significant ERN vs. CRA classification accuracy, in line with previously reported studies (Salazar-Gomez et al., This study observed a small detection performance of correctly detecting error trials against the background EEG signals, which can be considered a limitation of the current work. The issue can be mitigated by using exponential moving averages; however, greater accuracy is still required before using such a system outside the lab environment. Detecting brain signals against the background EEG activity is a classic problem due to the low signal-to-noise ratio of EEG signals. Nevertheless, it is expected that the classification performance can be improved by having a larger size of the Training-ErrP dataset and by using deep learning-based methods. In the future, we will further explore the experimental protocol, wherein patients would have greater autonomy to start and stop a rehabilitation exercise. Such protocol would require synchronization between Azure Kinect sensor and EEG data stream and the processing of the recorded data in real-time, which will be explored in the future. This study will form the basis of such an investigation. Notably, any variation in the task in the final RASRS setting can introduce variations in the ERN signal (Iturrate et al., This study proposed an error-related negativity-based robot-assisted stroke rehabilitation system, which uses ERN signals as a basis to increase/decrease the robotic assistance given to a patient to complete a rehabilitation exercise. Including a patient's brain in the control loop of a rehabilitation system is quite marked as it allows the use of the patient's intrinsic feedback mechanism for quick adaptation of the rehabilitation system without the presence of a rehabilitation doctor or therapist, which enables patients to carry out their rehabilitation treatment in an unsupervised environment. The present study has reported, for the first time, the design of the ERN-based RASRS and illustrated its working mechanism through a timing diagram. The study has further shown a distinguishable neural response when a participant fails to perform a rehabilitation exercise against when succeeds in a given time. The study has also demonstrated that these neural signals can be detected in a single trial, particularly against background EEG activity, which is crucial for developing the proposed rehabilitation system. In the future, after working on this studies' limitations, we will fabricate the ERN-RASRS and assess its efficacy against established rehabilitation therapies.The raw data supporting the conclusions of this article are available upon reasonable request from the authors.The studies involving human participants were reviewed and approved by the Ethics Committees of the 2nd Hospital of Jiaxing and the First Affiliated Hospital of Shantou University Medical College, China. The patients/participants provided their written informed consent to participate in this study.AK contributed to the idea formation, experiment design, data collection and analysis, result, discussion, and manuscript preparation. LG and JL contributed to ethics approval, participant recruitment, and data collection. JM and SM contributed to results, discussion, and manuscript preparation. JF and XG contributed to ethics approval and discussion. QF contributed to idea formation, experiment design, discussion, and manuscript preparation. All authors contributed to the article and approved the submitted version.This work was supported by the Li Ka Shing Foundation [Grant No. 2020LKSFG03C].JM is employed by OMRON SINIC X Corporation, Tokyo, Japan. The remaining 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.


A single-center study in New York estimated the rate of FFA to be 5.41 in 100,000.A 63-year-old woman presented with pigmentation and rhytides . The patThe aftercare routine consisted of 7 days of topical white soft paraffin and Cetaphil cleanser along with dressing and wound checks every 48 hours. On day 6, areas of erosion developed on the superior forehead, bilateral infraorbital areas, and superior lip and were extensively swabbed for bacteria and viruses, the results of which were all negative. Complete re-epithelialization was achieved by day 12, with residual erythema settling in the next 5 weeks .2 laser  treatments followed by topical triamcinolone suspension (40 mg/mL) under 3-hour occlusion. Methylprednisolone aceponate ointment was prescribed for pulse regimen twice daily for 3 consecutive days with 4 rest days. Silicone gel was applied to the perioral area for the thickest scars 3 times a day.Extensive global scarring over the treatment fields was noted at 7 weeks, with the most extensive involvement in the forehead and perioral area. Scar revision protocols were commenced, involving 3 weekly nonablative low-density COSixteen weeks after the initial resurfacing procedure, the complete resolution of scarring was achieved , with no,FFA is a challenging entity, with a marked increase in incidence in the past years.,The pathogenesis of FFA remains complex and not fully understood.,Ablative laser therapy achieves its effect through the ablation of the full-thickness dermis and the subsequent re-epithelialization.,2 laser, as the healing process did not require follicular stem cells.The pathogenesis of FFA and the biology of re-epithelialization in wound healing offers a potential explanation for the extensive facial scarring after ablative laser therapy. The re-epithelialization process requires new cells to replace the lost keratinocytes from the initial injury; lineage tracing studies on both human and animal skins have demonstrated the role of hair follicle stem cells in optimal wound healing.FFA is a condition of scarring hair loss, with an increasing incidence being reported in the current literature. It is often a clinical diagnosis and has several distinct clinical features to guide the clinician toward a diagnosis. Laser procedures are increasingly common, with evidence-based efficacy and safety. In this article, we have presented the first known case, to our knowledge, of extensive facial scarring in a patient with undiagnosed FFA after an ablative erbium laser resurfacing procedure. We hope to illustrate the importance of recognizing FFA, or scarring alopecia in general, in patients presenting for laser therapy and avoiding ablative procedures to avoid potentially serious complications that may lead to potentially serious scarring.None disclosed.


Zingiber officinale) that has been shown to lower blood sugar levels, because it possesses antioxidant properties and it functions as an antioxidant in the complicated biochemical process that causes hyperglycemia to be activated. Gingerol not only helps in treating hyperglycemia but also shows effectivity against diseases related to it, such as cardiopathy, kidney failure, vision impairments, bone and joint problems, and teeth and gum infections. Moreover, fresh ginger has various gingerol analogues, with 6-gingerol being the most abundant. However, it is necessary to investigate the efficacy of its other analogues against hyperglycemia and associated disorders at various concentrations in order to determine the appropriate dose for treating these conditions.Hyperglycemia is seen in approximately 68 percent of patients admitted to a medical intensive care unit (ICU). In many acute circumstances, such as myocardial infarction, brain, injury and stroke, it is an independent predictor of mortality. Hyperglycemia is induced by a mix of genetic, environmental, and immunologic variables in people with type 1 diabetes. These factors cause pancreatic beta cell death and insulin insufficiency. Insulin resistance and irregular insulin production cause hyperglycemia in type 2 diabetes patients. Hyperglycemia activates a number of complicated interconnected metabolic processes. Hyperglycemia is a major contributor to the onset and progression of diabetes’ secondary complications such as neuropathy, nephropathy, retinopathy, cataracts, periodontitis, and bone and joint issues. Studies on the health benefits of ginger and its constituent’s impact on hyperglycemia and related disorders have been conducted and gingerol proved to be a potential pharmaceutically active constituent of ginger ( Gingerol is the most active and abundant component of ginger. The therapeutic effects of ginger are attributed to a mixture of gingerol derivatives known as 6-gingerol, 8-gingerol, and 10-gingerol, which are responsible for ginger’s moderate pungency ,3. GingeIn both adults and children, hyperglycemia is a regular occurrence in the intensive care unit, and it has been associated with poor outcomes . It has Research has been done in this context to examine gingerol’s role as an anti-hyperglycemic and therapeutic agent against diseases caused by hyperglycemia. In a 2021 study by Almatroodi et al. , treatmePrevious research on ginger found that it has a renoprotective effect by regulating lipid peroxidation and maintaining histopathological alterations. In diabetic rats, ginger has a shielding effect against kidney impairment. Furthermore, after therapy with ginger, histological investigation revealed that diabetes-induced glomerular degenerative alterations were reduced. The effects of ginger powder on diabetic nephropathy have been assessed using antioxidant capacity and lipid peroxidation measurements. Ginger reduces lipid peroxidation, and reduces renal nephropathy, according to this study ,21.In short, gingerol is one of the most efficient compounds for treating hyperglycemia and the numerous catastrophic disorders that follow from it. It offers tremendous promise in the realms of human health care and treatment of illness. In this context, we wanted to assess the progress made in the use of gingerol as an anti-hyperglycemic molecule, as well as its influence on other disorders linked to it.J. C. Thresh isolated gingerol from the ginger plant’s rhizome in 1879 . In 1917More than 70 analogues of gingerols have been discovered thus far . GingeroIt is easy to convert 6-gingerol to (S)-.Hyperglycemia is derived from the Greek words hyper which means “high” and glykys which means “sweet/sugar” and haema which means “blood”. Hyperglycemia is defined as blood glucose levels of more than 125 mg/dL when fasting and more than 180 mg/dL 2 h after eating ,34. In tUntreated hyperglycemia can lead to a variety of potentially life-threatening problems, including impairment to the eyes, kidneys, heart, vascular system, and nerves ,37,38. HAs mentioned earlier, gingerol is known for its high potential antioxidative properties, and these properties are majorly responsible for the prevention and cure of a number of diseases. Masuda et al. 2004 found that gingerol has antioxidant and anti-inflammatory properties . Ginger The capacity of the phenolic molecule to receive electrons and serve as a free radical scavenger by forming a stable phenoxyl radical may be connected to its antioxidant characteristics ,46. PatuAccording to Kuhad et al. , 6-gingeAccording to the International Diabetes Federation, there are currently 382 million individuals living with diabetes, and this number is expected to rise to 592 million by the end of 2035  DiabeticP 0.01) [Oxidative stress is a key factor in the progression of hyperglycemia, and gingerols can play a very important role in fighting against oxidative stress ,61. It hP 0.01) . In addiP 0.01)  reportedAbnormal regulation of lipid glycometabolism is one of the causes of hyperglycemia . DiabetiYu et al.  found thBy modulating inflammation, oxidative stress, metabolic anomalies, and cellular death pathways, Yu et al.  hypothesDiabetic nephropathy (DN) is among the very common microvascular concerns resulting from long-term hyperglycemia ,80. PersSome issues, such as negative outcomes and inability to manage blood glucose levels, seriously restrict the therapeutic efficacy of such medications ,90,91. MAccording to Almatroodi et al. , treatmeFurthermore, it has been found that gingerol improves the state of renal tissue by altering p38MAPK and NF-κB activity, as well as controlling inflammatory reactions and oxidative stress . It has Diabetic retinopathy (DR) is the most prevalent microvascular consequence of long-term hyperglycemia and the primary cause of vision impairment and blindness in adults all over the world. The overall prevalence of DR is 34.6% and vision-threatening DR has a prevalence of 10.2% . A groupThe function of AGEs in diabetic vascular damage has been hypothesized. Inflammation, which is thought to be the major driver in the pathogenesis of DR, is exacerbated when AGEs are exposed to retinal vascular endothelial cells . ImproveIn the retinas of 6-gingerol-treated rats, Dongare et al.  found anBy regulating NF-κB expression and lowering the expression of pro-inflammatory cytokines, gingerol can help to prevent retinal damage caused by hyperglycemia. The blocking of the AGE/RAGE/NF-κB pathway is thought to be the cause of zerumbone’s impact .Clouding of the ordinarily clear lens of the eye can lead to blindness . AGE proAccording to Li et al.  althoughGinger might help in the therapy of musculoskeletal problems . OsteoarOne of the most important components of inflammation is 5-lipoxygenase, and lowering this factor helps to reduce inflammation. According to Flynn et al.  gingerolThe therapeutic efficacy of crude extract was compared to that of gingerol and its derivatives, a phytochemical ingredient. It was discovered that specific phytochemicals had a significant impact. Surprisingly, the crude extract that included essential oils and more polar chemicals had greater anti-inflammatory and anti-bone-degeneration properties. It was observed that non-gingerol substances, as well as gingerol, exhibited significant anti-arthritic efficacy. Another study, by Sharma et al., found that ginger oil had powerful anti-arthritic and anti-inflammatory properties . SrivastLantz et al. also found gingerols to have potent anti-inflammatory effects, but they focused on its ability to suppress LPS-induced COX2 expression . Pragasa+2 influx and altering mitochondrial membrane potential. As a result, inducible nitric oxide synthase and TNF-α expression were lowered and inflammation was reduced. Moreover, 1-dehydro-10-gingerdione has been identified an important anti-inflammatory, reducing the NF-kB-controlled expression of inflammatory genes linked to innate immunity through toll-like receptors (TLRs) [Further research has been done on how to reduce chronic inflammation or arthritis swelling before it leads to extensive and irreparable bone loss. Lee et al.  found ths (TLRs) . In thiss (TLRs) .Periodontitis is a condition that develops as a result of localized infections in the oral cavity that permanently destroy the mechanism of attachment of the tooth via the root cementum, peripheral ligament, and alveolar bone. Over time, the delicate gums and bone that surrounds the teeth disintegrate. This may result in tooth loss .Hyperglycemia appears to be a risk factor for greater periodontal damage, although treating periodontitis can also help with glycemic management. Hyperglycemia and periodontitis have a bidirectional relationship, according to epidemiological data. Hyperglycemia can affect microbial assemblages in the subgingival space, disrupt functions inside the cell, and modify the metabolism of collagen. The production of AGEs can alter the extracellular matrix further and receptor binding in cells can exacerbate inflammation. Further, periodontitis causes hyperlipidemia and insulin resistance .Dental researchers are fully aware of the high frequency of periodontitis in people with hyperglycemia. Periodontal disease has been associated to the generation of proinflammatory mediators connected to hyperglycemia  .Gingerol-related components have been shown to prevent the proliferation of germs in the mouth linked with chronic peritonitis in the human oral cavity . Javid eGinger’s medicinal potential as an antioxidant with anti-inflammatory, anti-hyperglycemic, and anti-cancer properties has been extensively researched and published. Almost all published studies concern whole ginger extract. However, there are few investigations into the function of gingerol in hyperglycemia. Furthermore, research shows that 6-gingerol is the form of gingerol most commonly utilized to treat hyperglycemia and associated disorders. Other variants of gingerol, such as 4-gingerol, 8-gingerol, 10-gingerol, and 12-gingerol, should be investigated for their potential medicinal use in the treatment of hyperglycemia . FarjrinGingerol is chemically linked to capsaicin, the fiery component found in chili peppers, and piperine, a substance found in black pepper. Its natural antioxidant properties are behind its extreme potency in preventing and curing a variety of ailments. It is a possible medication for hyperglycemia and its resultant potentially morbidity-causing disorders, such as cardiomyopathy, nephropathy, retinopathy, cataract, bone and joint problems, and periodontitis. It does so by modulating inflammation, oxidative stress and metabolic anomalies. It has also been shown to prevent the growth of oral bacteria connected to chronic peritonitis in the oral cavity. Studies have been conducted in this area, although the majority are focused on 6-gingerol, the most prevalent component of ginger, which shows considerable promise in the treatment of hyperglycemia and the diseases that accompany it. Clinical trials are, however, needed to prove gingerol’s medicinal effectiveness.


We further establish the selectivity profile of the cyclic peptide for UCH-L5 compared to other members of the UCH-DUB family and other cysteine DUBs in cell lysate. Furthermore, the cyclic peptide infiltrated cells resulting in the accumulation of polyUb chains, and was found to be non-toxic at the concentrations used here. Taken together, our data suggest that the cyclic peptide permeates the cell membrane, inhibits UCH-L5 by possibly blocking its deubiquitinating function, and contributes to the accumulation of polyubiquitinated substrates. The implications of inhibiting UCH-L5 in the context of the 26S proteasome render it an attractive candidate for further development as a potential selective inhibitor for therapeutic purposes.The ubiquitin-proteasome system is an essential regulator of many cellular processes including controlling protein homeostasis. The degradation of proteins by the multi-subunit proteasome complex is tightly regulated through a series of checkpoints, amongst which are a set of deubiquitinating proteases (DUBs). The proteasome-associated DUBs, UCH-L5  and USP14 (Ubiquitin-specific protease 14), and the integral-DUB in the proteasome, Rpn11, is known to regulate proteasomal degradation by deubiquitination of distinct substrates. Although selective inhibitors for USP14 and Rpn11 have been recently developed, there are no known inhibitors that selectively bind to UCH-L5. The X-ray structure of the Ubiquitin (Ub) bound to UCH-L5 shows a β-sheet hairpin in Ub that contains a crucial hydrophobic patch involved in the interaction with UCH-L5. Herein, we designed and developed both a Ub sequence-based linear- and cyclic- β-sheet hairpin peptide that was found to preferably inhibit UCH-L5. We show that these peptides have low micromolar IC Ubiquitination is a crucial post-translational modification (PTM) involved in various cellular processes , tightlyGiven the highly promiscuous nature of proteasomal degradation, the 26S proteasome is tightly regulated by kinases, phosphatases, and deubiquitinases amongst others . The 26SAberrant proteasome-mediated degradation is one of the hallmarks of cancer progression . Targeti3CN (0.1%). Data processing was performed using Waters MassLynx 4.1 software. Preparative HPLC was performed on a Waters XBridge™ Prep C18 Column  at a flow rate of 37.5 ml/min using aq. 0.05% TFA (Solvent A) and acetonitrile containing 0.05% TFA (Solvent B) as eluents. For purification of peptides, a gradient from 25% B to 95% B over 18 min was used. All samples containing pure peptides were pooled and lyophilized.All commercial materials  were used without further purification. All solvents were reagent grade or HPLC grade. LC-MS analysis was performed on a system containing a Waters 2795 separation module (Alliance HT), Waters 2996 Photodiode Array Detector (190–750 nm), Phenomenex Kinetex XB-C18 (2.1 × 50 mm) reversed-phase column, and a Micromass LCT-TOF mass spectrometer. Samples were run at 0.80 ml/min with the use of a gradient of two mobile phases: A) aq. formic acid (0.1%), and B) formic acid in CHN,N-Diisopropylethylamine (DIPEA) were used accordingly. Linear Ub1-17 peptide was synthesized on H-Rink amide Chemmatrix® resin (Sigma-Aldrich), and the N-terminus of this peptide was capped with an acetyl group using acetic anhydride. After synthesis, the peptide was completely deprotected using Trifluoroacetic acid (TFA) cleavage mix for 2 h (TFA: H2O: Triisopropylsilane (TiPS): Phenol (92.5/2.5/2.5/2.5 v/v/v/v)). The cyclic peptide Ub1-17 was synthesized on TentaGel Trt R resin with a free N-terminus. Immediately after synthesis, the cyclic peptide was cleaved from the resin using Hexafluoroisopropanol (HFIP) in Dichloromethane  so that the side chains remain protected while the N- and C-terminus are liberated. Cyclization was carried out using 1.2 equiv. PyBOP, 1.4 equiv. DIPEA in Dimethylformamide (DMF) at a peptide concentration of 0.5 mg/ml, overnight at room temperature. After cyclization, the peptide was completely deprotected using the same TFA cleavage mix used for the linear peptide. Following deprotection, the peptide was precipitated in the cold ether:pentane (v:v 1:1) and lyophilized. The peptides were then dissolved in aqueous Dimethylsulfoxide  and purified twice using preparative RP-HPLC. All purified peptides 1, 2, and 3 were lyophilized and dissolved in DMSO before being stored at -20°C.SPPS was performed on a Syro II MultiSyntech Automated Peptide synthesizer using standard 9-fluorenylmethoxycarbonyl (Fmoc) based solid-phase peptide chemistry at 20 µmol scales. All amino acids were used in 5-fold excess and coupling mix containing Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) and Circular Dichroism (CD) was measured on a JASCO CD J1000 spectrometer. Samples were diluted in 20 mM Tris.HCl, 20 mM NaCl pH 7.4, to a final concentration of 4 μM. Measurements were performed at 25°C using wavelengths ranging from 185 to 260 nm in a span of 100 mdeg at a scanning speed of 20 nm/min. Measurements from 10 experiments were accumulated. CD plots were drawn based on the observed values of CD measurements and concentrations used in measurements.50 assay for Rpn11, we set up a Fluorescent Polarization (FP) assay using 2 µM Ub-FP substrate in an assay buffer containing 50 mM HEPES.NaOH, 100 mM NaCl, 100 mM KCl, 1 mg/ml CHAPS and 0.5 mg/ml BGG at pH 8.0 . The parent enzyme stock of UCH-L5 was diluted into the assay buffer at a final concentration of 1 nM. For UCH-L1, UCH-L3 and BAP1, the final enzyme concentration was 100 pM, 20 pM, and 1 nM, respectively. Rpn11 was expressed in-house as a heterodimeric Rpn11/Rpn8 complex and used at a final concentration of 1 µM  and boiled before running on 4–12% SDS-PAGE agarose gel using MOPS buffer. A fluorescence scan was made of the gel on a Typhoon FLA 9500  using filters set for Cy5 (λex/λem 640/680 nm) or Rhodamine (λex/λem 480/520 nm). Coomassie staining was carried out using InstantBlue™ Protein Stain (Sigma-Aldrich).Recombinant UCH-L1, UCH-L3, UCH-L5, and BAP1 were diluted at a concentration of 1 μM in a labeling buffer containing 25 mM Tris pH 7.5, 100 mM NaCl, and 5 mM DTT. For the UCH-L5 competition assay, cyclic peptide http://www.addgene.org/19415/; RRID: Addgene_19415 ) by incubating them in a cold room for 30 min. Lysed cells were centrifuged at 20,000 rcf for 20 min at 4°C. Cyclic peptide 2 was added to cell lysate at different concentrations ranging from 0.2 to 100 µM and incubated for 60 min at 37°C. Subsequently, 0.5 µM of fluorescent Cy5-UbVME probe was added and incubated for 5 min at 37°C. The reaction was stopped by the addition of reducing sample loading buffer  and boiled before running on 4–12% SDS-PAGE agarose gel using MOPS buffer. A fluorescence scan was made of the gel on a Typhoon FLA 9500  using filters set at 600 nm (excitation wavelength) and 640 nm (emission wavelength). Following the fluorescent scan, proteins transfer to the nitrocellulose membrane. Endogenous UCH-L5, HA-UCH-L5, and actin (as a loading control) protein levels were analyzed by western blotting using rabbit anti-UCH-L5 , mouse anti-HA  and mouse anti-β-actin  antibodies as primary antibodies. IRDye 680LT goat anti-rabbit IgG (H + L)  and 800CW goat anti-mouse IgG (H + L)  were used as secondary antibodies. The signal was detected using direct imaging by Odyssey® CLx Infrared Imaging System (LI-COR).MCF7 cells were seeded into a 10 cm dish. The next day cells were transfected with HA-UCH-L5 plasmid  by usin2 at 5 μM, 10 μM, and 25 µM final concentrations for 24 h, 1 µM final concentration of bAP15 (UCH-L5 and USP14 inhibitor) for 3 h  antibody . Mouse anti-β-actin  was used to detect actin as a loading control. 800CW goat anti-mouse IgG (H + L)  were used as secondary antibodies. The signal was detected using direct imaging by Odyssey® CLx Infrared Imaging System (LI-COR). The experiment was repeated in triplicates. The total amount of ubiquitinated substrates and the actin level was quantified using Licor Image studio densitometry software, and the total level of ubiquitinated substrates was normalized to the actin level.MCF7 cells were seeded in 6-well plates 24 h before incubation with peptide  for 3 h  or 5 µM  for 3 h . DMSO wa2 at the indicated final concentrations for 24 and 48 h. DMSO was used as vehicle control. Cell viability was determined by using the CellTiter-Blue® Reagent assay . CellTiter-Blue® Reagent is added directly to each well in 1:20 dilution, MCF7 cells were incubated at 37°C to allow cells to convert resazurin to resorufin. The fluorescent signal was measured at λex/λem 560nm/590 nm.MCF7 cells were seeded at a density of 5,000 cells/well on a 96-well plate 24 h prior to incubation with peptide t-test (two-tailed distribution). * indicates significant differences as followed *p < 0.05, **p < 0.01, and ***p < 0.001 while ns shows not significant). All error bars correspond to the mean ± SD.Statistical evaluations report on Student’s in-vitro when tested in Ub-based fluorescence assays. In cells, Rpn13 was shown to augment the activity of UCH-L5 by providing additional recognition elements of Ub thereby reorienting the C-terminus of Ub into the active site of UCH-L5. On the other hand, INO80G completely abolishes the deubiquitinating activity of UCH-L5 by mimicking Ub and blocking the Ub binding site , we designed a cyclized β-sheet peptide (2) that is known for its resistance to intrinsic exopeptidase activity in cells  was prepared uneventfully with a yield of 24% after HPLC-purification carrying an acetyl group on the N-terminus and a carboxamide on the C-terminus. The cyclic version of the peptide (2) and the control peptide (3) were generated by coupling the N-terminus of Met1 to the C-terminus of Val17 from the fully-protected synthetic peptide using PyBOP and DIPEA in DMF at a lower concentration to avoid intermolecular couplings , while BAP1 is inhibited three times less efficiently than UCH-L5 (IC50 = 6.8 µM). UCH-L1 activity is completely unaffected even at the highest concentration of 100 µM of the cyclic peptide. Hence we concluded that among the other members of the UCH family, the cyclic β-sheet peptide 2 inhibits UCH-L5 most efficiently.UCH family consists of four DUBs, namely UCH-L1, UCH-L3, UCH-L5, and BAP1, which share a common UCH domain and similar binding pocket for Ub . To checho assay . The cyc2 inhibits the activity of Rpn11, the metalloprotease DUBs found in the 19S cap of the 26S proteasome, we carried out a standard fluorescence polarization assay using a Ubiquitin-Fluorescence Polarization (Ub-FP) substrate containing Ub linked by an isopeptide bond to a TAMRA-labelled Ub peptide, comprising residues 41 to 54 of Ub  for an hour at 37°C, followed by 5 min incubation with a Cy5-UbVME probe. The bands observed in the fluorescent scan represent the active DUBs in the cell lysate, and the disappearance of the fluorescent band can indicate the inhibition of any DUB activity upon treatment with peptide 2. We observed the disappearance of HA-UCH-L5 and endogenous UCH-L5 in the immunoblot ubiquitinated substrates similar to that of the previously reported non-specific UCH-L5 inhibitor.Taken together with the previous data from ICThe 26S proteasome is a strategically important complex both in the context of diseases and therapeutic intervention. Many drugs targeting the 26S proteasome have ended up as an effective treatment for diseases such as cancer . A well-The 26S proteasome is a huge protein complex consisting of many checkpoints to regulate its activity, including the three DUBs associated with it. Although the structure of the 26S proteasomal complex has been elucidated, the exact mode of action of these associated DUBs is a constant subject of debate . A few s