Approximately 80% of people with a disability live in developing countries, where they face multiple challenges in rehabilitation. The goal of the study was to conduct an analysis of indoor rehabilitation programs based on the demographics and medical conditions of the admitted patients and to relate to the available basic health and rehabilitation facilities.This was a mixed method study conducted in an inpatient rehabilitation ward of a tertiary level academic university hospital in a developing country. All admitted patients who stayed for a period of minimum two weeks were included in the study. Demographic and clinical data were obtained by means of a retrospective medical record review utilizing a standardized data extraction form. The study was further strengthened by an online literature search for the available documents for analysis, relation, and discussion.Among the 1,309 admitted patients was male- female ratio was 10:7, with the majority (31.4%) cases falling between the ages of 46 and 60yrs. Rehabilitation outpatient department was the principal mode of admission (78%), and musculoskeletal and neurological conditions represented the maximum number (79.8%). Majority of patients (60.8%) were discharged home on completion of the rehabilitation program with a large number of patients who were absconded. Poor health budget allocation and lack of prioritization of the rehabilitation sector face multiple challenges, including the rehabilitation team functioning resources, space crisis for expansion which was further impacted by the COVID-19 pandemic.The country's current health-related rehabilitation process and socio-demographic variables have a negative relationship. There was a large number of missing data in the medical records and many patients were lost prematurely from the indoor rehabilitation program. Musculoskeletal disorders were common, and the majority of patients were discharged home once the program was completed. The World Health Organization (WHO) defines rehabilitation as a combination of interventions meant to improve functioning and decrease impairment in people with health complications . In someHealth-related rehabilitation is beneficial for all age groups to become independent of daily living activities. Physical rehabilitation is vital for patients to regain maximum function, and many of the attending patients, including stroke, spinal cord injury, traumatic brain injury, sports trauma, and postsurgical conditions, require a period of comprehensive rehabilitation in an indoor facility .Health care professionals, health care facilities, medicine devices, and other technologies, including information systems and financing, are the five fundamental components for high-quality health services .Following admission to a postacute rehabilitation care facility, where rehabilitation services are provided by a team of skilled professionals, it can help achieve the best possible outcome, preventing complications, facilitating recovery, optimizing medical therapy, and lowering healthcare costs . When paAccording to a recent survey in Bangladesh, 3.29% of men and 2.34% of women in the country have some form of disability, and most of them are physically challenged .Earlier studies of an indoor rehabilitation service described the clinical profiles of disability conditions being managed from a developing country's perspective . Few stuObjectives: To present an analysis of the indoor rehabilitation programme and to relate the findings to the basic sociodemographic and rehabilitation status of Bangladesh.Study design: a mixed-method study comprising a cross-sectional study and a literature review. The online literature search was conducted using PubMed, Google scholar, and Banglajol with the key words “Inpatient Rehabilitation”, “Bangladesh”, “Rehabilitation”, and “Developing Country” for the available documents for analysis and discussion.Setting: The cross-sectional study was done in the PMR inpatient rehabilitation wards of BSMMU—a tertiary-level academic university hospital in Dhaka city during the period of June 2015 to December 2019.Demographic and clinical data were obtained by means of a retrospective medical record review utilizing a standardized data extraction form with institutional ethical board permission. All admitted patients, both male and female, who stayed for a period of a minimum of two weeks were included in the study. Subjects who expired, could not complete the 2-week rehabilitation program, or who had an incomplete data set were excluded from the study.Data was compiled and coded in SPSS Version 26 and analysis was done through quantitative approaches. Descriptive statistics were calculated. Categorical variables were tabulated asfrequencies and percentages and continuous variables as mean, medians, and standard deviations (SD). Prior to the main analysis, the dataset was assessed for non-normality. The results were expressed as frequency, mean, and percentage in tables, graphs, etc.A total of 1,309 patients were admitted to the rehabilitation ward between June 2015 and December 2019. There were 770 males and 539 females with a male-to-female ratio of 10:7.The rehabilitation outpatient department (OPD) was the most common mode of admission (78%), and the majority of patients (60.8%) were discharged home following a period of rehabilitation. There is a wide gap in information about the health and rehabilitation sector in general. Poor health sector budget al.location and lack of prioritization of the rehabilitation sector face multiple challenges, including the rehabilitation team's functioning resources, infrastructure, and settings, which were further impacted by the COVID-19 pandemic. Basic health and rehabilitation indicators are placed in BOX 1–*Bangladesh – LMIC in South Asia–2population- 168,500,000, population density −1265/km–median age 27.6 years and life expectancy 72.59 years–Per capita health care spending −42 US Dollar with 70% out of pocket expenditure–Hospital Beds −08 hospital beds per 10,000 population–Doctors and Nurses – 0.5 doctors and 0.2 nurses/1,000 people–6.8 rehabilitation unit/million people–Rehabilitation Physicians- Total 250–*Premedical staff including rehabilitation therapists −9.4 PT, 1.3 OT, 0.9 SLT, 0.2 P&O/million people*LMIC-Lower-Middle -Income Country, PT-Physiotherapist, OT-Occupational Therapist, SLT-Speech language therapist and P&O-Prosthetics and orthoticsThe WHO Rehabilitation 2030 initiative expects rehabilitation should be available at all stages of life and builds a comprehensive rehabilitation service delivery model to achieve equitable access to quality services . HoweverOut of 1,309 patients, 1,023 (78.1%) patients were admitted through PMR OPD , primariThe main goal of a course of inpatient rehabilitation is to discharge the patient back home or to the community. In this study, most of the patients (68.8%) were discharged home  and 14 pOf the 727 patients examined for the broad heading diagnosis and clinical conditions, more than one-third (37.3%) of the subjects were admitted with a diagnosis of musculoskeletal (MSK) disorder , althougThe length of stay and rehabilitation outcomes at a rehabilitation facility are largely governed by multiple factors , 30. In The barriers and challenges for inpatient rehabilitation of this LMIC rehabilitation facility were summarized in Box 2.BOX 2–timely referrals from acute care facilities–rehabilitation team member constraints and team management difficulties–a massive workload–a lack of adequate time allocation for individualized or group therapy–no insurance and universal health coverage.The current national health-related rehabilitation process and socio-demographic variables have a negative relationship. OPD provided the main source of inpatient rehabilitation. Despite a large number of missing data, MSK conditions constituted the maximum number, and the majority of the patients completed two-week programs and were discharged home. The study provided an overview of inpatient rehabilitation in an LMIC setting, which might be useful for setting rehabilitation goals and administering rehabilitation therapy modalities. and facilitating discharge planning. Indoor rehabilitation should align with the national model of health care. Further research at a multicenter based in a cross-cultural rehabilitation setting is recommended.The principal limitation of the study was a failure to retrieve a large number of participants' information on different characteristics, including mode of admission and discharge, and clinical characteristics.


National holidays are associated with high mortality in some diseases, but little is known about patients undergoing peritoneal dialysis (PD). The research aimed to investigate the impact of national holidays on the health outcomes of PD patients.Over ten years, all episodes of unplanned hospitalization, death, and peritonitis in PD patients were collected in our center. Seven national holidays in China were chosen, and non-holiday days were selected as the control period. The effect of national holidays was observed by comparing the hospitalization, death, and peritonitis rates between holiday and non-holiday groups.p = 0.175). So is the death rate  and peritonitis rate  between the two groups. Significant differences were observed in the distribution of peritonitis causes between the two groups (p = 0.017). The rate of secondary to other infections in the holiday group was significantly higher than in the non-holiday group .There were 297 events in all holiday periods and 1247 in non-holiday periods. There is no significant difference in hospitalization rate between holiday and non-holiday groups (32.4% ± 6.4% vs. 29.2% ± 3.4%, Our study suggested no national holiday effect on health outcomes of PD patients based on ten-year data in our center. A CanAlthough few studies focused on the ‘holiday effect’ on chronic diseases, the results were inconsistent. A study on patients with type 1 diabetes showed that their adherence to metformin was reduced during South Australian official public holidays, resulting in a higher hospitalization rate and mortality rate . HoweverPD patients need regular follow-ups and guidance to prevent and control medical negligence and complications ,11. DecrIt is a retrospective study on PD patients in the Department of Nephrology, First Affiliated Hospital of Dalian Medical University, China. All PD patients with unplanned hospitalization, death, and peritonitis were enrolled from 1 January 2009, to 31 December 2019. The study was carried out following the Declaration of Helsinki. Related data about the personal identity of patients were treated anonymously.Supplemental Table 1.According to the General Office of the State Council of the People’s Republic of China, there are seven official holidays in China, including New Year, Chinese New Year, Tomb-Sweeping Day, Labor Day, Dragon Boat Festival, Mid-Autumn Festival, and National Day. Their holiday periods are seven days for Chinese New Year, National Day, three days for New Year, Tomb-Sweeping Day, Labor Day, Dragon Boat Festival, and Mid-Autumn Festival, respectively . ConsideMost of the clinical data were obtained from the electronic medical record of our hospital, including gender, age, PD vintage, etiology of end-stage of renal disease (ESRD), hospitalization data, death, and peritonitis. In addition, there are complete follow-up records of PD patients about hospitalization, death, peritonitis, total weekly Kt/V(urea), and creatinine clearance (Ccr) in our PD center. All the causes of peritonitis were also collected. The primary outcomes were the rates of hospitalizations, deaths, and peritonitis in holiday and non-holiday periods.9/L (after a dwell time of at least two hours), and polymorphonuclear leukocytes is >50%; (3) positive dialysis effluent culture.According to the guidelines of peritonitis of International Society for Peritoneal Dialysis (ISPD) in 2022 , peritonn) and percentages (%) for categorical variables. Baseline demographic differences between holiday and non-holiday periods were analyzed using t-tests for normally distributed continuous data and the chi-squared (χ2) tests for categorical data. T-tests and rank sum tests were used to compare the incidence of hospitalization, death, and peritonitis between the holiday and non-holiday groups. The incidence rate is defined as rate = number of episodes/days (year) [p-value <0.05. All data were analyzed using SPSS 22.0 .The data were presented using mean ± standard deviation for normally distributed data and numbers (s (year) . The ChiAll the events  in holiday and non-holiday periods were identified in our department between 1 January 2009, and 31 December 2019, including 297 holiday episodes and 1247 non-holiday episodes. The characteristics of each group are summarized in p = 0.175). The death rate was 6.3% (4.8–12.3%) in the holiday group and 5.0% (4.2–8.9%) in the non-holiday group, but no significant difference was observed between the two groups (p = 0.324). The peritonitis rate was also analyzed, it was 0.19 (0.13–0.53) episodes per patient-year in the holiday group and 0.22 (0.18–0.27) episodes per patient-year in the non-holiday group; however, there was no significant difference between the two groups (p = 0.445).In order to observe whether there was a holiday effect on the health outcomes of PD patients, we first compared the difference in the event rates between holiday and non-holiday groups . There ip = 0.015). There were significant differences in the distribution causes between holiday and non-holiday groups (p = 0.017) (Supplementary Table 2).In the analysis of the causes of peritonitis, enteric causes, secondary to other infections, touch contamination, and others were included. Although enteric causes ranked first in both groups, there were more episodes due to secondary to other infections in the holiday group than those in the non-holiday group   and pulmInterestingly, there were not dramatically decreased episodes of peritonitis during holidays in the present study, which is inconsistent with one previous study on the weekend effect. A study from Australia and New Zealand found that the number of patients with peritonitis on weekends decreased. The reason may be that patients had more time to perform PD on weekends carefully and reduced the possibility of making mistakes . HoweverThere are some strengths and limitations to this study. It is the first study to evaluate the ‘holiday effect’ on the health outcomes of PD patients. The study covered all the Chinese holidays, and the holiday period was extended enough to reflect the holiday effect, making our research more comprehensive. However, as a single-center study, although we have collected data for ten years, the study’s results still cannot represent the ‘holiday effect’ in all regions. As a retrospective study, we could not obtain detailed clinical information about our patients, which may affect the research results. Therefore, multiple-center and large-sample research on the ‘holiday effect’ is in great need in the future.In conclusion, our study showed no ‘holiday effect’ on hospitalization, death, and peritonitis in PD patients in our center. Further studies are needed in multiple centers for extended observation periods to explore the ‘holiday effect’ in PD patients.Click here for additional data file.


Augmented reality (AR) is a potentially disruptive technology that enriches the consumer experience and transforms marketing. With the surging popularity of AR in marketing practice, academic efforts to investigate its effects on consumer experience, response, and behavior have increased significantly. To obtain an integrated and comprehensive view of the front-line in AR marketing research and identify the gaps for future research, we analyze the existing AR marketing literature through a systematic literature review. Using 99 journal articles selected from the Web of Science core collections, this research sheds light on the general characteristics such as publication year, publication outlet, research design, and research method. Moreover, this research also gains insight into the AR marketing relevant factors such as application area, application context, AR type, and theoretical lenses. The findings of the analyses reveal the state-of-the-art of scholarly publications on AR marketing research. First, the number of journal articles on AR marketing increased rapidly in the past few years, and the journals that published articles on AR marketing cover a wide range of disciplines. Second, the empirical studies in most literature adopted the quantitative research design and used survey or experiment methods. Third, the studies in more than half of the journal articles used mobile AR applications in various online contexts. Fourth, the Technology Acceptance Model (TAM) and the Stimulus-Organism-Response (S-O-R) framework are the two most widely used theoretical lenses used in the literature. After that, the major application areas of AR in marketing are retail, tourism, and advertising. To identify the focal themes discussed in the three application areas, this research summarizes the studies by the outcome variables. Specifically, the outcome variables have five categories: technology-related, product-related, brand-related, tourist destination-related, and advertisement-related. Finally, this research proposes the agenda for future academic efforts in AR marketing. Augmented reality (AR) is an emerging cutting-edge technology in marketing, It enhances the visual, auditory, tactile, and olfactory perception of users by augmenting or superimposing digital content such as text, geolocation information, graphics, audios, and videos onto a live view of the physical objects and environments in real-time . AR estaThe surging popularity of AR in marketing practice has attracted more and more academic efforts to investigate its effects on consumer experience, response, and behavior . This grThis systematic review differs from existing literature reviews in four ways. First, this review conducts an extensive examination of AR marketing literature. We initially identified 442 journal articles from 200 journals for manual evaluation. These journal articles cover a publication period from 2000 to 2021. After assessing the details following the guidelines of a systematic review methodology, we have 99 journal articles in the final set for analysis. Second, this study adopts a systematic review approach, thus allowing better synthesis and integration. It can help AR marketing researchers better understand existing findings and identify potential topics for future research. Third, this research gains insight into the factors specific to AR marketing, such as application areas, application context, AR type, and theoretical lenses, and summarizes the literature in terms of these factors. Finally, this research identifies and categorizes the AR marketing literature by its application areas, which offers a new perspective to gain insight into the state-of-the-art of AR marketing research.The remainder of this paper is organized as follows. First, we present the concept of AR and discuss its application in marketing. First, we present the concept of AR and discuss its applications in marketing. Second, we explain the methodology used in the literature search and select the journal articles reviewed in this study. Third, we summarize the journal articles for final analysis in terms of the general factors  and the AR relevant factors . Fourth, we analyze the focal themes in the three application areas of retail, tourism, and advertising. Lastly, we present the contributions and concluding remarks, future research agenda, and limitations of this research.Augmented reality originated from Morton Heilig’s bold and innovative idea that cinema needed to draw viewers into the onscreen activities by effectively taking in all senses . AlthougAugmented reality is built on computer vision and object recognition technologies. It enhances consumer experiences by augmenting or superimposing digital content  a live view of the physical objects and environments  in real-time . The disA typical AR system consists of three components: a geospatial datum for the virtual object, a surface to project virtual elements, and an image processing unit . Early AAugmented reality marketing refers to the application of AR in marketing to enhance consumers’ experiences, increase their satisfaction, shape their behavior, and boost companies’ revenues . The novFirst, AR engages consumers in online settings by providing real-time direct product/service experiences in various aspects of marketing . SpecifiSecond, AR offers a novel and fantastic on-site experience . The appThis research adopts the systematic literature review approach to avoid the well-known limitations of literature selection in narrative reviews and expert reviews  and syntQuestion formulation is crucial for a well-conducted systematic review. To obtain a deeper understanding of the AR marketing literature, we conduct a pilot search in the first stage. Based on the findings of the pilot search, we establish the research scope, formulate research questions, and clarify the inclusion and exclusion criteria. The pilot search leads us to the central questions of this research: what are the roles of AR in marketing? and how does AR contribute to marketing? Specifically, we propose four research questions: (RQ1) How is AR marketing defined in the literature? (RQ2) What are the characteristics of the AR marketing literature? (RQ3) What are the major application areas investigated by the AR marketing literature? and (RQ4) What are the focal themes examined in each application area?We perform the first search with the term “augmented reality” in the Web of Science (WOS) core collections, which return 9,145 journal articles on the subject of AR. However, most papers come from WOS categories such as Computer Science, Engineering, Medical, Education, and other fields not related to marketing. Therefore, we perform a second search in the WOS core collections using the following query applied to the title, abstract, and keywords: [“augmented reality” AND (marketing OR consumer OR customer)]. As this research focuses on the most relevant studies of AR marketing, we keep the papers from the five WOS categories, such as Business, Management, Hospitality Leisure Sport Tourism, Computer Science Information Systems, and Computer Science Interdisciplinary Applications . FurtherTo ensure that no major AR marketing articles are ignored in the analysis, we use a “snowball” technique. Specifically, we review citations from the key studies in the 341 journal articles retrieved in the previous search and identify more keywords related to AR marketing. After that, we perform the third search using the following query applied to the title, abstract, and keywords: [“augmented reality” AND (marketing OR consumer OR customer OR retail* OR advertis* OR brand* OR touris*)]. There are multiple possible terms under the root word. Hence, some of the words in the query are followed by a wildcard. Meanwhile, we also limit the five WOS categories in the previous search, the publication year to “1990–2021,” language to “English,” and document type to “Article.” From the query, we obtain 442 journal articles.For the 442 journal articles, we conduct manual screening of the titles, keywords, abstracts, and text under the following three inclusion and exclusion criteria:(1)The study should focus on AR. Thus, we not only exclude the journal articles that discuss VR, XR, AI, and emerging innovative techniques but their combinations with AR.(2)We focus on AR applications in the marketing context. Therefore, we exclude the articles that discuss the technical details of AR and AR-empowered systems and the application of AR in the non-marketing context.(3)We aim to shed light on the findings of empirical studies. Hence, we exclude the conceptual papers and review papers.After removing 343 journal articles, there are 99 journal articles included in the final set for further content analysis. During the screening process, two authors first identify potentially relevant articles independently. Then, we discuss the conflicts to obtain the journal articles for final analysis so that the agreement (Cohen’s Kappa coefficient) is larger than 0.85. The authors manually develop a data extraction process to report the main characteristics of the journal articles, such as publication year, publication journal, application areas, application context, AR type, research design, research method, and theoretical lenses. Then, two authors independently code the selected journal articles in themes, which offer us a more comprehensive understanding.In this section, we summarize the 99 journal articles on AR marketing by examining the general characteristics such as publication year, publication outlet, research design, and research method, as well as the AR relevant characteristics such as application area, application context, AR type, and theoretical lenses.As presented in Journal of Retailing and Consumer Services has 22 articles, which ranks first in all journals. The number of journal articles published in this journal accounts for more than one-fifth of all publications. Journal of Business Research has nine articles, which ranks second in all journals. Computers in Human Behavior and Technological Forecasting and Social Change tie for the third place with four articles each.The 99 articles are published in 43 journals of which 25 journals only have one article and nine journals just have two articles. Second, a fine-grained examination of the research design by single-method vs. multi-method and single-study vs. multi-study demonstrates that a considerate proportion of the journal articles use the multi-method or multi-study research design. Specifically, the single-method research design or multi-method research design refers to whether there are one or multiple research methods, such as survey, experiment, interview, and focus group, in the research design. Moreover, the single-study research design or multi-study research design refers to whether there are one or multiple studies in the research design. It is noteworthy that a single study can only use one research method. However, a single-method research design may have one or multiple studies. Thus, from the perspectives of single-method vs. multi-method and single-study vs. multi-study, we have three types of research design: single-method single-study, single-method multi-study, and multi-method multi-study. As presented in We identify retailing, tourism, and advertising as the three major application areas of AR marketing. Specifically, AR marketing research originates from retail. The studies in the first journal article and most of the early journal articles are conducted in retail. Moreover, the number of journal articles that shed light on AR in retail has increased significantly over the last few years. Tourism is the second application area of AR marketing. However, the increase in the number of journal articles on AR in tourism keeps steady after the first years. Advertising is the latest application area of AR in marketing. The first journal article on AR in advertising is published in 2018. Nevertheless, the number of journal articles on this topic remained limited until 2021.The application context of AR includes both online settings and on-site scenarios. In online settings, AR enriches consumers’/tourists’ experience and improves their satisfaction with online retail, virtual tourism, and online advertising . In on-sThe AR applications that consumers interact with are built upon stationary devices , mobile devices , wearable devices , and somatosensory devices  . AccordiEarly applications of AR in marketing are web-based. In particular, consumers experience the products such as sunglasses, watches, makeup, clothes, shoes, and furniture through web-based AR applications  installed on their PCs . SpecifiExtant AR marketing literature builds upon a wide range of theory lenses. To have a fine-grained understanding of the AR marketing literature, we summarize the focal themes in the three application areas  based on the outcome variables. Retail is the earliest application area of AR in marketing. Recently, the recognition and adoption of AR marketing by retail giants, leading on-site retailers, and well-known consumer brands have increased significantly. Both industrial practice and academic research have provided evidence for the potentials of AR to entertain, educate, and engage consumers. Specifically, AR can transform online and on-site experience, inspire brand love, facilitate pre-purchase product fit evaluation, boost product sales, and enhance post-purchase consumption experience . Extant Technology-related outcome variables examined in the literature on AR in retail include consumers’ attitude toward, satisfaction with, adoption/use intention of, continued use/reuse intention of, and recommendation intention of AR technology/AR retail application . Among these outcome variables, consumers’ attitude toward and reuse intention of AR technology/AR retail application are the most popular. It is noteworthy that many journal articles examined two or more responses simultaneously. In particular, consumer attitude toward AR technology/AR retail application is frequently investigated together with their adoption/use intention of, recommend intention of, and reuse use intention of AR technology/AR retail application.Consumers’ attitude toward AR technology/AR retail application refers to their feelings associated with using it . ConsumeThe literature on AR in retail has two primary streams. The first stream of literature sheds light on the effects of AR use and delves into the underlying mechanisms. The second stream of literature gains insight into the impacts of specific AR characteristics and reveal how these impacts take place. First, AR use, that is, the inclusion of AR-empowered product presentation and interaction capabilities in retail applications has positive effects on consumer responses to the AR technology/AR retail application . Specifically, AR use can stimulate favorable consumer attitude toward , increasSecond, extant literature examines the impacts of specific AR characteristics such as interactivity, augmentation, informativeness, vividness, novelty, and aesthetics on consumers’ attitudes toward , satisfaFurthermore, compared with the studies focused on the effects of AR use, research on the impacts of AR characteristics delves deeper into the underlying mechanisms of how AR characteristics influence consumers’ responses to the AR technology/AR retail application. Except for the evaluation of the utilitarian value and hedonic value , this stAs shown in Similar to the studies on the impacts of AR on technology-related outcomes, literature on this theme also has two streams. The first stream of literature sheds light on the effects of AR use. The second stream of literature gains insight into the impacts of AR characteristics. First, AR experience/use stimulates the consumer purchase intention by increasing cognitive control , elicitiSecond, AR characteristics such as interactivity , vividneCompared with the AR marketing literature investigating technology-related and product-related outcome variables, the studies examining brand-related outcome variables are both new and limited in quantity. As presented in Consumers’ brand attitude refers to their feelings about a brand . ConsumeSimilar to AR marketing literature on product-related and technology-related outcome variables, the journal articles that investigate the effects of AR on brand attitude can be categorized into two groups. First, AR use  enhances consumers’ brand attitude by eliciting their perception of spatial presence, personalization, and utilitarian and hedonic benefits , 2020. HSecond, AR characteristics such as augmentation and anthropomorphism influence consumers’ brand attitudes. In particular, augmentation drives changes in consumers’ brand attitudes through inspiration . AnthropTourism is an emerging application area of AR marketing. Different from retail in which increasing product sales is the central point, the primary concern for tourism is enhancing visitors’ experience. AR is valuable for the tourism industry in multiple ways, such as economic, experiential, social, epistemic, cultural and historical, and educational . The appThe first journal article on AR in tourism was published in 2015, which is just one year after the publication of the first journal article on AR in retail. The number of journal articles exploring AR in tourism keeps increasing over the past few years. Prior studies on AR in tourism examined the influence of AR on various technology-related and tourist destination-related outcomes. Some journal articles also delved into the underlying psychological and behavioral mechanisms. Besides, several journal articles gained insight into the broader themes, such as the perceived value of AR for the tourism industry  and the The technology-related outcome variables examined in the literature on AR in tourism are similar to those investigated in the literature on AR in retail. As presented in First, scholars have proposed improved models of the well-recognized models, such as the Technology Acceptance Model (TAM), Unified Theory of Acceptance and Usage of Technology (UTAUT2), and Task Technology Fit (TTF). These models can better explain the determinants of the adoption of AR in tourism by incorporating new antecedents or combining existing models . ParticuSecond, the three quality dimensions of the AR tourism application  affect tourists’ satisfaction with and recommendation intention of it. The effect of the quality dimensions on tourists’ intention to recommend the AR tourism application is mediated by their satisfaction with it. Furthermore, this effect is more prominent for the tourists with high innovativeness than for those with low innovativeness .Tourist destination-related outcome variables include tourists’ knowledge acquisition of, visit intention of, satisfaction with, memory of, and WOM generation for tourist destinations, as well as tourists’ choice of products and willingness to pay a price premium in tourist destinations. Specifically, AR enriches tourists’ sensory, affective, behavioral, social, and intellectual experiences . The enrTourists’ knowledge acquisition of a tourist destination refers to their learning of new, interesting, or necessary things about it . TouristThe studies delving into the underlying mechanisms of the effects reveal that they are achieved by creating an immersive experience, stimulating tourist engagement, and increasing processing fluency . MoreoveAdvertising is the latest and fast-growing application area of AR marketing. The application of AR in advertising is mobile apps based  or in thA variety of advertisement characteristics affect the consumers’ affective, cognitive, and behavioral response to AR advertisements. The characteristics of AR advertisements include AR advertisement type  , AR inteAdvertisement-related outcome variables examined in AR advertising literature is consumers’ attitudes toward AR advertisements. It refers to consumers’ feelings toward AR advertisements . OverallBrand-related outcome variables examined in the literature on AR in advertising include consumers’ brand attitude and brand liking. Brand attitude and brand liking are consumers’ feelings about a brand . AR adveThe product-related outcome variable examined in the literature on AR in advertising is consumers’ product purchase intention or willingness to pay. Consumers’ product purchase intention or willingness to pay refers to their desire to buy the advertised product . CompareThis study makes two important contributions to research in AR marketing. First, we delve into the factors specific to AR marketing research. In addition to the shared aspects such as publication year, publication journal, research design, and research method, we shed light on the factors specific to AR marketing such as application area, application context, AR type, and theoretical lenses. Our analyses show that retail, tourism, and advertising are the major application area of AR marketing research. Specifically, retail is the earliest and most popular application area, advertising is the newest and least investigated application area. Next, most prior studies investigated AR applications in online settings, but only a small portion of the literation examined AR applications in on-site scenarios. Third, mobile AR applications and web-based AR applications are the most prevalent AR type in the three application areas. On-site AR applications, wearable AR applications, and somatosensory device-based AR applications have received little scholarly attention in some of the application areas. Finally, TAM, S-O-R Framework, Self-Referencing Theory, UGT, Equity Theory, Flow Theory, TRA, and UTAUT are the most prevalent theoretical lenses in AR marketing research. These findings offer more comprehensive and integrated perspectives to understand the state-of-the-art of AR marketing research.Second, we identify the focal themes in the three application areas to illustrate the current status of scholarly works. We obtain the focal themes by the outcome variables used in the empirical studies. The outcome variables describe the effects of AR use in general and specific AR characteristics on the AR technology/AR application, products, brands, tourist destinations, and advertisement campaigns. Our analyses show that technology-related variables, product-related variables, and brand-related variables are the shared outcome variables examined in the literature of more than one application area. Tourist destination-related and advertisement-related outcome variables are studied in the literature on a single application area. Specifically, technology-related outcome variables include consumers’/tourists’ attitudes toward, satisfaction with, adoption/use intention of, continued use/reuse intention of, and recommendation intention of the AR technology/AR applications. Product-related variables include consumers’ product attitudes, product purchase intention, willingness to pay a price premium, and WOM intention. Brand-related outcome variables include consumers’ brand attitudes, perceived brand personality, brand liking, and brand purchase intention. Tourist destination-related variables include tourists’ knowledge acquisition of, intention to visit, satisfaction with, the memory of, and WOM generation for tourist destinations. The advertisement-related outcome variable is consumers’ attitudes toward advertisements. These findings provide a clear guideline to grasp the main streams of the AR marketing literature.A systematic literature review integrates research papers in a comprehensive, structured, and analytical way. Therefore, it can identify the gaps in extant literature  and highAs the methods used in most literature are the survey and lab experiment, the outcome variables examined in the literature are self-reported ones collected through scales. With the proliferation of AR applications, the availability of more data collection methods and data analysis techniques will increase significantly. Thus, future research can investigate additional outcome variables and mediating variables obtained from the AR application systems in natural settings  or measuFurthermore, most existing AR research examined consumers’ immediate experiences and behavioral intentions toward AR. Future research can explore the persistent impacts of AR adoption and design features on consumers’ motivation, experiences, responses, and behavior in various contexts using longitudinal approaches . OverallThe effects of AR are heterogeneous across consumers with different characteristics, products/services in different categories, and scenarios in different contexts. Although existing literature examines the heterogeneous effects of AR across some general characteristics of consumers, products/services, and contexts, future studies can delve deeper into more nuanced effects of AR regarding consumers, products, services, and contexts with different AR relevant characteristics.With the fast-growing the application of AR in marketing, consumers using these applications, and products/services offered through these application, future research can delve deeper into the heterogenous effects of AR on consumers’ responses and behavior across consumer characteristics such as gender , age groFuture research can also examine the heterogeneous effects of AR on consumers’ responses and behavior regarding different product or service characteristics such as product type  , productMoreover, future research can investigate the effects of AR on consumers’ responses and behavior under the contexts with different characteristics such as customer experience stages  , noise lAs both the industry practice and academic investigation of AR marketing are still in the infant stage, most existing studies focus on the effects of AR use or AR characteristics. In this regard, deeper investigations of the impacts of sophisticated AR design features in marketing applications on the outcome variables that describe consumers’ experiences of and responses to the AR technology/AR application, products/services, brands, tourist destinations, and advertisements are needed .Particularly, to provide enriched information and offer rapid responses to consumers, further research needs to focus on the AR design elements and features that can increase the realisticness, authenticity, vividness, novelty, interactivity, and efficiency . For insIn conclusion, academic research can help better understand how AR design elements and features will affect consumers’ motivations, experiences, responses, and behavior regarding products/services, brands, and product/service providers. Also, product/service providers can figure out ways of improving AR applications and better satisfying the needs of consumers. Finally, the stakeholders can reach a win–win situation in which both consumers will derive high experiences value and product/service providers can achieve high-revenue profit .Most extant AR marketing literature focus on the bright side of AR use and the positive effects of AR characteristics. However, little studies discuss the dark side of AR application in marketing. To provide enriched personalized services , AR applications need to collect, process, store, and transmit a variety of consumer data such as the face, body, and personal space . Thus, pAlthough this research has many meaningful contributions, we acknowledge that this research still has several limitations. These limitations provide opportunities for further investigation. To begin with, the journal articles included in this research are extracted and selected according to our criteria. Thus, we may miss some valuable materials. For instance, we use the WOS core collections as the data extraction source to ensure the high quality of the literature analyzed in this research. Future research can extract literature from more databases such as Scopus, Elsevier, Emerald, Wiley, and Google Scholar to incorporate information from conference proceedings, research reports, working papers, theses and dissertations, books, magazines, white papers, and industry reports. Including more sources and casting the net wider help to gain additional insights. Also, as AR marketing research is still in the infant stage, we use descriptive analysis and thematic analysis in the systematic review. Moreover, the literature analysis is based on the authors’ expertise and understanding. Therefore, the results of this research may have limited generalizability. With the increase in the number of publications on AR marketing, future research can gain more insights into the increased literature by using analytic techniques such as meta-analysis, bibliometric analysis, and text mining.ZD and JL designed the research, collected the data, and conducted the data analysis. ZD, JL, and TW contributed to the drafting and revision of the manuscript. All authors approved the submitted manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Physiologically, catecholamines activate β1-AR to initiate a positive chronotropic, inotropic, and dromotropic change. It is believed that β1-AR couples to Gs protein and transmits the signal through second messenger cAMP. However, increasing research shows that β1-AR can also bind with Gi protein in addition to Gs. When β1-AR-Gi is biasedly activated, cardioprotective effects are introduced by the activated cGMP-protein kinase G (PKG) pathway and the transactivation of epidermal growth factor receptor (EGFR) pathway. The discovery of β1-AR-Gi signaling makes us reconsider the selectivity of G protein with regard to β1-AR, which also provides new ideas for the treatment of heart diseases. This review summarizes the discovery of β1-AR-Gi pathway, including the evidence that supports β1-AR’s capability to couple Gi, details of the transduction process and functions of the β1-AR-Gi signaling pathway.β In the heart, β1-AR accounts for approximately 80% of β-adrenergic receptors, with the remaining 20% belonging to β2 adrenergic receptor (β2-AR) and β3 adrenergic receptor (β3-AR) respectively [1-AR is a critical receptor protein regulating cardiac function. β1-AR can be activated by catecholamines, such as norepinephrine (NE) and epinephrine, to play the role of positive inotropic, positive chronotropic and positive dromotropic action to meet the needs of the body’s fight-or-flight response1-AR is also the target of drug therapy for heart diseases1-AR such as propranolol, metoprolol and carvedilol, can be used for the treatment of heart failure, coronary heart disease, atrial fibrillation,etc. [G-protein-coupled receptors (GPCRs) are the largest family of membrane proteins in the human body, which transmit extracellular information into the intracellular signalingn,etc. –7 .1-AR is regarded to couple only Gs [1-AR binds to the Gs protein and induces the synthesis of the second messenger cyclic adenosine monophosphate (cAMP) catalyzed by adenylate cyclase (AC), which phosphorylates downstream proteins through protein kinase A (PKA) to complete signal transductionG protein, a guanine-nucleotide-binding protein, is a trimeric complex comprising subunits of Gα, Gβ, and Gγ. According to the variations of the α subunits, G protein can be divided into Gs, Gi, Gq/11, and G12/13 –10 . Tr2-AR, β1-AR can also couple Gi protein in addition to Gs [1-AR-Gi pathway and exerts cardioprotective effects through cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway1-AR-Gi complex also underlies a solid foundation for research of the complexYet, increasing studies have shown that resembling βn to Gs ,16 . Re1-AR-Gi signaling as a clue, reviewing the course of the β1-AR-Gi pathway discovery from the very evidence of β1-AR coupling Gi to the process and function of β1-AR-Gi signal transduction, while looking forward to the future β1-AR-Gi research directions.Here, we use the beginning and end of β1-AR has the ability to couple Gi by using neonatal myocytes from β1-AR knockout (KO), β2-AR KO, and β1/2-AR KO mice1-AR and PDZ domain-containing scaffolding proteins, through which the coupling of β1-AR and Gi is limited. PDZ domain binding motif mediates specific protein reactions and is, in essence, a protein module with a conserved structure1-AR PDZ domain binding motif ~ESKV~ into ~EAAA~ to form the mutant β1-AR (β1-AR-PDZ). Subsequently, HA-labeled mouse wild-type β1-AR or β1-AR-PDZ was transfected into β1/2-AR KO mouse neonatal myocytes, and their contraction rate was recorded. The results demonstrated that the contraction rate of isoproterenol (ISO) was first increased and then decreased below the basic level, showing a biphasic contraction rate response, which was consistent with the results shown in β1-AR KO mouse neonatal myocytes expressing β2-AR. All of above phenomenon can be blocked by Gi inhibitor pertussis toxin (PTX).In 2002, researchers found that β2-AR is another β-adrenergic receptor in cardiomyocytes that couples Gs and Gi [2-AR KO myocytes were treated with a membrane permeable polypeptide Tag-β1PDZ (466GRQGFSSESKVCOO~ of β1-AR) that mimics the binding mode of β1-AR PDZ domain, and ISO stimulation also caused a biphasic contraction response. This effect was inhibited by PTX as well1-AR has the potential to couple the Gi protein, but the presence of PDZ restricts the binding of β1-AR to Gi.β and Gi ,20 . Ad1-AR, NE, can also active the β1-AR-Gi pathway. It was found that in Chinese hamster ovary (CHO) cells, when overexpressed β1-AR was stimulated by NE, ERK activity was increased significantly, which could be completely blocked by PTX.In 2004, Lefkowitz’s group1-AR when stimulated by carvedilol using the proximity ligation assay (PLA) and co-immunoprecipitation (CO-IP)1-AR-β-arrestin signaling1-AR, with the increase of carvedilol concentration (10–9–10–5 M), the amount of Gi coupling β1-AR gradually increased in a concentration-dependent manner. However, ISO did not trigger β1-AR to Gi binding even in the concentration range of 10–9 M to 10–5 M. Forby, the β1-AR-Gi interaction was detected after treating HEK293 cells with 10–5 M carvedilol for 5 min. This is, in fact, time-dependent, as more Gi is bound to β1-AR in a prolonged stimulation time (30 min)1-AR to Gi, detected by either PLA or CO-IP experiments, could be blocked by PTX1-AR-Gi-biased ligand and promotes the binding in concentration-dependent and time-dependent manners.In 2017, researchers directly validated Gαi binding to β1-AR, this study also confirmed the cardioprotective effect of β1-AR-Gi activation in animal models of cardiac dysfunction. Almost simultaneously, Huang’s group1-AR-Gi complex by cryo-electron microscopy with a resolution of 3.0 Å. Together, these results suggest that Gi can couple β1-AR in response to agonist or blocker stimulation.In 2021, Xiang’s group1-AR-Gi binding? The PDZ domain binding motif is one of the reasons, but not the only one that is preventing the binding of β1-AR to Gi. This is because the PDZ is located at the C-terminal of the receptor. It has been demonstrated that the C-terminal alone is not sufficient to determine the binding of β1-AR to Gi1-AR C-terminal PDZ domain binding motif that prevents ISO to activate β1-AR-Gi combination [1-AR can still bind to Gi even in the absence of external intervention on β1-AR PDZ domain binding motif stimulated by carvedilol [1-AR-Gi complex is ISO, there are no PDZ domain-containing scaffolding proteins under the experimental conditions1-AR-Gi binding. Apparently, while carvedilol causes β1-AR-Gi coupling after 5 min of stimulation1-AR-Gi binding in 15 min1-AR under physiological conditions? We speculate that NE can also induce β1-AR binding to Gi under physiological conditions, because it has been shown that NE can induce β1-AR binding to Gi in CHO cells1-AR and Gi were formed under certain experimental conditions and disease models. Yet, does β1-AR also bind with Gi when catecholamines activate β1-AR under normal physiological conditions? That is also a question which needs to be answered in the future.But still, some confusions need to be clarified in order to put us in the picture. (1) How much influence does PDZ domain binding motif have on βination ,16 . Suvedilol  . Althou2-AR is a typical representative of such kind. When β2-AR is activated by ISO, the receptor interacts first with the Gs protein and then transmits the signal through the AC-cAMP-PKA pathway. PKA, as a protein kinase, phosphorylates β2-AR, which in turn promotes the switching of β2-AR from Gs protein to Gi2-AR activation was demonstrated by an experimental method of neonatal rat cardiac myocyte contraction rate, which occurred approximately 15 min after ISO stimulation [The switching of G protein refers to the ability of certain GPCRs to bind multiple G proteins to convert from one type of G protein to another when stimulated by a ligand. βulation ,12 .1-AR-biased binding to Gi deviates from that of β2-AR. In HEK293 cells, although stimulation by ISO causes β1-AR to bind with Gi, it is not sufficient to show that β1-AR can bind with Gs and Gi sequentially like β2-AR1-AR differs from that of β2-AR in HEK293 cells2-AR G protein switching, the Gs-receptor binding and the receptor phosphorylation by PKA have little effect on the G protein switching regarding β1-AR. Rather, the C-terminal of β1-AR plays a key role in determining the binding of Gi protein to β1-AR. Through interchanging the C-terminal of β1-AR and β2-AR, two chimeras were obtained: β1/2-AR  and β2/1-AR . Carvedilol promotes the recruitment of Gi to β1-AR, but not β2/1-AR or β1/2-AR1-AR hinders the binding of Gi to β1-AR in neonatal myocytes1-AR C-terminal influences the selection of Gi by the β1-AR, the act is not sufficient by C-terminal alone. However, the results of Lefkowitz’s group1-AR in CHO cells. It was found that in CHO cells, NE activation of β1-AR increased ERK activity. Both the PKA inhibitor H-89 and the Gi inhibitor PTX reversed this phenomenon. The results are different between different groups concerning the question of whether PKA affects the switching of Gs/Gi in β1-AR. We speculate that the difference in experimental conditions between the groups may have led to the difference in conclusions. In CHO cells, NE activation of β1-AR increases ERK activity. Both PKA blocker H89 and Gi blocker PTX reversed this phenomenon1-AR. Mutating the PKA phosphorylation site of β1-AR or using H-89 did not affect the binding of Gαi to β1-AR . In animals, however, besides the exogenous administration of ISO or carvedilol, the local catecholamines in the body are also β1-AR agonists. The results of carvedilol-treated mice with heart dysfunction have proved that carvedilol biasedly activates β1-AR-Gi and exerts cardioprotective effects through the cGMP-PKG pathway1-AR to trigger its biased binding to Gs; carvedilol, also as an orthotopic ligand1-AR to Gi. Therefore, it raises a question: how does the switching of β1-AR-G protein engagein vivo? It is reasonable to speculate that Gs is coupled to β1-AR in the body in response to stimulation with catecholamines, yet carvedilol switches β1-AR-bound G protein from Gs to Gi. In this process, the C-terminal of β1-AR is involved in the selection of G protein. However, the specific mechanism of β1-AR G protein switching remains to be further explored.However, the above studies were carried out in cells, and the ligand appertained to β1-AR-Gi complex at the resolution of 3.0 Å with the full agonist isoproterenol. The structural analysis of this complex has greatly helped us to understand the binding mode of β1-AR to Gi.Recently, Huang’s group1-AR adopts the same active-state conformation as the β1-AR-Gs complex [1-AR, while TM7 is moved inward by ~5 Å1-AR-Gi complex, the α-helical domain is rotated open by ~79°, and thus is displaced ~37 Å of its mass center relative to the Ras-like GTPase domain: this is the conformational change that is of the most significance in the Gαi subunit1-AR-Gs complex. However, in Gs, the α-helical domain has a rotation of ~96° instead, and the distance between mass centers is ~38 ÅIn this complex, βcomplex ,25 . Br1-AR can bind with both Gs and Gi, the selectivity of β1-AR to Gs is significantly higher than that of Gi under ISO stimulation [1-AR, like ICL2 and ICL4 , contribute to the determinants of G-protein biased selection. As a result, based on the analysis of complex conformation, the overall structure of β1-AR-G protein complex determines the selectivity of G proteinAlthough βulation ,27 . Mu1-AR is in an activated state under ISO stimulation, exposing the transducer binding pocket to couple Gs or Gi protein; on the other hand, carvedilol, a special beta-blocker with biased agonist activity1-AR to bind with Gi [1-AR-Gi complex? This perplexity can only be explained by analyzing the structure of the carvedilol-β1-AR-Gi complex. Gi coupling requires the outward movement of TM6 of β1-AR, which is a hallmark of GPCR activation1-AR couples to Gi, suggesting that carvedilol has the ability to induce β1-AR to an active conformation. Unfortunately, the structure of β1-AR-Gi complex with carvedilol as a ligand has not yet been resolved. Recently, human β1-AR was analysed1-AR-Gi.In summary, on one hand, βwith Gi ,24,28 1-AR-β-arrestin activation. Ten years later, they [1-AR to bind Gi, and then recruits β-arrestin and Src to transactivate the EGFR-ERK pathway  is the key enzyme in nitric oxide (NO) production. NO is a promotor which triggers cGMP synthesis by activating soluble guanylyl cyclases (sGCs) ,33 . ThAlthough the two signal pathways are different, their function is to protect the heart. It may help clarify the mechanism of carvedilol in the treatment of heart diseases.1-AR lies in its binding with G protein to achieve the purpose of information transmitting1-AR was shown to bind to Gs1-AR-Gs pathway, for example, explaining the mechanism of β1-AR function1-AR can actually recruit Gi, growing evidence supported that β1-AR can indeed bind to Gi and play a cardioprotective role through different signaling pathways [1-AR over G protein. Therefore, we used “G protein coupled receptor” as the word base and modified it appropriately to emphasize Gi-protein-coupled β1-adrenergic receptor.As a GPCR, the key to the function of βathways ,16,17 1-AR [1-AR agonists NE and ISO, and blocker carvedilol can induce β1-AR binding to Gi [1-AR conformation must be suitably altered to expose the transducer binding pocket to bind with Gi proteins1-AR1-AR-Gi1-AR to Gi requires strict conditional constraints. Thus, it is a coordinated action of multiple factors that drives β1-AR to finally bind to Gi protein.Of course, there are many factors which influence the specificity selection process of G protein, such as the conformational changes of β1-AR ,25 , th1-AR ,12,17 1-AR ,21 . Bog to Gi ,17,21 1-AR-Gi coupling, including (1) the prerequisites for β1-AR-Gi binding; (2) the β1-AR-Gs/Gi switch mechanism; (3) analysis of carvedilol-β1-AR-Gi complex.In the meantime, there are still many issues to be resolved in the whole process of re-evaluating the β1-AR-Gi pathway is exciting. The biased binding of β1-AR to Gi and its cardioprotective effects provide vast vistas for the treatment of cardiac conditions. Currently, the cardioprotective effect of the β1-AR-Gi pathway is mainly achieved by carvedilol. Clinical studies have shown that, as a beta-blocker, carvedilol is also widely used in the treatment of hypertension [1-AR-Gi pathway in the above diseases, the very existence of this pathway provides a theoretical basis for exploring strategies to treat these diseases. Hopefully, the treatment targeting β1-AR will not only block the Gs pathway, but also provide the full value of β1-AR-Gi pathway in bringing welfare to patients with heart diseases.The discovery of the βtension ,40 , ci


FOLR1) gene contribute to CFD. In this study, we identified six genetic variants in histone lysine demethylase 6B (KDM6B) in 48 CFD cases. We demonstrated that these KDM6B variants decreased FOLR1 protein expression by manipulating epigenetic markers regulating chromatin organization and gene expression. In addition, FOLR1 autoantibodies were identified in CFD patients’ serum. To the best of our knowledge, this is the first study to report that KDM6B may be a novel CFD candidate gene in humans.Cerebral folate deficiency syndrome (CFD) was defined as any neurological condition that was associated with low concentrations of 5-methyltetrahydrofolate in the cerebrospinal fluid. Previous clinical studies have suggested that mutations in the folate receptor alpha  Methods: Exome sequencing (ES) was performed on 48 isolated CFD cases. The effect of KDM6B variants on KDM6B protein expression, Histone H3 lysine 27 epigenetic modification and FOLR1 expression were examined in vitro. For each patient, serum FOLR1 autoantibodies were measured; (3) Results: Six KDM6B variants were identified in five CFD patients, which accounts for 10% of our CFD cohort cases. Functional experiments indicated that these KDM6B variants decreased the amount of KDM6B protein, which resulted in elevated H3K27me2, lower H3K27Ac and decreased FOLR1 protein concentrations. In addition, FOLR1 autoantibodies have been identified in serum; (4) Conclusion: Our study raises the possibility that KDM6B may be a novel CFD candidate gene in humans. Variants in KDM6B could downregulate FOLR1 gene expression, and might also predispose carriers to the development of FOLR1 autoantibodies.(1) Background: The genetic etiology of most patients with cerebral folate deficiency (CFD) remains poorly understood.  Cerebral folate deficiency  syndrome was defined as any neurological condition that was associated with low concentrations of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF) . CFD patIn humans, folate concentrations are from 1.5 to 3-fold higher in CSF than in serum, and the ratio is much higher in infancy and decreases through adolescence ,5. FolatSLC46A1  gene variants  folic acid  was added and incubated for 20 min at room temperature. Free [3H] was removed by dextran-coated charcoal. The receptor-bound radioactivity in the supernatant fraction was determined. Blocking autoantibodies prevent the binding of [3H] folic acid to FOLR1. The autoantibodies titer was expressed as picomoles of FOLR1 blocked per milliliter of serum.For each patient, FOLR1 blocking autoantibodies were measured in serum according to previously established methods . Brieflyt-test. Statistically significance is defined as p-values < 0.05. Data are presented as mean ± SEM.All data were analyzed via two-tailed Student’s FOLR1, PCFT, DHFR, CIC) were observed. Using the filtering rules described above, we found 23 genes that have minor allele frequency >0.05 in our sporadic cases, and we considered them to be potentially enriched genes. After Bamcheck Validation and Fisher Exact Test, we determined that only one gene is highly enriched in this CFD cohort compared to the public dataset, and this gene is KDM6B. There were 7 allele counts in 96 alleles (7 in 48 cases), while, in over 250,000 gnomAD alleles, 5625 missense alleles are identified . All six variants were predicted to be deleterious using SIFT software, indicating that they are likely pathogenic variants. Four of the six variants were highly (>80%) conserved across multiple mammalian species (KDM6B p.Thr321Ala (c.A961G) were available for evaluation. The mother DNA sample was not available for the patient with variant KDM6B p.Ser826Tyr. For the other four KDM6B variants for which DNA samples were successfully collected from both parents, Sanger sequencing indicated that all five KDM6B variants were inherited from either their mother or their father  or heterozygous variant  of the EARS2 gene was also identified, which may be partly responsible for the low CSF folate levels. Despite folinic acid treatment, all patients showed poor outcomes. Patient 1 experienced the most beneficial effects of the folinic acid therapy, and it is notable that treatment was initiated at the early age of 2 ½ months, clearly demonstrating the importance of early genetic testing and initiation of reduced folate therapy.The clinical data are summarized in KDM6B variants to determine the effects of KDM6B variants on protein expression and localization. KDM6B protein was expected to be located within the cell nucleus. As seen in KDM6B variants. Western blotting analysis was then performed, and compared to the wild-type, flag-KDM6B protein levels were significantly reduced in all the six variants (p < 0.01)  B,C, whicKDM6B variants affected FOLR1 protein levels. As depicted in p < 0.05), and overexpression of all the six flag-KDM6B mutants significantly decreased FOLR1 protein expression level compared to wild-type flag-KDM6B (p < 0.001).FOLR1 has been shown to be an important receptor for the uptake of folates into the cells and play a crucial role in neural development. Previous genetic studies have demonstrated that human FOLR1 loss of function variants contribute to CFD . We initIt is known that KDM6B plays a role in H3K27Me3/2 demethylation. Therefore, we investigated whether KDM6B variants affected its demethylation function. We initially examined the levels of H3K27me2 protein, which is the dominant modification form, in cells overexpressing wild-type and mutated KDM6B. As shown in KDM6B and CFD, and six variants of KDM6B were identified among 48 sporadic CFD patients, all of which were predicted to be damaging. One of the patients was a biallelic KDM6B variant (p. p.Thr761Ser and p.Arg1016Gln) carrier with the lowest CSF folate concentrations among these five CFD patients, indicating a potential additive genetic model for KDM6B association with CFD. Two of the patients were siblings, both of whom inherited the KDMB p.Arg908Cys variant from their father. All variants identified in our CFD cohort were missense variants, and most of them were known to be inherited from parents, while those in Stolerman and colleagues’ neurodevelopment delay cohort were de novo nonsynonymous variants, including missense, frameshift insertion and stop gain variants. It is known that about 80% of CFD patients suffer from neurodevelopment delays. In this study, all five patients with KDM6B variants had neurodevelopment problems, including autism, language delay and intellectual disability. It is unknown whether the patients in Stolerman and colleagues’ KDM6B study had CFD. Based on Stolerman and our KDM6B study, KDM6B loss of function variants can cause neurodevelopment defects. Although some parents were heterozygous for KDM6B missense variants, they lacked any CFD-associated phenotypes; thus, we assume that single rare deleterious heterozygous KDM6B missense variants may not be sufficient to cause CFD. That said, such variants interacting with other genetic  or/and environment factors, as well as biallelic KDM6B variants , might be sufficient to induce the CFD syndrome phenotype.In this study, we performed the first genetic association analysis of FOLR1 or FOLR2 were identified in patients with KDM6B variants. Through in vitro experiments, we found that, consistent with KDM6B protein levels, FOLR1 protein levels in HeLa cells overexpressing wild-type KDM6B were increased compared to the control, while FOLR1 levels in all six of the KDM6B variants were significantly decreased compared to the wild-type KDM6B.We also performed further experiments to explore the possible underlying mechanisms by which KDM6B contributes to the etiology of CFD. The most common primary causes of CFD include dysfunction of FOLR1 and elevated serum FOLR1 autoantibody titers ,23. AlonKDM6B variants might be due to decreased H3K27Ac which might compromise FOLR1 transcription  were reported to be required for T-cell differentiation through regulating Jmjd3-Irf4 axis [We found that 80% (4/5) of these rf4 axis ,32,33. Krf4 axis . TherefoWe also investigated the remainder of the cohort for autoantibodies and found that more than 89% of CFD patients tested positive for autoantibodies . The comKDM6B variants affected FOLR1 protein levels. H3K27 methylation modification levels were also disrupted by CFD associated KDM6B variants. Future investigations are necessary to explore the underlying pathophysiological mechanisms in more detail, to enhance our understanding of the etiology of CFD and provide a theoretical basis for the treatment of these devastating neurodevelopmental disorders.To our knowledge, this is the first report of KDM6B variants being associated with human CFD syndrome, and our functional analyses indicated that CFD associated KDM6B variants from 48 isolated CFD cases. We also performed several functional experiments and determined that KDM6B variants decreased the amount of KDM6B protein, which resulted in elevated H3K27me2, lower H3K27Ac and decreased FOLR1 protein concentrations. In addition, FOLR1 autoantibodies have been identified in patients’ serum. To the best of our knowledge, this is the first study indicating that KDM6B may be a novel CFD candidate gene in humans. Our findings will enhance our understanding of a new CFD etiology.In this study, we identified 6


Control mice received olive oil (5 μl/g body weight). Different assays such as immunohistochemistry, immunostaining, Western blotting, qRT-PCR, immunoprecipitation, immunoprecipitation, and GST pull-down assays, and in vivo and in vitro ubiquitination assays were conducted. We found that NRP1 expression was significantly elevated both in mouse and human fibrotic livers, mainly in activated HSCs at the fibrotic foci. NRP1 promoted HSC activation via the cytokine TGF-β1, VEGFA, and PDGF-BB. Moreover, USP9X was found to be a critical deubiquitinating enzyme for the stability and high activity of NRP1 and NRP1 deubiquitination mediated by USP9X enhanced HSC activation and liver fibrosis. NRP1 deubiquitination mediated by USP9X enhances HSC activation, implying that targeting NRP1 or USP9X potentiates novel options in the treatment of liver fibrosis.Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whether NRP1 regulates HSC activation remains unknown. C57BL/6 male mice (6–8 weeks old) were intraperitoneally injected with 10% CCl Liver fibrosis (LF) is a repair response to chronic hepatic injury which is described by an abnormal wound-healing process of which functional liver parenchyma is gradually replaced by fibrotic tissue with an increased accumulation of collagen-rich extracellular matrix (ECM) . Most chAbout 10% of liver cells are nonparenchymal hepatic stellate cells (HSCs) which are the major source of ECM and play a major role in the progression of liver disease . In the Neuropilin-1 (NRP1) is a transmembrane receptor which contributes to the semaphorin and VEGF signaling cascades. NRP1 also contributes to angiogenesis, tumor development, vascular permeability, and immune functions . In receProteolytic enzymes that cleave ubiquitin or ubiquitin-like proteins from target proteins or pro-proteins are known as deubiquitinating enzymes (DUBs) . So far,4-induced LF. At the molecular level, we found that USP9X was a key DUB in regulating NRP1 ubiquitylation and its stabilization in HSCs. Thus, our findings provide new insights into the antifibrotic effects of NRP1 and USP9X.In the present study, we determined the function of NRP1 in HSC activation as well as the mechanism that underpins its dysregulation in HSCs. We revealed that the NRP1 expression was significantly elevated in the liver of LF patients as well as in the mouse LF model. NRP1 is predominantly expressed in activated HSCs exist at the fibrotic foci. Moreover, we found that NRP1 promotes HSC activation, and NRP1 inhibition suppresses mouse primary HSC activation and protects mice from CCl4) solution (5 μl/g body weight) was delivered intraperitoneally to mice three times per week for four weeks. The mice in the control group were given olive oil (5 μl/g body weight). GenePharma  produced adenovirus (100 μl) with shRNA sequences targeting USP9X or nontargeting control sequences and administered it through the portal vein to establish USP9X’s participation in liver fibrosis. The shRNA sequence was 5′- GCCCAAATGAAGAAGTGACAA -3′.6–8-week-old C57BL/6 male mice were obtained from The Chongqing Medical University’s Animal Experiment Center and housed in an environment free of pathogens with unlimited access to food and water. All procedures were approved by The Ethics and Medical Animal Care Committees of Chongqing Medical University. To create a liver fibrosis model, olive oil with carbon tetrachloride (CCl2 (5%) in a humidified environment. Primary HSCs were treated with PDGF-BB (20 ng/mL), TGF-β1 (5 ng/mL), and VEGFA (5 ng/mL) to identify the role of NRP1 in regulating HSC . By western blotting (WB), qRT-PCR, and immunofluorescence staining. The transfection of ShRNA sequences or adenovirus vectors  containing the cDNA of murine NRP1/USP9X was carried out into primary HSCs according to the manufacturer’s introduction.The isolation of primary HSCs (from around 3–6 mice) was carried out by collagenase-IV  perfusion, and then density gradient centrifugation was performed with OptiPrepTM, as discussed previously , 25. Try-ΔΔCt technique was utilized to calculate gene expression and GAPDH was used to normalize it. The oligonucleotide primers utilized in this study are shown in Table Total RNA was isolated By the RNA Simple Total RNA Kit  according to the manufacturer’s introduction. The PrimeScript RT Reagent Kit  was used to synthesize cDNA from the total RNA  using a reverse transcriptase enzyme. The 2Antibodies utilized in this study are as follows: anti-α-SMA (GTX629702) from GeneTex; anti-USP9X (ab19879), anti-NRP1 (ab81321), Anti-Myc tag (ab9106), anti-Flag-Tag (ab205606), and anti-GST (ab92) from Abcam; anti-collagen I (91144S), anti-rabbit IgG (3900), anti-mouse IgG (5415), from Cell Signaling Technology; anti-GAPDH (10494-1-AP) from Proteintech.The SDS-PAGE gel was employed to isolate proteins, followed by transferring onto the PVDF membrane. After blocking the membrane with 5% bovine serum albumin (BSA), primary antibodies (1:1000)were added, followed by rinsing and incubating with the secondary antibodies conjugated with the horseradish peroxidase . An enhanced chemiluminescence kit  was then employed to detect signals.For immunoprecipitation, NETN buffer was utilized to prepare cell lysates. For each immunoprecipitation experiment, 400 μg cell extracts were subjected to immunoprecipitation with NRP1 or USP9X antibody overnight at 4 °C. The immunocomplex was precipitated with protein A/G agarose beads (Thermo Fisher Scientific) and evaluated by WB.For the GST pull-down test, bacteria expressing GST, GST-NRP1, GST-USP9X-WT, or GST-USP9X-C1566S were coupled to glutathione-Sepharose 4B beads  and incubated with Flag-USP9X WT, Flag-USP9X C1566S, or His-NRP1 expressed in murine HSCs for 2 hours at 4 °C. Post reaction, GST-binding buffer was utilized to rinse the complexes (at least 4 times), followed by elution in SDS-PAGE loading buffer (via boiling), and then WB analysis was conducted with the indicated antibodies.Cells were transfected with various shRNAs as indicated for 72 h and then were incubated with MG132 (10 μM) 8 h and lysed with NETN buffer. Proteins were purified with IP with 400 μg cell extracts with S-protein agarose (Novagen)., After five times washing, the beads were eluted with SDS loading buffer, and then protein ubiquitinations were evaluated by WB.The transfection of the primary mouse or murine HSCs was carried out with both His-NRP1 and HA-ubiquitin, followed by exposure to MG132 (10 μM) for 8 h to prepare ubiquitinated NRP1 as the substrate for the in vitro ubiquitination experiment. Ubiquitylated NRP1 was enriched by using an anti-His affinity column and then incubated with recombinant GST-USP9X-C1566S or GST-USP9X-WT proteins at 37 °C for 2 h in deubiquitylation buffer, and then protein ubiquitinations were examined by WB.The fibrotic liver biopsy samples were from the clinical patients in First Affiliation Hospital of Chongqing Medical University between June 2018 and July 2021. Normal liver tissues were from the patient with trauma underwent liver resection. This study was approved by the ethics committee of First Affiliation Hospital of Chongqing Medical University and all subjects signed a written informed consent form before sample collection. Specimens were fixed in paraformaldehyde (4%) after surgical liver resection for histological examinations or frozen in liquid nitrogen for mRNA and protein analyses.2O2 for 10 minutes. Sections were rinsed three times in PBS-T (0.1% Tween-20) and incubated in 5% BSA for 10 minutes. After the removal of the blocking solution, slides were placed into a humidified chamber and incubated overnight with primary antibodies in blocking buffer (5% BSA in PBS) and incubated overnight at 4 °C. After washing, slides were covered with SignalStain Boost IHC Detection Reagent  for 30 min at room temperature. After washing two times with PBS-T, the Substrate-Chromgen Solution  was applied, and slides were incubated 5–10 min and counterstained with Hemtoxylin. Images were acquired using a Zeiss Axiolab 5 Digital Lab Microscope .Samples were fixed with 4% paraformaldehyde and cut into 4µm-thick sliced. After deparaffinization and rehydration, antigen retrieval was achieved by heating in a pressure cooker for 5 min in 10 mM of sodium citrate (pH6) or 1 mM EDTA (pH8). Peroxidase activity was blocked by incubation in 3% HFor immunofluorescence, After deparaffinization, rehydration and antigen retrieval, tissue slices were blocked with 5 % BSA before being incubated with the appropriate primary antibodies overnight at 4 °C. After washing, the slides were with secondary antibody , followed by counterstaining of the nuclei with DAPI. Images were acquired using a Zeiss Axiolab 5 Digital Lab Microscope .P < 0.05 was considered statistically significant.All quantitative data were presented as the mean ± SEM of at least three independent experiments. Statistical analysis was performed by using SPSS software (version 19.0). Differences between unpaired groups were determined by using One-way ANOVA with parametric/nonparametric distributions. Unless otherwise stated, Further information on research design is available in the 4 also displayed a substantial elevation in the expression of NRP1, particularly in the foci with broad fibrotic alterations (shown by positive Sirius red staining)  Fig. . The resice Fig. .Fig. 1El4-induced LF were infected with an adenovirus containing NRP1-interfering sequences (NRP1 shRNA). Interfering with NRP1 expression led to a marked remission of LF in CCl4-induced mice, as evidenced by a significant reduction in fibrotic areas (Masson and Sirius red staining)  Fig. and decring) Fig..The above date indicated the colocalization of NRP1 and α-SMA so we evaluated whether NRP1 promotes liver fibrogenesis by modulating the activity and function of HSCs by using primary HSCs. According to the results, NRP1 transcript and protein expression levels gradually elevated, which is associated with the elevation of HSC activating biomarkers, i.e., collagen I and α-SMA Fig. . NRP1 exTo explore how NRP1 was upregulated in liver fibrosis, we transfected Flag-NRP1 in mouse primary HSCs, followed by Co-IP and LC-MS/MS proteomic analysis to examine NRP1-interacting proteins Fig. . The resWe further examined whether USP9X influences NRP1 stability, murine HSCs were transfected with WT USP9X or the catalytically inactive mutant C1566S USP9X and examined NRP1 protein level Fig. . NRP1 prTo further assess whether USP9X is required for maintaining NRP1 stability, we knocked down USP9X in primary mouse HSCs and murine HSCs and examined NRP1 protein levels Fig. . USP9X kWe further assessed whether USP9X catalyzed deubiquitination of NRP1 by coexpressing NRP1 with USP9X WT or the C1566S mutant in primary mouse HSCs and murine HSCs cell lines and compared ubiquitination levels Fig. . NRP1 prTo further examine whether NRP1 was a direct deubiquitinated substrate of USP9X, we performed in vitro deubiquitination assay by incubating purified USP9X C1566S and USP9X WT and incubated with NRP1 under cell-free conditions and examined NRP1 ubiquitination Fig. . The res4. We evaluated fibrosis by Masson and with Sirius red staining. CCl4-treated livers showed prominent disordered architecture with the formation of septa between nearby vascular structures and signs of fibrosis involving certain features of parenchymal nodules. The sh-USP9X-CCl4-treated group had a significantly lower degree of diaphragm development  are one of the key cell types implicated in hepatic fibrosis . HSCs arNRP-1 is best recognized for its activity as a cell surface receptor and its participation in cellular signaling . ReceptoThe current study provides evidence supporting the extraordinary significance of NRP1 in stimulating HSC activation. However, there is a lack of clarity regarding their underlying upstream regulatory mechanisms. The current study’s Co-IP and LC-MS/MS proteomic analysis showed that USP9X could bind to NRP1. This study also confirmed that their mutual interactions require the CUB1 domain (1–141 amino acids) of NRP1 and the middle sequences (1201–2000 amino acids) of USP9X. USP9X is a crucial deubiquitinating enzyme that stabilizes various substrates and directly regulates numerous proteins’ functions. USP9X has been linked to endocytosis regulation, a remarkable function of NRP1. USP9X has been shown to regulate EGFR endocytosis in tumor cell lines by deubiquitinating its endocytic adaptor Eps15 and ubiquitin ligase Itch .In contrast, USP9X also binds directly to receptors such as ErbB2/HER2, thereby regulating their intracellular localization and transport . Given tWe further investigate the function of the USP9X/NRP1 signal in LF and discovered that the expression of USP9X was upregulated in LF tissues. Moreover, USP9X expression inhibition attenuated HSC activation and liver fibrosis, accompanied by low NRP1 expression. NRP1 has been confirmed as a novel substrate for the deubiquitinating enzyme USP9X. USP9X induced HSC activation and LF development in an NRP1-dependent manner, as shown by these results.In conclusion, NRP1 contributes to HSC activation and liver fibrosis. We further showed that USP9X is a critical deubiquitinating enzyme for the stability and high activity of NRP1. Thus, targeting NRP1 or USP9X for treating liver fibrosis could bring up new therapeutic options.Reporting SummarySupplemental Figure 1 The NRP1 expression in activated primary hepatocytes were assessed by immunofluorescence (A) and WB (B).Original Data FileOriginal Data FileOriginal Data FileOriginal Data FileOriginal Data FileOriginal Data FileSUPPLEMENTAL figure1EDITORIAL CERTIFICAT


In contrast, manual QTcFR (Fridericia correction), JT (Fridericia correction), Tpeak-to-end, and Tpe/QT ratio were significantly increased in the TdP [+] group, respectively: 486 ± 70 ms versus 456 ± 53 ms (p = 0.04); 433 ± 98 ms versus 381 ± 80 ms (p = 0.02); 153 ± 57 ms versus 110 ± 40 ms (p < 0.001); and 0.27 ± 0.08 versus 0.22 ± 0.06 (p < 0.001). Conclusions: The incidence of TdP complicating acquired AVB was 17%. Longer QTcFR, JT, and Tpeak-to-end were significantly increased in the case of TdP but also in the presence of permanent AVB during the hospitalization.Background: Female gender, degree of QT prolongation, and genetic susceptibility are known risk factors for developing torsades de pointes (TdP) during high-grade atrioventricular block (HG-AVB). Our objective was to analyze the prevalence and clinical characteristics of patients presenting with TdP and AVB (TdP [+]) in comparison with non-TdP patients with AVB (TdP [−]). Methods: All the ECGs from patients prospectively admitted for AVB  at the University Hospital of Nice were analyzed. Automated corrected QT (QTc), manual measurements of QT and JT intervals, and Tpeak-to-end were performed at the time of the most severe bradycardia. Results: From September 2020 to November 2021, 100 patients were admitted for HG-AVB. Among them, 17 patients with TdP were identified . No differences could be identified concerning automated QTc, manual QTc (Bazett correction), baseline QRS width, or mean left ventricular ejection fraction between the two groups. Potassium serum level on admission and mean number of QT-prolonging drugs per patient were not significantly different between the two groups, respectively: 4.34 ± 0.5 mmol/L in TdP [+] versus 4.52 ± 0.6 mmol/L ( Torsades de pointes (TdP) are a specific form of polymorphic ventricular tachycardia that is preceded by QT interval prolongation and occurs in a variety of conditions . TdP is Our objective was to analyze the prevalence, clinical, and ECG characteristics of patients prospectively admitted for AVB and TdP (TdP [+] group) in comparison with non-TdP patients (TdP [−] group).All the patients admitted at the University Hospital of Nice for acquired AVB were prospectively included in this study, and their electrocardiograms (ECGs) were systematically collected. The cohort included patients presenting with 2 to 1, high grade (HG), and complete AVB leading to bradycardia that was severe enough to justify hospital admission. The patients with the following forms of AVB were excluded from this study: AVB in the setting of acute myocardial infarction, drug toxicity, or vagally mediated episodes. All the patients underwent continuous cardiac monitoring during their hospitalization stay, until pacemaker implantation (if needed). The ECG tracings  were reviewed by one experienced electrophysiologist (S.-S.B.). AVB was classified as permanent in this study if complete AVB was observed throughout the hospitalization stay during cardiac monitoring, or intermittent if complete AVB was observed in alternation with 1:1 conduction .AUTO) were collected, and manual measurements of the following intervals were performed at the time of the most severe bradycardia: RR, QT, JT, and Tpeak-to-end intervals (FR uses the Fridericia heart rate correction formula  group if more than 10 TdP beats were recorded during telemetry. The clinical and electrocardiographic characteristics of the patients were analyzed, as well as the number of QT prolonging agents and potassium serum level on admission. ECGs were recorded at a gain of 10 mm/mV and a paper speed of 25 mm/s. Automated corrected QT intervals .The statistical analysis was performed using Excel . Categorical variables are described as numbers and percentages. Continuous variables are described as mean ± SD for normal distributions or median for a range for non-normal distributed. Between-group differences in categorical variables were compared using a chi-squared test. Differences between continuous variables were compared using a Student’s t test. To test whether different variables were influencing the occurrence of TdP, a binary logistic regression was performed with TdP as the dependent variable and other variables as covariates.p = 0.02. Two patients (12%) in TdP [+] elicited a pause-dependent (phase 4) AVB mechanism versus 12 (14%) in TdP [−], p = 0.77  versus 0.34 ± 0.5 (p = 0.13). QTc, QTcFR, the JTc interval, and Tpeak-to-end were significantly prolonged in the TdP group in comparison with the TdP [-] group .No differences could be identified between the two groups concerning QTng drugs  per pati-] group . Univario-end/QT . QTc wasAvailable data are sparse concerning the prevalence of TdP in AVB patients, reaching 11% in older reports . In thisAs reported in early observations, TdP may be associated with Adams–Stokes seizures in addition to syncopal episodes related to the asystole itself . This maAnother concern should be the development of pacing-induced cardiomyopathy and the likelihood of ventricular arrhythmia recurrence in patients with initial TdP on admission . It is ap = 0.11). Finally, the most discriminant factor was the presence of permanent AVB at presentation, which was significantly increased in the TdP [+] group as compared to the TdP [−] group (p = 0.02). In previous studies, female gender was found to be an independent risk factor for TdP occurrence; this was not the case in our study  group  group . The JT ng agent ,20,21.This is a monocentric study with a limited number of patients, but its prospective nature provided some new information about the expected prevalence of TdP complicating acquired AVB. Genetic testing was not systematically performed in our elderly TdP [+] group. Recent studies ,25 foundFR, increased JT interval, and Tpeak-to-end were electrocardiographic predictors of TdP. The presence of permanent AVB was more likely associated with TdP in comparison with intermittent AVB at initial presentation.The prevalence of TdP complicating acquired AVB was 17%. Longer QTc


Physical rehabilitation medicine is a diverse specialty; its main objective is to provide comprehensive rehabilitation involving multiple health care professionals to optimize function and improve the quality of life for people with disabilities. There is an increase in the number of people with disabilities, and people with disabilities in lower income countries do not receive the required rehabilitation. Rehabilitation intervention includes functional assessment, rehabilitation goal setting, composition of the focused team and coordination of the team works, all of which require a highly skilled team leader. No single professional is likely to have all the necessary skills to achieve optimal results alone. There is a knowledge gap between the theory, existing situation, and practice in rehabilitation team functioning. In this short communication challenges for quality rehabilitation services were highlighted, including the importance of the leadership role of team functioning. The continued occurrence of injuries and the emergence of noncommunicable chronic diseases increases the number of people with disabilities, particularly in developing countries, and the growing need for rehabilitation remains largely unmet globally , 2. PeopMedical rehabilitation is a diverse specialty. The conditions commonly dealt with include but are not limited to musculoskeletal disorders including joint problems, neurological disorders including stroke, spinal cord injury, brain injury, cardio-respiratory conditions, metabolic conditions including neuromusculoskeletal complications presenting in acute, postacute or chronic care settings .The rehabilitation interventions include exercises; modifying an individual's home environment; training and education on healthy living; prescribing medicines; providing psychological support; fitting an orthosis, prosthesis, or assistive devices . ClearlyThis was a short communication based on minireview of the available online literatures made during the period April to Sept 2022. The principal focus was on Developing country, Rehabilitation and Team works.Effective rehabilitation team working has been recognized and described since World War 1 . TeamworEffective team management is considered essential for rehabilitation goal setting team meetings and subsequent team coordination. Many of the developing countries' rehabilitation is not a health priority and faces multiple challenges in rehabilitation team functioning , 15, 16.Multiple challenges were identified for developing a physician-led rehabilitation team functioning in developing countries presented in BOX 1•Lack of relevant course contents of the rehabilitation professional curriculum•Poor training monitoring system and feedback options•A scarcity of trained and experienced rehabilitation professionals, a lack of infrastructure development, and inadequate funding in the rehabilitation sector•Overburdened rehabilitation professionals with poor attitudes toward service providers•Low rate of education of the persons with disability with political interference of administration•Potential ethical issues and dilemmas in team functioning•Minimal or no preparedness for disaster related onslaught casualtiesThere is a knowledge gap between the theory, existing situation, and practice in rehabilitation team functioning. Rehabilitation team functions better when it is led by a physiatrist. Multiple challenges exist for developing a physician-led rehabilitation team in developing countries, which may be addressed with local arrangements.


Research shows an important association between job exposures and various health- and employment-related outcomes. On contrast, little is known about the impact of job exposures on the employment status after medical rehabilitation. Thus, the aim of this study is to investigate the association between job exposures and employment, unemployment, and disability pension entry 2 years after rehabilitation.A retrospective cohort study was performed based on the scientific use file “SUFRSDLV15B” of the German Pension Insurance containing rehabilitation and occupational data at a monthly level. We included n = 597,021 insured persons aged 18 to 63 years completing a medical rehabilitation between 2008 and 2013 in Germany and traced their employment status over a 24-month follow-up period. Job exposures were operationalised with the Overall Job Exposure Index  by applying job-exposure-matrices.Persons with high job exposures in comparison to those with low job exposures were less likely to be employed (87.6% vs. 92.6%) and more likely to be unemployed (13.9% vs. 7.7%) and to draw disability pension (4.8% vs. 4.4%) for at least one month in the 2-year-period after rehabilitation. One minus survival curves showed that the differences were already evident in the first month after rehabilitation and further increased during the following 24 months. Cox regressions revealed that these associations remained stable when adjusting for gender, age, and employment status before rehabilitation.The results underline the importance of addressing job exposures during rehabilitation to enhance return-to-work and stay-at-work after rehabilitation. These findings could help to identify particularly vulnerable groups of insured persons based on routine data at an earlier stage than has been the case so far and to give them access to structured workplace-oriented medical rehabilitation programmes that have been established in recent years.• High job exposures are associated with less work participation after medical rehabilitation.• To increase return-to-work, it may be useful to address job exposures in rehabilitation more than before.