Like many other transit modes, the metro provides stop-to-stop services rather than door-to-door services, so its use undeniably involves first- and last-mile issues. Understanding the determinants of the first- and last-mile mode choice is essential. Existing literature, however, mostly overlooks the mode choice effects of traffic safety perception and attitudes toward the mode. To this end, based on a face-to-face questionnaire survey in Shenzhen, China, this study uses the two-sample t-test to confirm the systematic differences in traffic safety perception and attitudes between different subgroups and develops a series of multinomial logistic (MNL) models to identify the determinants of first- and last-mile mode choice for metro commuters. The results of this study show that: (1) Walking is the most frequently used travel mode, followed by dockless bike-sharing (DBS) and buses; (2) Variances in traffic safety perception and attitude exist across gender and location; (3) Vehicle-related crash risks discourage metro commuters from walking to/from the metro station but encourage them to use DBS and buses as feeder modes; (4) DBS–metro integration is encouraged by the attitude that DBS is quicker than buses and walking, and positive attitudes toward the bus and DBS availability are decisive for the bus–metro and DBS–metro integration, respectively; and (5) Substantial differences exist in the mode choice effects of traffic safety perception and attitudes for access and egress trips. This study provides a valuable reference for metro commuters’ first- and last-mile travel mode choice, contributing to developing a sustainable urban transport system. Cities are now encountering a large number of transport-related problems (mainly attributed to the extensive use of private cars or car dependency), including traffic congestion, deteriorated traffic safety situation, air pollution, increased vehicle emissions, environmental degradation, and excessive consumption of natural sources. “Reclaiming the city from cars” has constantly been advocated. Some of these vexing problems  even adversely affect the population’s health ,2,3. AddThe metro is a popular transit mode implemented in a multitude of cities, particularly large cities. Many motorized  and non-motorized  modes have been encouraged to serve as the feeder modes of the metro (or first-/last-mile modes before/after riding the metro), thereby attracting more commuters to use the metro. In a great many car-oriented U.S. metropolitan areas, park-and-ride is preferable, due in part to high car ownership and poor transit service . In EuroHowever, the decision-making process of the feeder mode choice is complicated and is determined by various factors. Previous studies offer insights into why individuals use specific transfer modes to connect transit . They maTo this end, based on a case study of Shenzhen, China, this study explores how the perceived traffic safety and the attitude toward transfer modes correlate to the feeder mode choice of metro commuters. A field questionnaire survey was conducted at many metro stations in Shenzhen, in which the metro commuter’s transfer mode for the access/egress trip has been examined. The two-sample t-test is used to confirm the systematic differences in traffic safety perception and attitudes between different subgroups, and a series of multinomial logistic (MNL) models is developed to identify the determinants of first- and last-mile mode choice for metro commuters. The study aims to address the following four research questions: (1) What is the mode share of access/egress trips in today’s Chinese mega cities? (2) Do traffic safety perceptions and attitudes vary by gender and location? (3) Are perceived traffic safety and attitudes toward transfer modes important in determining the transfer mode choice? (4) Are the effects of perceived traffic safety and attitudes toward the mode different between access and egress trips? We believe that this study contributes to the promotion of green and healthy urban mobility and serves as a valuable reference for Chinese mega cities and other settings with similar traffic conditions. The remainder of the paper is organized as follows. Walking, a travel mode with economic, environmental, social, and health impacts ,33, is oThe bicycle’s integration with transit (bike-and-ride) is also common for commuters. The synergy of the bicycle and transit for access/egress trips can be summarized into three patterns: bicycle-and-transit, transit-and-bicycle, and bicycle-on-transit (taking a bicycle on transit) ,35. TherAs for motorized feeder modes, the motorcycle (two-/three-wheeled motor vehicle), which usually carries 1–2 passengers, has a similar function with the taxi in many developing countries, such as China, Thailand, Vietnam, and India ,39. MotoThe private car is an option to access transit stations, and it involves two manners: park & ride and kiss & ride  . The avaOther modes such as traditional and electric scooters, e-bike, taxi, and ride-hailing can serve as the feeder modes of transit. However, few empirical studies have discussed their integration with transit .Traffic safety is usually measured by how unlikely accidents occur. It is reported that traffic accidents kill about 1.2 million people all over the world each year . TrafficPerceived traffic safety refers to individuals’ perceived likelihood of an accident-free traffic outcome  ,46. It vFurthermore, the perception of traffic safety may significantly affect mode choice decision . AccordiAttitude can be defined as ‘‘global and relatively stable evaluations that people do about persons, things or ideas” . Thus, aSome behavior theories, such as the theory of reasoned action (TRA) and its extension, namely the TPB, emphasized that the individual’s travel behavior is significantly influenced by attitudes. In TRA and TPB models, attitude is a predictor of the individual’s behavioral intention, which is a predictor of behaviors ,60,61. TIn addition to the specific attitude toward the travel mode, the travel behavior effects of general attitudes with a broad concept have been studied. For example, a positive attitude toward physical activity promotes bicycling and walking behaviors . Based oHowever, studies on the effect of traffic safety and attitude toward mode choice are still scarce in terms of the specific condition of feeder trips. Previous studies have mostly investigated mode choice for general trips but paid limited attention to the first- and last-mile trips. Therefore, more sophisticated analyses are indispensable to explore the associations between traffic safety, attitude, and feeder mode choice.2, indicating a high population density (6730 people/km2). Shenzhen had a vast amount of GDP in 2019 (390.34 billion dollars), ranking third in China. Over the last ten years, Shenzhen has widely been known as one of the Tier 1 cities in China  [Shenzhen, a famous international metropolis located on the southern coast of China and adjacent to Hong Kong, is selected as our study area. In 2019, Shenzhen had a population of 13.44 million and covered an area of 1997 kmangzhou) . Compareangzhou) , rankinggongjiao dushi)” by the Ministry of Transport of China, the local government has implemented a series of policy measures, such as establishing bus stops and allocating shared bikes  around metro stations, to promote the seamless connection between the metro and its feeder modes. The metro is an important travel mode for commuters, accounting for over 40% of trips taken by residents . AccordiAlthough Shenzhen witnessed an accomplished development of public transit, it experienced a sharp growth of private cars over the last decade. As of 2018, the number of motor vehicles in Shenzhen was approximately 3.37 million, and the total length of the road was 6443 km. This means that the density of motor vehicles (522.58 vehicles/km) is very high, which may result in an increased risk of traffic safety issues such as pedestrian/bicycle/vehicle-related crashes. Obviously, traffic safety issues are more acute in metro catchment areas with concentrated populations and vehicles than in other areas. As formerly mentioned, this study aims to identify factors influencing the feeder mode of the metro, paying special attention to perceived traffic safety and attitude; and feeder mode includes walking, DBS, private bicycles, buses, taxi/Didi, cars, scooters, and other modes. We, therefore, collected the data by conducting a field questionnaire survey at 22 randomly selected metro stations in Shenzhen, China, between October and November in 2019 . During The questionnaire was composed of several parts, including transfer mode choice, the individual’s perceptions of and attitudes toward specific transport modes, and socio-demographic characteristics. In this study, traffic safety concerns were measured in a subjective way by considering two safety issues: pedestrian–bicycle crash and pedestrian/bicycle–vehicle crash. Metro users’ attitudes toward typical first-/last- mile travel modes were investigated. Additionally, relative attitudes of metro users, such as DBS versus walking and DBS versus bus, were recorded. Furthermore, questions on the attitude toward metro users’ ability to access DBS and buses and the attitude toward daily physical activities were asked. Questions related to traffic safety perception were designed by referring to the “Neighborhood Environment Walkability Scale (NEWS)” questionnaire, which includes questions on individuals’ perceptions of the environment . Based oWe received 1702 questionnaires, 1167 of which were valid . The number of valid questionnaires for each metro station ranged from 30 to 93 . Among vThe average score of bicycle crash is approximately 3 (“somewhat agree”), which is modestly larger than vehicle crash. This observation indicates that the bicycle-related crash could be a major safety concern for metro users in first-/last-mile trips and may significantly affect metro commuters’ first-/last-mile mode choice. Similarly, metro commuters may face a risk of crashes with vehicles along their feeder routes. As for the transport mode, metro riders usually have a positive attitude or fondness toward non-motorized modes  but a negative attitude toward the bus (the average score is only 2.3). As for the access trip connecting home and the metro station, DBS/bus availability involves how easy to find DBS bikes/bus stops around their home. In terms of the egress trip connecting the metro station and the workplace, DBS/bus availability means that how easy to find DBS bikes/bus stops around metro exits. However, we observe that many metro users agree that it is not easy to find a DBS bike for both access and egress trips. By contrast, metro users hold an attitude that the bus stop is relatively easy to access. Moreover, respondents usually want to have some daily physical activities. The feeder trip distance is calculated via a geographic information system by connecting the geo-coded home/workplace addresses and the metro station reported by the respondents. The result shows that metro users have a longer transfer distance of home–metro feeder trips  than that of the workplace–metro feeder trips .This study applies two analysis approaches, namely the two-sample (two-tailed) t-test and the multinomial logistic (MNL) model. First, the two-tailed t-test is widely used to determine the statistical significance of difference between the means of two groups. In this study, it was performed to identify the variance in traffic safety perception and attitude among groups segmented by gender and location . Second, the MNL model is a popular method to relate a nominal  outcome variable to its predictors . One of Access MNL model and Egress MNL model) are developed. As the name explicitly states, the Access MNL model scrutinizes the determinants of feeder mode choice for access trips, while the Egress MNL model does so for egress trips. Additionally, collinearity was assessed by calculating the variance inflation factor (VIF), and the result shows that the VIF values of all variables were less than 5.Two kinds of transfer trips, namely access trips and egress trips, were considered. Thus, two MNL models  indicate that the MNL models have acceptable goodness of fit. Obviously, the MNL models can explain more variances in the access integrated use than the egress integrated use. The vehicle-related safety concern has significant effects on the feeder mode choice, while bicycle-related safety risk does not play such a significant role. The perception of bicycle-related crashes only affects mode choice between DBS and walking for access trips. A one-unit increase in the score of the perceived bicycle-related crash decreases the odds for choosing DBS relative to walking by 23.6% (= 1–0.764), holding all the other variables constant. A higher perceived risk of the vehicle-related crash encourages the choices of DBS and buses rather than walking to/from the metro station. For instance, high-speed vehicles crossing the intersections may make pedestrians feel dangerous. Thus, the exposures to vehicle-related crashes are deterrents for walk–metro users. Bikeway can provide cyclists with safety protection from the vehicle crash, and the bus is a sheltered mode protecting commuters from slight collisions with vehicles. For access trips, we see a 35.4% and 46.4% increase in the odds for opting for DBS and buses, respectively, relative to walking for a one-unit increase in the perceived risk of the vehicle-related crash, while the values for egress trips are 30.2% and 31.6%, respectively. This finding indicates that metro passengers are more affected by vehicle-related safety risks for access trips than for egress trips.Access model and OR = 0.647 in the Egress model). Similarly, by comparing the coefficients of the same variable, we find that favorable attitudes toward DBS and cycling behavior also promote the substitution effect of DBS to buses as the feeder mode. Moreover, it is found that the attitude toward buses does not significantly affect mode choice. We only observe that a negative attitude toward walking increases the possibility of choosing buses for an access trip, particularly when the bus service is easily perceived to be offered around the home. This observation is reasonable.Specific attitudes toward transport modes are observed to have an essential role in determining mode choice. As many previous studies concluded, bike-sharing mostly replaces walking for travel ,79. Our Access model and OR = 1.921 in the Egress model). Moreover, a relative attitude that DBS is quicker than buses can increase the odds of choosing DBS as an egress mode. Our results are consistent with the study by Heinen and Bohte [Relative attitudes between travel modes are also crucial to metro passengers’ feeder mode choice. If metro users think that DBS is faster than walking to connect the metro station, they will have a higher possibility of adopting DBS as the feeder mode  for connecting the metro transit . ApproprHowever, there are some limitations that deserved future research. First, limited by the questionnaire design, we only include two traffic safety variables (bicycle crash and vehicle crash) in the MNL models. As such, more perceived safety factors such as in-vehicle safety in buses and cars should be considered in future studies . Second,In a departure from existing literature, this study explores how perceived traffic safety and attitude factors are associated with metro commuters’ feeder mode choice during the morning peak time. Our analysis results basically answer our four research questions see  and can


We are currently experiencing the disaster of the COVID-19 pandemic. Since the first case of Coronavirus disease 2019 (COVID-19) was confirmed in South Korea on January 20, the number of COVID-19 cases in South Korea has been rapidly increasing until early March due to a local spread in Daegu, which is one of the eight metropolitan cities in South Korea with a population of 2.5 million. As the medical academy has social accountability as professionals, Daegu-Gyeongbuk branch of the Korean Academy of Family Medicine (Daegu-Gyeongbuk branch) developed the health counseling program for discharged COVID-19 patients. The Daegu-Gyeongbuk branch communicated with Daegu Medical Association and Daegu city for this program and incorporated available resources and capabilities as a leader of this program. This newly developed counseling program consists of medical consultations, sending healthcare brochures and medical supplies, and the appraisal at the end of the program. Not only COVID-19 related symptoms but also other psychological problems are also dealt with during consultations. This program started on March 18, and over 1,700 recovered patients have been receiving counseling as of April 28. Communication and cooperation between the medical academy, medical association, and government are essential to overcome the COVID-19 pandemic. Besides, we expect to apply this health counseling program and our model of setting this program cooperating with medical association and government to different infectious pandemic crisis. Twenty-seven cases of pneumonia of unknown origin were reported by the China National Health Commission on December 31, 2019 in Wuhan, Hubei province , the 31sThe health counseling program after recovery from COVID-19 is a newly developed medical counseling program by family physicians at the Daegu-Gyeongbuk branch based on phone consultations. The purposes of the health counseling program focus on the management of medical and psychological problems and early recognition of coronavirus reactivation. Thus, not only medical symptoms associated with COVID-19 but also other psychological problems such as depression, anxiety, and even family relations are included in the counseling process. In addition, physicians provide emotional support to individuals in every counseling session. This program was scheduled to be held for a month for each participant.As the first step to start this program, the Daegu-Gyeongbuk branch proposed this program to the Daegu Medical Association and Daegu city. In the emergent situation of rapid spread of COVID-19, the Daegu-Gyeongbuk branch communicated and cooperated closely with Daegu city and Daegu Medical Association reaching an agreement that management for patients who recovered from COVID-19 is necessary. As a rapid response to the proposal of this program, Daegu city was responsible for introducing this newly developed program to discharged Daegu citizens, getting the consent for program participation, and providing individual information including the date of isolation and discharge to the Daegu-Gyeongbuk branch. Daegu city also provides resource assistance, such as mobile phones for consultations. Daegu Medical Association has helped in terms of communication and coordination between Daegu city and the Daegu-Gyeongbuk branch. Furthermore, the Korean Academy of Family Medicine provided donations to the Daegu-Gyeongbuk branch. As a leader of this program, the Daegu-Gyeongbuk branch contributed by coordinating each organization's role as well as suggesting this program. Besides, the Daegu-Gyeongbuk branch distributed funding resources to program participants based on the principles of justice. Regarding physicians, the Daegu-Gyeongbuk branch recruited volunteers to counsel the recovered COVID-19 patients, and a total of 20 family physicians decided to participate in the program. All these processes are briefly demonstrated in As shown in A total of 1,706 recovered patients have been receiving counseling, which means 25% of all recovered patients from COVID-19 in Daegu have had medical consultation. Most of the participants were female (66.2%), and the mean age was 39.6 years (range: 0–79 years). This program ended at the 1st week of June considering new confirmed cases in Daegu have declined since mid-April. During this program, we assessed recovered patients' depression, anxiety, stress, quality of life, and family relations along with clinical presentations of COVID-19.Here is an example of actual consultation; A 26-year-old woman who was confirmed as COVID-19 on March 4 and released from quarantine on March 19 had first consultation on March 24. She has had asthma and still complained of mild dyspnea in the first consultation. She also complained of mild anxiety and depression from stigma attached with COVID-19. Her father and her colleagues treated her as an infection source even after discharge with twice negative on COVID-19 tests. Counseling physician recommended watchful waiting for mild dyspnea since she did not have other related symptoms and its course was getting better per participant. However, she seemed to need further consultation for anxiety and depression. So, the physician recommended follow up consultation a week later, and introduced COVID-19 mental health hot line which is available for 24 h a day. On the 2nd consultation, the participant said she felt much better for her breathing, but still anxious to meet other people. Though, she mentioned that she felt somewhat relieved after having conservation with the physician. In the final consultation, the participant said she went back to work without any symptoms, but she was still cautious when talking with other people even with her mask on. The physician ended the counseling program congratulating her recovery from COVID-19, and emphasizing the health education again such as hand hygiene and wearing mask when going for work.According to the participant satisfaction survey at the end of the program, about 78% of participants were satisfied with the consultation, 16% reported neither positive nor negative, and only 6% were dissatisfied with the consultation. As reasons for satisfaction with this consultation, health education including hygiene education to prevent COVID-19 and early recognition against COVID-19, and emotional support such as active listening and showing empathy was mainly selected. On the other hand, a lack of empathy was presented as a reason for dissatisfaction. According to the physician satisfaction survey, 7 physicians among 20 reported their routine work was disturbed a little. However, most of the physicians reported they felt overwhelmed and proud to have been part of this newly developed program as medical professionals in the COVID-19 pandemic. One of limitations that physicians pointed was immediate testing or prescribing was impossible due to phone-based consultation.We are currently experiencing the disaster of the COVID-19 pandemic. Rapid diagnosis, treatment, and isolation of confirmed or suspected cases are essential to cope with this global health crisis. Along with these actions, the management strategy for patients who have recovered from COVID-19 is also crucial. To the best of our knowledge, this is the first health counseling program for patients who have recovered from the COVID-19 pandemic, conducted by physicians. This phone-based counseling program surveyed not only current remain symptoms which might be the early signs of coronavirus reactivation, but also each participants' mental health. However, there are some limitations in this program. First, this health counseling program might not be well-organized since it was urgently designed, and promptly performed responding to COVID-19 outbreak in Daegu. The performance evaluation for both physicians and participants has been completed and being analyzed in regard to planning, action, and overall satisfaction. Second, we could not involve all patients recovered from COVID-19, and this program was limited to only Daegu citizens. Thus, individualized adaptation should be required when this program is applied to different government or country. Last, we could not evaluate this program in terms of comparison with other counseling programs since the organized counseling program by physician in COVID-19 pandemic has not been reported yet. Considering that COVID-19 is still ongoing and over hundreds of thousands of patients will be discharged worldwide, communication and cooperation between the medical academy, medical association, and government are essential to overcome the COVID-19 pandemic. Moreover, as the medical academy and medical association have social accountability as professionals, they should provide leadership and cooperation between national authorities and other medical associations to incorporate available resources and capabilities during this pandemic crisis. Besides, we expect to apply this health counseling program and our model of setting this program cooperating with medical association and government to different infectious pandemic crisis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the institutional review board of Daegu Catholic University Medical Center. The patients/participants provided their written informed consent to participate in this study.GHL developed the research questions, provided critical revision of the article, and provided final approval of the version to publish. KML, HJK, DWL, and ASK provided substantial contributions to the program management and supervision. YAK contributed to writing and submitting the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Internet-based cognitive behavioral therapy (iCBT) for children and adolescents is a persuasive system that combines 3 major components to therapy—therapeutic content, technological features, and interactions between the user and program—intended to reduce users’ anxiety symptoms. Several reviews report the effectiveness of iCBT; however, iCBT design and delivery components differ widely across programs, which raise important questions about how iCBT effects are produced and can be optimized.The objective of this study was to review and synthesize the iCBT literature using a realist approach with a persuasive systems perspective to (1) document the design and delivery components of iCBT and (2) generate hypotheses as to how these components may explain changes in anxiety symptoms after completing iCBT.A multi-strategy search identified published and gray literature on iCBT for child and adolescent anxiety up until June 2019. Documents that met our prespecified inclusion criteria were appraised for relevance and methodological rigor. Data extraction was guided by the persuasive systems design (PSD) model. The model describes 28 technological design features, organized into 4 categories that help users meet their health goals: primary task support, dialogue support, system credibility support, and social support. We generated initial hypotheses for how PSD (mechanisms) and program delivery (context of use) features were linked to symptom changes (outcomes) across iCBT programs using realist and meta-ethnographic techniques. These hypothesized context-mechanism-outcome configurations were refined during analysis using evidence from the literature to improve their explanatory value.A total of 63 documents detailing 15 iCBT programs were included. A total of six iCBT programs were rated high for relevance, and most studies were of moderate-to-high methodological rigor. A total of 11 context-mechanism-outcome configurations  were generated. Configurations primarily comprised PSD features from the primary task and dialogue support categories. Several key PSD features  were consistently reported in programs shown to reduce anxiety; many features were employed simultaneously, suggesting synergy when grouped. We also hypothesized the function of PSD features in generating iCBT impacts. Adjunct support was identified as an important aspect of context that may have complemented certain PSD features in reducing users’ anxiety.This synthesis generated context-mechanism-outcome configurations (hypotheses) about the potential function, combination, and impact of iCBT program components thought to support desired program effects. We suggest that, when delivered with adjunct support, PSD features may contribute to reduced anxiety for child and adolescent users. Formal testing of the 11 configurations is required to confirm their impact on anxiety-based outcomes. From this we encourage a systematic and deliberate approach to iCBT design and evaluation to increase the pool of evidence-based interventions available to prevent and treat children and adolescents with anxiety. Anxiety is one of the most common and early emerging mental health concerns for children and adolescents , 20% of persuasive system—an intervention designed to change user’s attitudes and behavior toward their desired health goal  certain concepts in the program” , providiaterial” .Talk Time was used to prompt the mother  and child to discuss a therapy topic or work together on a task  built into the start and end of core program modules to monitor symptom change and to help the user choose customized streams of program content specific to their emotional distress ” . Anotherpersonal Web-based workbook that could be accessed by them at any time  explored in the program.” . Similarto help users understand themselves and others better [Universal prevention programs for adolescents with minimal or no symptoms, delivered with teacher facilitation, that include rehearsal may produce postintervention reductions in user’s self-reported anxiety symptoms. The e-couch Anxiety and Worry program included rehearsal exercises s better . The Moos better . RehearsOur study systematically documented important similarities and differences in the design and delivery of iCBT components across 15 existing programs, which to our knowledge, is the first study of its kind for children or adolescents with anxiety. Anxiety reductions were reported in more than 98% of studies we reviewed. Our use of realist synthesis methods enabled the development of 11 context-mechanism-outcomes configurations that hypothesized the PSD features (technology-based mechanisms) that might contribute to the observed reductions in anxiety symptoms (outcomes), as they relate to key user and delivery features (context). Our results point to the need for increased emphasis on PSD in the development, evaluation, and reporting of iCBT programs for children and adolescents with anxiety concerns and further research designed to establish their relationship with improved anxiety symptomatology.The 11 configurations included PSD features from all 4 support categories. However, some category features were more often linked to iCBT program effects than others. Our findings highlight the central role of primary task supports in iCBT interventions for children and adolescents with anxiety, followed by dialogue support and system credibility support categories. Only 1 social support feature was supported by our analysis. These findings are in line with others ,109 who work as such  and (2) different PSD features have different functions, so we cannot assume that more features are better. We identified features from within and across different PSD support categories that were employed simultaneously, suggesting some synergistic or additive effect in their grouping . There have been attempts to examine the quantity and combination of PSD features in relation to the effectiveness of other health-based programs [All iCBT programs in this study contained multiple PSD features. Although detailing the frequency of PSD features in iCBT provides some insight into what a user does within a program (activity), this information does not describe the important patterns or combinations of PSD features or explain why a program may or may not be effective. However, our findings suggest that (1) no PSD feature is applied in isolation and will likely not programs ,115-117,programs  indicateprograms . Additivprograms . Future Overlap with the proposed context-mechanism-outcome configurations we generated and the literature on internet-based interventions indicate larger patterns for how these features operate. For example, others have hypothesized that self-monitoring might be used to increase user’s knowledge, self-awareness, and ability to monitor and manage their health ,119. Simsignature features that appeared to be particularly effective at producing the desired effects of iCBT regardless of the program type—perhaps because of the mental  activity and the interactions  between the user, the program content, and its features they incite. Our proposed key PSD features may produce symptom reductions in iCBT because they initiate higher-order cognitive processes, such as information recall, mental reflexivity, and future planning, much similar to the CBT content in these programs as well  [The consistent incorporation of specific key PSD features  in configurations across all program types indicates that these may be cturing) , that macturing) ,130.at risk behaviors targeted), and expected benefits  differ depending on program type  [Differences in key PSD features may distinguish iCBT programs of one program type from another . It has been recognized that user characteristics , the focus of a program  . It may eatment) ,131,132.program type together. For example, we found that the context of all universal prevention programs involved widespread delivery in schools, during regular class periods, to all students in attendance, by a teacher with no specialized mental health training. This aspect of context differed considerably from indicated prevention and treatment programs that had a primarily self-led delivery format  where minimal, but some, Web- or email-based interaction with an adjunct support person was provided. PSD features could be affected by program contexts in a way that determined their presence or absence and the quality or how they were delivered. An example of this is that personalized feedback was provided to users only if an adjunct therapist was available to craft and deliver the message—a feature provided to users of treatment and indicated prevention programs. Another example is, in terms of iCBT practice, at-home or clinic-based delivery of programs required users to complete Web-based homework , whereas with some school-based universal prevention programs, paper-based homework (non-Web-based) was assigned to users during class.Realist synthesis methods focus on uncovering both the mechanisms of a complex intervention and their relationship to context ,133-135.School-based universal prevention programs have aspects of context  that are different from indicated prevention and treatment programs, making their design and delivery unique . In thisWe took a high-level perspective to develop hypotheses that may explain the effects of iCBT as a complex intervention. To our knowledge, this is the first study to systematically describe what and how PSD features may relate to symptom reductions in iCBT across programs for children and adolescents with anxiety. Although our findings may be similar to those of adult-based studies of internet-based interventions  that may produce the outcomes observed. With increasing emphasis being placed on the need for theory to guide internet-based intervention development [This review has several strengths. We followed established and rigorous methods for conducting and reporting realist syntheses ,26,27. Welopment -146, espelopment , our finelopment ,148, andelopment . Althougformal consideration of program type  before designing and evaluating a program, as there are important differences in the target users, program design and delivery, and outcome measures used that may have a significant impact on program effects that should not be overlooked.Several challenges placed limitations on our findings. The 11 context-mechanism-outcome configurations we developed were dependent on the level of detail provided in the documents included in this synthesis. iCBT program descriptions were brief and details around therapeutic or technological features used (and associated theory or justification) were limited. Thus, the specifications of each technological (PSD) feature are not accounted for with our approach (which required a high level of abstraction) and readers should consider that the differences within features of the same type may be just as large as the differences across feature types . We hope the hypotheses that we have generated can be applied to more detailed studies in the future that explore this important issue. In addition, few ineffective interventions (those that did not generate anxiety reductions) were identified for our review; therefore, we were unable to explore aspects of the delivery context or PSD features that might contribute to undesirable treatment effects with iCBT. As the dissemination and use of reporting standards  and reqfirst principles for how the individual and most basic applications of PSD features in iCBT programs work, so we can scale up our understanding of their effects in parallel with advancing technology and the complexity of program design. This review highlights 2 recommendations for future directions in the iCBT field.As more complex and sophisticated technological mediums or delivery methods  and features  are being developed and incorporated into new technology-based treatments, we need to understand the First, studies designed to assess the impact and functions of identified program components and identify other components that are relevant for the design of new iCBT programs for children and adolescents with anxiety are needed. Evaluating individual program features to understand their theoretical level of action , instantiation , quality , and their effect  -156 may Evaluation of individual features requires the use of certain methodological frameworks ,158 and Second, to advance our understanding of the causal mechanisms that underpin effective iCBT programs, we will need to address what and how therapeutic content  is delivered using PSD (technology-based) features to produce the intended and actual attitude or behavior changes. This will involve developing a framework that integrates the PSD model with the CBT framework and a theory of behavior change (for a review of theories see ) to idenAlthough iCBT effectiveness for children and adolescents with anxiety has been demonstrated, not all programs benefit users in the same way. This leaves room for programs to be further optimized. PSD  features can be intentionally selected and incorporated into the design and delivery of iCBT programs, making it an aspect of treatment that is under the control of developers. The hypotheses that we generated suggest that multiple key PSD features may work together to help users actively engage with therapeutic content and practice newly acquired skills. The type and degree of adjunct support will vary based on the level of prevention and user characteristics  the program was designed to target and can influence what and how certain features operate within the program. The key PSD features and aspects of context identified require formal testing to understand whether, and to what extent, they are effective and how they function. These next steps may involve new conceptualizations of effectiveness and evaluation methods. As we improve our understanding of how the components of iCBT work (their proposed purpose) and what users prefer and need, we can create programs with better objective and subjective effectiveness. This systematic and deliberate approach to iCBT design and evaluation will increase the pool of evidence-based interventions available to prevent and treat anxiety in children and adolescents.


Preferentially expressed antigen in melanoma (PRAME), which belongs to the cancer/testis antigen (CTA) gene family, plays a pivotal role in multiple cellular processes and immunotherapy response in human cancers. PRAME is highly expressed in different types of cancers and is involved in cell proliferation, apoptosis, differentiation and metastasis as well as the outcomes of patients with cancer. In this review article, we discuss the potential roles and physiological functions of PRAME in various types of cancers. Moreover, this review highlights immunotherapeutic strategies that target PRAME in human malignancies. Therefore, the modulation of PRAME might be useful for the treatment of patients with cancer. Moreover, PRAME can act as an oncogene or a tumour suppressor gene in different cancer types Table . PRAME eAlthough the function of PRAME has been discussed, there are still several remaining questions. For instance, what are the upstream signalling pathways that regulate PRAME? How does PRAME govern their downstream targets? What other innovative technologies can improve the effect of PRAME‐based immunotherapy? To address these issues, we will need to use whole‐body or tissue‐specific knockout or knock‐in mouse models that will help us determine the carcinogenic effects of PRAME in human cancers. Altogether, in‐depth studies could contribute to the development of novel countermeasures and innovative technologies to target PRAME in immunotherapy for fighting human malignancies.This work was supported by the Science and Technology Planning Project of Wenzhou City (No. ZS2017006).The authors declare that they have no conflict of interest.Y.X. searched the literature and wrote the manuscript. R.Z. and J.W. made the figure and table. ZW.W. and X.Z. critically viewed, edited and approved the manuscript.


N = 14) benefitted in a moderate to very large extent relative to a similar control group (N = 52). In contrast, team members (N = 148) displayed no such benefits. Specifically, higher levels of autonomy satisfaction are said to lead to higher levels of psychological well-being and motivation. Still, the link with business performance is absent in most organizational studies within self-determination theory, making the present study one of the first to fill this gap. The study discloses the program design, compares the effects to a relevant control group, evaluates the lessons learned, and provides practical suggestions.The present quasi-experimental study tested the business impact of a leadership development program focusing on psychological well-being through the satisfaction of basic psychological needs. Based on the concept of engaging leadership and self-determination theory, the 8-month program targeted midlevel team leaders of the customer fulfilment center of a health systems multinational organization. The program was designed in co-creation between senior leadership and the team leaders that participated in the program. Outcomes showed positive business results through significant increases in a preselected key performance indicator and decreased employee absenteeism. Through changes in autonomy satisfaction and intrinsic motivation, the team leaders ( Leadership effectiveness is of primary concern to organizations—hence the popularity of leadership development programs and the considerable investment organizations make in such programs . OrganizThe principal ambition is to create a work environment where both employees and leaders may flourish, self-develop, and meaningfully contribute . New andWe chose self-determination theory (SDT) as the theoretical point of departure for the current study because of its integrative approach. SDT links a theory of human development and motivation with a view on organizational effectiveness and leadership. Through basic psychological needs theory (BPNT) , and orgIn short, SDT posits that people flourish, are optimally motivated, perform well, and contribute positively to the organization’s performance by positively identifying with and positively integrating leadership experiences . Hence, Autonomous and intrinsic motivation associate with the satisfaction of the basic psychological needs of autonomy, competence, and relatedness ; the fulThe engaging leadership concept was selected because it draws on BPNT and aims explicitly to identify leadership behaviors that may induce work engagement through the satisfaction of basic psychological needs . ThroughPrior studies on the effectiveness of leadership development within SDT refer to “autonomy-supportive leadership” and found that leadership behaviors promoting the satisfaction of basic needs and autonomous motivation can be learned . Still, Periodical progress in business performance is generally measured using the balanced scorecard methodology developed by Kaplan and Norton , which aAnother widely used KPI is the level of sick-leave absenteeism, which is considered an objective, operationalized performance measure linked to organizational performance . PositivFor the present study we used individual sick leave reports documented by the HR department and the occupational health and safety provider. Two separate periods were analyzed to measure sick-leave absenteeism: a pre-intervention period covering the 12 months preceding the intervention and a post-intervention period covering the 12 months after the program . The meaThe primary aim of the current study was to improve objective business performance and decrease absenteeism through a leadership development program of which co-creation formed an integral part to support autonomy of participating midlevel team leaders. The secondary aim was to test whether the content and the design of the leadership program would benefit participating team leaders and whether the positive effects would spill over to the team members. Three hypotheses were formulated:Hypothesis 1.As a result of the leadership program, (a) the business performance of the department of the intervention group will increase to or exceed the agreed target level, and (b) absenteeism within the department will decrease.Hypothesis 2.(a) The team leaders participating in the leadership development program will report higher levels of engaging leadership compared to the control group, and (b) they will experience an increase in their levels of autonomy satisfaction and (c) intrinsic motivation.Hypothesis 3.The effects of the leadership program will positively spill over to the team members, who are expected to benefit from the program indirectly. As a result, team members will perceive more engaging leadership and higher levels of autonomy and intrinsic motivation than those whose leaders did not participate.N = 14, female 29%) and 148 team members, and team size averaged 10–12 members per team. At pre-test (T0), 13 team leaders, 93% response rate, female = 29%, age = 38.57 , tenure 3.88 (SD = 2.35) and 106 team members, 71% response rate, female = 51%, age = 39.32 (SD = 9.55), tenure 2.5 (SD = 2.23) completed the survey. At follow up (T1) eight months later, 14 team leaders completed the questionnaire, 12 of whom had also responded at T0; this difference in follow up was due to a staff change in the team, as one of the team leaders left the department. Regarding the team members, 109 responses were received at T1 (74% response rate), 81 respondents had also completed the survey at T0.The present study used a quasi-experimental, pre-test–post-test control group design. The intervention and control groups were selected from the same multinational organization, which develops, produces, and services health systems. The intervention and the control group were responsible for back-office processes and delivered their information and services to other departments of the organization. The intervention group consisted of team leaders and team members of the customer fulfilment centre, whose main task is to manage the back-office processing of new orders from sales to production, shipping, delivery, and invoicing. The control group members were information analysts from the information management department, whose jobs are to gather, analyze, control, and distribute information across the organization. The control group was selected on comparable qualities to the intervention group, such as department size in full-time equivalents, business process , and locality. The intervention group consisted of 14 team leaders  team leaders and (2) team members, instead of one leader per team with his or her direct reports. The control group consisted of 52 team leaders and 218 team members. At T0, 39 team leaders, 74% response rate, female = 30%, age = 42.42 (SD = 8.38), tenure 2.06 (SD = 1.10) and 119 team members, 55% response rate, female = 43%, age = 44.36 (SD = 11.70), tenure 1.95 (SD = 1.31), completed the survey. At T1 eight months later, 23 team leaders responded, 21 of whom had also participated at T0. A total of 104 responses were received from the team members, of whom 62 had also completed the survey at T0.The leadership development program consisted of three phases: (a) co-creation; (b), intervention or execution; and (c) evaluation and sustainment ,51. FiguWith the control group, the design and purpose of the program were discussed with representatives of the control group’s senior leadership team, who then informed the team leaders, who invited direct reporting team members to participate in the survey on a voluntary basis through email. Team members were, however, not informed about the intervention group’s leadership program.The second phase of the intervention consisted of three building blocks : six traThe training program  commenceThree guided peer-consultation sessions were offered between the training days. Peer-consultation provides a structured method of facilitated conversation for improving personal functioning and professional performance, addressing leadership challenges, and engaging in group problem solving based on mutual support and consultation with peers. The team leaders also had two personal coaching sessions to address their leadership challenges confidentially. The peer consultation sessions and coaching sessions were facilitated by two coaches, who worked according to the International Coach Federation (ICF) guidelines.Business performance was measured with the metric OBOT as defined earlier. The business metric was selected because it was considered the essential business metric for the department. Absenteeism was measured following the procedure described previously. The company’s overall target for absenteeism was to remain below a 3% threshold. At the time of the initiation phase of the project, absenteeism in the department had risen to 7.7%, which raised a red flag to senior management and accelerated the development of the leadership development program. Engaging leadership (EL) was measured with the 9-item Engaging Leadership scale developed by Schaufeli , which wAutonomy satisfaction (AS) was measured with the three items from the Balanced Measure of Psychological Needs (BMPN) Scale developed and validated by Sheldon and Hilpert . The iteIntrinsic motivation (IM) was measured with the three items for intrinsic regulation from the Multidimensional Work Motivation Scale . The iteThe business outcome measures were reported every month to the global department head and continued after the intervention had ended. In contrast, the survey was administered at two time-points, at pre-test and post-test after the intervention program had completed. The business measures were followed for another six months beyond the intervention program to evaluate whether the intervention results were sustained into the next year.2(103) = 119.01, p = 0.134. Nevertheless, it was checked whether one of the variables could be predictive of subsequent dropout of respondents through examining systematic attrition ; d = 0.69). The other two variables (autonomy satisfaction and intrinsic motivation) did not and presumably counterbalanced the dropout risk. By the same token, low scores on autonomy satisfaction may have contributed to a medium-low risk of team members dropping out in the control group (t(117) = 2.23; p < 0.05; 95% CI, ; d = 0.41). No further steps were taken since the missing data were MCAR.First, we screened the data for multivariate outliers using the Mahalanobis distance procedure, which identified one outlier in the intervention group at pretest: the respondent had dropped out and was thus not considered in the analyses. Skewness and kurtosis were verified to be within an acceptable range. The MCAR (missing completely at random) procedure was run ,54 to esttrition  for the t(117) = 1.92, p = 0.06, 95% CI , d = 0.63. Although the difference was nonsignificant, the effect size was of medium strength. In the control group the difference between the leaders self-assessment and their team members was similar in strength and significance: t(156) = 3.00, p = 0.003, 95% CI , d = 0.62.The descriptive statistics were calculated for both the intervention and control group at baseline . At pre-The means, standard deviations, and intercorrelations between variables were examined at the two time-points for the team leaders and the team members .2  = 295.88, p < 0.001, 95% CI . The percentage increased another 3% in the six-month period after the intervention (June) to 95%: χ2  = 167.50, p < 0.001, 95% CI . Additionally, the average number of orders booked on time per fulltime equivalent developed positively: At pre-test, this was 304 OBOT/FTE, at post-test, this was 324, and 6 months after post-test this was 357.Hypothesis 1a predicted that business performance would increase to or exceed the target level set. To assess the department’s business performance, as measured by OBOT, the “N-1” chi-square test  was perfwithin-group differences between the pre- and post-test measurements. As depicted in p > 0.05). In contrast, the intervention group’s sick-leave absence decreased significantly over the twelve months after the intervention by 3.4% (p < 0.001). The total net number of lost workdays per month declined by almost 60%, from an average of 113 per month in the twelve months preceding the leadership program to 66 after the program (p = 0.02). Overall, the outcomes confirmed the hypothesis that sick-leave absenteeism would drop as a result of the leadership intervention program.Hypothesis 1b predicted that absenteeism decreases as a result of the leadership program. The sick-leave absenteeism data obtained from the service provider were analyzed using nonparametric statistics due to the skewed nature of the sickness absence data. We applied the Wilcoxon signed ranks procedure for related samples to test the p < 0.001) between the two groups for all absenteeism tests performed, except for frequency . However, the differences between the two groups were non-significant in the post-test analysis, except for frequency , presumably due to the significant decreases in the intervention group and the parallel increases in the control group regressing to the mean.The “between”-group differences between the intervention and control groups were tested with the Mann-Whitney U test for independent samples. The pre-test outcomes comparing the intervention and control groups indicated significant differences (Hypothesis 2a predicted that team leaders would (a) report higher levels of engaging leadership (EL) and (b) display an increase in autonomy satisfaction (AS) and (c) intrinsic motivation (IM). A multivariate test of variance was used to test the differences between the two groups over the two time-points, with EL, AS, and IM at T1 as dependent variables. The same variables were used as covariates at pre-test, to adjust the means between the intervention and control groups at the pre-intervention level. Additional checks on the underlying assumptions for a successful two-way multivariate analysis were conducted. The regression slopes were linear, and homogeneity checks were performed. Levene’s test to assess the equality of the variances confirmed there were no significant differences in variance between the two groups or the leads and members. Box’s M test was conducted to assess the equality of co-variance and supported the assumption that the co-variance matrices between the groups could be assumed to be equal. As far as demographics variables are concerned, age had a positive and tenure had a negative effect on engaging leadership and motivation for team leads. Conversely, tenure had a positive effect on engaging leadership, autonomy, and motivation for team members. Therefore, we decided to control for age and tenure for team leads and tenure for team members.p2 = 0.25) for autonomy satisfaction and a large affect for intrinsic motivation (εp2 = 0.12). Hence Hypotheses 2b and 2c were supported by the data, whereas Hypothesis 2a was not.Two separate analyses, one for team leaders and one for team members, were conducted. The intervention effects were non-significant for the team leaders and team members . ConsideF = 4.23, p = 0.04, εp2 = 0.04) increase in AS for team leaders  compared with team members . Also, the IM scores for team leaders  were significantly higher  = 5.88, p = 0.02, εp2 = 0.05) than those of team members . The corresponding effect sizes indicated a medium-small (AS) to medium (IM) strength.Hypothesis 3 predicted that the effects of the leadership program would positively spill over to team members. However, no relevant changes were found in the team members’ levels of perceived EL, AS, or IM . Next, tThe present intervention study aimed to generate positive business outcomes in terms of KPI performance, reduced absenteeism, and elevated motivation and well-being through an engaging leadership development program. The program consisted of an initial co-creation phase. It targeted midlevel team leaders who were subsequently trained in engaging leadership and the satisfaction of basic psychological needs through six one-day training sessions. Peer consultation and personal coaching were offered to support the integration of the program contents in small groups and one-on-one coaching sessions. The program resulted in a significant increase in KPI performance (OBOT), which continued after the program had ended and was in support of Hypothesis 1a. The total rise in OBOT had a beneficial monetary impact (8% more orders booked on time per month with the same number of FTEs and resources). The department was also able to invoice earlier, which led to a substantial positive effect on cash, as the department head reported.Sick-leave absenteeism among the department’s team leaders and team members decreased considerably during and after the program, which outcome was as expected (Hypothesis 1b). The longer-term sick-leave absenteeism analysis, averaging the 12 months before and the 12 months after the intervention, resulted in a significant drop in absenteeism to 2% in the intervention group. Additionally, the net number of lost workdays dropped by almost 60%. As with the KPI performance, the sick-leave absence rate continued to improve post-program, underscoring the sustainability of the intervention effects over time and beyond the program. With these two outcomes, KPI performance and absenteeism, the department’s leadership considered the intervention to be a success.Parallel to the organization’s metrics, the team leaders and team members’ psychological effects were measured and referenced with a control group. As expected, and in support of Hypotheses 2b-c, the team leaders displayed higher levels (very large effect size) of autonomy (2b), and motivation  relative to the control group. The effect sizes match the general conclusions from a meta-analysis of leadership development programs in the private sector (between 1952 and 2002) based on similar study designs ,60. For The current leadership development program was titled “Co-creating a great place to work” and consisted of three phases: co-creation, intervention, and evaluation and sustainment. Co-creation was considered an expression of autonomy-supportive and engaging leadership. It aimed to facilitate productive dialogue between the leadership levels and helped align the global leadership team and the local team leaders. The selected business KPI, the ambition to lower sick-leave absence, and the aim to increase the levels of motivation via engaging leadership and autonomy satisfaction all stemmed from this first phase. Presumably, the co-creation process, as an integral part of the development program, facilitated achieving the observed changes in the autonomy and motivation of the team leaders relative to the control group.Despite the positive effects of autonomy and motivation, the team members reported no relevant changes, which was unexpected (Hypothesis 3). The ambition to indirectly improve employee well-being by training their team leaders may prove problematic . Other lTeam members were not involved in co-creation and did not participate in the program, which may explain the absence of effects of the program for this group. A recent longitudinal study, however, illustrated the beneficial impact of perceived line management support and active employee participation on job outcomes . InvolviA practical proposal to involve employees as active participants may consist of including approaches such as action learning, where team leaders and team members collectively work on joint assignments . IncludiThe present study is the first in the domain of SDT to report the impact of a leadership development intervention on actual business performance, as measured with business key performance indicators . Previous studies published on leadership impact within SDT reported on, for example, performance evaluations by supervising managers  or self-Moreover, the present study also contributes to leadership development. The design of the leadership intervention facilitated the collective leadership experience through the participatory process of co-creation of senior leaders and the participating team leaders, and hence followed the call of Petri  for moreWe believe that designing a leadership development program in a real-time work environment with a real business challenge (cf. ) answersThere are a few important implications of the current leadership development program for practitioners. First, involving the target group of participants in a co-creation process is beneficial. It helps create direction, alignment, and commitment (DAC)  across tA major strength of the current study is that it was carried out in a real-world and, thus, dynamic organizational context. Despite its high ecological validity, it has a few limitations. The study is based on a single intervention within one organization. A second limitation is that the study relies on two measurement points, where three or more measurements over time could have added to the solidity of the findings, which is supported by the organizational outcomes displaying continued improvements six months after the second measurement. Third, the study incorporated small groups of team leaders, and the results could not be nested because of the survey protocol of the organization. Because of the small sample size, the power was too low to obtain significant parameter estimates and we relied on effect sizes only. We selected the partial epsilon squared because it is said to be the least biased in small samples . A futurConsequently, we could not distinguish the leadership impact of the various team leaders on their teams. Most likely, some team leaders had a positive and significant impact on their team members’ AS and IM, which was learned from the peer group consultation sessions and the individual coaching sessions with the team leaders during the program. However, for reasons of confidentiality, these sessions were not recorded or transcribed. Additionally, the small sample size for team leaders and the resulting low statistical power brings the risk of Type II errors for the interpretation of the psychometric results. A fifth limitation is the quasi-experimental study design itself, which makes it more challenging to conclude the causality effects of the experiment. To balance this limitation, some measures were taken, such as the selection of a comparable control group and the correction for mean differences to create equivalence at baseline . AnotherA seventh limitation is the substantial difference in sick-leave absenteeism between the intervention and control group at pre-test. During the intervention period, both absence rates seemed to regress towards the mean, which potentially implies that it may be a natural regression rather than a real effect . NeverthThe present study showed that a leadership development program focusing on engaging leadership and psychological well-being led to significant positive business results and lower absenteeism. Additionally, the intervention had a moderate to large effect for the motivation of team leaders and a substantial impact on the experienced autonomy of team leaders compared to the control group. The business outcomes exceeded the leadership team’s ambitions and continued to improve post-program. The predicted positive spill-over effects on team members were absent despite the positive psychological effects on autonomy and motivation among team leaders and their subsequent well-being.From a practical point of view, co-creating a leadership program by actively involving its participants helped create direction, alignment, and commitment. It also supported the realization of business outcomes in a spirit of collaboration and continuous improvement. Embedding leadership development in everyday business processes with concrete business objectives and extending co-creation throughout the program supports team leaders in developing engaging leadership in their day-to-day practice and contributes to tangible results. The next step is to find ways to extend the program and engage team members in co-creation and implementation. Considering the current trend of self-management and agility in business organizations, we argue that leadership development should not be limited to management or a select group of high-potential individuals.Despite the positive results of the program, generalization across organizations is limited, because it comprised a single intervention in one organization and a relatively small group of team leaders. Additionally, co-creation may lead to different foci in different organizations and influence the outcomes. However, we believe that the described approach can be strengthened through replication in other organizations. The present study contributes to the practical knowledge of the relatively new concept of engaging leadership and its successful application in leadership development programs.


Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV). We investigated the detailed kinetics of serologic response in patients with SFTS. Twenty-eight patients aged ≥18 years were enrolled between July 2015 and October 2018. SFTS was confirmed by detecting SFTSV RNA in their plasma using reverse transcription polymerase chain reaction. SFTSV-specific IgG and IgM were measured using immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA). We found that SFTSV-specific IgG was detected at days 5–9 after symptom onset, and its titer was rising during the course of disease. SFTSV-specific IgM titer peaked at around week 2–3 from symptom onset. The SFTSV-specific seropositive rates for days 5–9, 10–14, 15–19, and 20–24 from symptom onset using IFA and ELISA were 63%, 76%, 90%, and 100%, and 58%, 86%, 100%, and 100%, respectively, for IgG, whereas they were 32%, 62%, 80%, and 100%, and 53%, 62%, 70%, and 100%, respectively, for IgM. The delayed IgM response could be attributed to the low sensitivity of SFTSV-specific IgM IFA or ELISA and/or impaired immune responses. The IgM test using IFA or ELISA that we used in this study is, therefore, insufficient for the early diagnosis of SFTS. Bandavirus, family Phenuiviridae, and order Bunyavirales [Haemaphysalis longicornis [Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (renamed as Dabie bandavirus) in the genus avirales , is an egicornis . Since igicornis , SFTS wagicornis ,4. SFTS gicornis ,6, and egicornis ,8,9.Previous studies ,11 have Adult patients, aged ≥ 18 years, with confirmed SFTS, were enrolled at four university-affiliated hospitals in South Korea during the period of July 2015 to October 2018. The four hospitals were Asan Medical Center, Soonchunhyang University Seoul Hospital, Chung-Ang University Hospital, and Dongguk University Ilsan Hospital. SFTSV RNA in plasma specimens was confirmed using real-time reverse transcription polymerase chain reaction (RT-PCR). Patients’ plasma specimens in ethylenediaminetetraacetic acid (EDTA)-treated vacutainers were obtained during their hospitalization period. Plasma samples were immediately separated from whole blood and frozen at −80 °C until further analysis. The study protocol was approved by the Institutional Review Boards of each hospital .SFTSV RNA in plasma specimens was confirmed using RT-PCR as described in our previous study . Briefly2 incubator at 37 °C for five days. Subsequently, cells were harvested, inoculated onto Teflon-coated well slides, and then fixed with acetone. IFA was carried out using a patient’s serum as the primary antibody and fluorescein-labeled antihuman IgG or IgM secondary antibodies . Serum specimens were diluted two-fold from 10 up to 2560. The incubation time of a patient’s serum for IgM detection was extended to 90 min, whereas 30 min incubation was performed for IgG detection. A monoclonal anti-SFTSV N antibody (manufactured in our laboratory) was used as the positive control. A titer of 80 was considered positive as applied in the previous study [Serological tests for detecting anti-SFTSV IgG and IgM were performed using the immunofluorescence antibody assay (IFA), as previously described . For IFAus study .E. coli-expressed recombinant nucleoproteins (NP) were purified. A Nunc-Immuno Plate  was coated with a predetermined optimal quantity of NP (100 ng per well) and incubated overnight at 4 °C. An absorbance reader  was used to measure the absorbance in the ELISA. A sample was considered antibody-positive if it yielded an optical density (OD) above the predetermined cut-off value at 405 nm (OD405). The average OD values for the negative controls were between 0.18 and 0.24. The IgM and IgG antibody-positive serum of an SFTS patient, presenting positive results in the immunofluorescence assay (IFA), was used as a positive control (OD405 of IgM = 1.36–1.95 and OD405 of IgG = 1.36–1.76). The anti-SFTSV IgM and IgG levels in the specimens obtained from the patients were considered positive if they were higher than the positive control (OD405 = 1.36).The enzyme-linked immunosorbent assays (ELISA) for anti-SFTSV IgM and IgG were performed as previously described . To use A total of 28 patients with confirmed SFTS were enrolled in this study. IFA for both IgG and IgM were performed on all patients during the course of the disease. Among these patients, 14 (50%) were men, and their mean age (±standard deviation) was 61.8 (±9.9) years. Detailed clinical characteristics of the patients in this study are shown in n = 25), only viral load at days 5–9 from symptom onset was statistically high in the non-survivors group (p = 0.008). Other parameters such as age, underlying diseases, and antibody response did not show significant differences between survivors and non-survivors groups.In addition, three patients (10.7%) died due to aggravated multi-organ failure during the course of this disease. Detailed clinical characteristics and serologic response of these three deceased patients are shown in Viral load peaked on days 5–9 after symptom onset, and then gradually decreased over the course of disease. Positive IgG titers against SFTSV using both IFA and ELISA were detected on days 5–9 after symptom onset, with a robust antibody response (≥1280) for IFA detected around week 3 after symptom onset. Anti-SFTSV IgM for IFA reached its peak level around week 3 after symptom onset. Although, for ELISA, anti-SFTSV IgG and IgM patterns based on disease course were similar, the IgM peak occurred 5 days earlier than for IFA. The detailed kinetic data of viral load and antibody responses are shown in The median times from symptom onset to the last detection of positive viremia to negative viremia, when patients were negative for viral load at discharge, were 14 days (IQR: 10.05–22.50) and 16 days (IQR: 13.00–23.75), respectively. In addition, the median time from the symptom onset to the positive IgG response and the robust IgG antibody response using IFA was 9 days (IQR: 6.00–11.25) and 17 days (IQR: 13.25–20.75), respectively. The median time from the symptom onset to the positive IgG response using ELISA was 9 days (IQR: 6.50–11.00).405 = 1.36 for ELISA for day 5–9, 10–14, 15–19, and 20–24 after symptom onset were: 63%, 76%, 90%, and 100%, and 58%, 86%, 100%, and 100%, respectively. The SFTSV-specific IgM positive rates for IFA and ELISA for days 5–9, 10–14, 15–19, and 20–24 after symptom onset were: 32%, 62%, 80%, and 100%, and 53%, 62%, 70%, and 100%, respectively (405 = 1.36 for ELISA) but was negative for IgM using both IFA and ELISA at day 9 from symptom onset. The detailed data depending on sampling times are shown in n = 14) in whom only early blood samples within 2 weeks from the symptom onset were available, the sensitivities of IgG and IgM IFA were 100% and 86%, respectively, and the sensitivities of IgG and IgM ELISA were 100% and 93%, respectively.The SFTSV-specific IgG seropositive rates at cut-off values of 80 for IFA and ODectively . One , including only three deceased patients with different specimen collection dates. For these reasons, there seems to be no significant difference between the survivor and non-survivor groups. Third, we did not perform any experiment on cell-mediated immune response which could have provided some important highlights on the mechanism of SFTSV infection. Fourth, we determined the cut-off value of OD in ELISA using positive controls rather than standard methods such as the average of negative controls plus three times the standard deviation (mean + 3SD) or receiver operator characteristic (ROC) analysis. Thus, the relatively high cut-off value of the ELISA we used might result in the underestimation of the sensitivity of this assay. However, this did not substantially alter our main findings in terms of the results of suboptimal sensitivity of SFTSV-specific IgM IFA during the early course of SFTS patients. Finally, we did not demonstrate that the IFA or ELISA we used were sensitive enough to detect small amount of SFTSV-specific antibodies. Therefore, it is difficult to draw a firm conclusion that the IgM test using IFA or ELISA is insufficient for the early diagnosis of SFTS. Further studies based on more robust designs, focusing on cellular and humoral immune responses against SFTSV, will be of pivotal importance in the quest for developing vaccines and antiviral agents.Nevertheless, there were several limitations in our present study. First, most of the sera specimens were collected on 5–19 days from symptom onset . For thiIn conclusion, our data suggest that SFTSV-specific IgM response was relatively delayed compared to that reported in previous studies. This may be related to the low sensitivity of SFTSV-specific IgM IFA or ELISA, and/or impaired adaptive immune response. Thus, the SFTSV-specific IgM IFA or ELISA that we used in this study are insufficient for the early diagnosis of SFTS, and further robust studies are required to elucidate the humoral and cellular immune responses against SFTSV.


The COVID-19 pandemic has had a significant impact on the delivery of care for chronic neurological diseases globally. As requirements for physical distancing have led to restrictions on the availability of health care services, many countries have adapted methods of telemedicine to sustain care access for patients . For peoIn resource limited settings, there is a paucity of neurologic care at baseline due to limited availability of specialists, diagnostics, and treatment options . During However, the workforce in Africa does provide a unique opportunity for care delivery through community health workers (CHWs). CHWs have been a longstanding method of mobilizing people from within a community with varying knowledge bases to deliver basic medical screening and education to those with limited access to clinical care, working through challenges due to differing belief systems, limited knowledge base, geographic barriers, and stigma. Through this system, there has been proven success in improving health seeking behaviors in the community, particularly in conditions such as HIV and epilepsy . In 2019The initial goals of our epilepsy CHW program were to improve adherence to treatment for children with epilepsy and provide education to reduce associated stigma and improve overall inclusion in society. We combined a training program for local health providers on epilepsy clinical management with the CHW program, and 10 CHWs were provided training on the basics of seizures, medication adherence, seizure safety in the home, and psychosocial issues, and were prepared for their role as a connection to the clinic for these families of children with epilepsy. The CHWs were then connected with 40 families, whom they visited twice monthly. They were 4 months into the program when the COVID-19 pandemic led to restricted activities in Zambia.In early March 2020, warnings of COVID-19 on ongoing clinical care were emerging quickly across Africa. During this time, a monitoring site visit of our CHW program was in process. As Zambia reported the first positive cases during that time and initial restrictions for COVID-19 prevention were implemented by the government, it became clear that adaptation of all services would be required. While necessary for safety, our team struggled like many others in this time with the potential impact on care and risk to our patients’ neurologic health. With this in mind, we re-evaluated how the existing infrastructure created from this program could be used in this time.Neri clinic, like many rural health centers in the region, is a small building with crowded spaces where people wait in close proximity to see clinicians and collect their medications on a monthly basis. Even if solely present for the purposes of medication collection, families would be at high risk for exposure. As adherence to medication is essential for seizure management, we wanted to ensure that families did not have gaps in coverage during this time period. We quickly realized that our CHW program provided an excellent opportunity to deploy individual workers to households for medication distribution, mitigating the risk of families congregating in the clinic.Personal protective equipment and hand sanitizer were provided for each CHW to decrease their own exposure risk. In addition, an educational component surrounding COVID-19 could be delivered to each household by the CHWs. While the Zambian Ministry of Health had provided guidance on appropriate hygiene and social distancing measures, many of our clients are illiterate and have limited access to information. The CHWs were able to deliver up to date education on COVID-19 and social distancing information to families in a reliable manner and in the local dialect with opportunity for discussion. Adaptations to make this process safer included reducing visits from twice monthly to once monthly, and incorporating basic screening questions  to determine if an urgent clinic visit was necessary, all in efforts to limit exposure but not compromise care for the child’s epilepsy. Antiseizure medication supply gaps, which have been exacerbated by resource shifting and increased purchasing restrictions, have been supplemented by the NGOs supporting the program.This CHW program has provided a unique opportunity to support the Linda compound community in Zambia during the COVID-19 pandemic. It has been possible to implement a system in which access to essential medications could continue to be provided in a safer manner, and children who were in need of urgent clinician visits could be specifically identified, to reduce overall outpatient volumes and allow spacing of visits for physical distancing. Additionally, we could continue to provide education and support to our families, in alignment with our original objectives for the program. During this time of crisis, we have seen the CHWs in our program continue to be motivated to help their community and continue to see the positive impact our program has on the participating families and the Linda community as a whole. Beyond our original goals, this program has provided a unique model of health care access for a chronic medical condition during times of infectious disease outbreaks requiring physical distancing, which is feasible to implement in a developing region where telehealth mechanisms are limited.


The objective of this study was to determine the advising and emergency medicine (EM) residency selection practices for special population applicant groups for whom traditional advice may not apply.A survey was distributed on the Council of Residency Directors in EM and Clerkship Directors in EM Academy listservs. Multiple choice, Likert-type scale, and fill-in-the-blank questions addressed the average EM applicant and special population groups ; couples; at-risk; re-applicant; dual-accreditation applicant; and military). Percentages and 95% confidence intervals [CI] were calculated.One hundred four surveys were completed. Of respondents involved in the interview process, 2 or more standardized letters of evaluation (SLOEs) were recommended for osteopathic (90.1% [95% CI 84–96]), IMG (82.5% [73–92]), dual-accreditation (46% [19–73]), and average applicants (48.5% [39–58]). Recommendations for numbers of residency applications to submit were 21–30 (50.5% [40.7–60.3]) for the average applicant, 31–40 (41.6% [31.3–51.8]) for osteopathic, and > 50 (50.9% [37.5–64.4]) for IMG. For below-average Step 1 performance, 56.0% [46.3–65.7] were more likely to interview with an average Step 2 score. 88.1% [81.8–94.4] will consider matching an EM-EM couple. The majority were more likely to interview a military applicant with similar competitiveness to a traditional applicant. Respondents felt the best option for re-applicants was to pursue the Supplemental Offer and Acceptance Program (SOAP) for a preliminary residency position.Advising and residency selection practices for special population applicants differ from those of traditional EM applicants. These data serve as an important foundation for advising these distinct applicant groups in ways that were previously only speculative. While respondents agree on many advising recommendations, outliers exist.The online version contains supplementary material available at 10.1186/s12909-020-02415-8. Graduate medical education training programs in the United States (U.S.) utilize the National Resident Matching Program (NRMP) each year to “match” applicants from U.S. allopathic and osteopathic medical schools, and international medical schools in a fair, efficient, and reliable manner. After applicants apply and interview at residency programs, they create a rank order list of their preferred programs. Using a computerized mathematical algorithm, this list is aligned with program directors’ rank order lists of applicants in order to fill available training positions at U.S. teaching hospitals in a way that attempts to produce the best possible outcome for all stakeholders.Advising increasingly heterogeneous emergency medicine (EM) applicants through this residency application process requires informed EM clerkship directors (CDs) and EM residency program leaders, including program directors (PDs), and assistant or associate program directors (APDs) , 2. AdviExisting EM student advising literature generally reflects U.S. allopathic seniors’ medical school experience –5. AlthoTo address the changing applicant pool and need for expanded advising resources, the Council of Emergency Medicine Residency Directors’ (CORD) Advising Students Committee in EM (ASC-EM), a group of PDs, APDs, CDs and other advisors from EM residency programs across the country, developed evidence- and consensus-based advising resources for special population applicant groups and their advisors . These gGoogle Forms online software. While exact listserv rosters are unavailable, in 2017 the Society of Academic Emergency Medicine (SAEM) clerkship directory listed 231 accredited EM residency programs and 167 EM clerkships  involved in the interview process reported USMLE Step 2 Clinical Knowledge (CK) as necessary for an interview of the “average” EM applicant. Most weigh Step 1 and Step 2 CK equally (49.5% [39.7–59.3]) or weigh Step 2 CK scores more than Step 1 scores (44.6% [34.9–54.3]).n = 91), 52.2% [42.0–62.4] will not consider applicants who have taken only the COMLEX, and not the USMLE. In contrast, 82.2% [74.3–90.1] will consider an osteopathic applicant who has only taken Step 1 and 57.3% [47.0–67.6] will consider an osteopathic applicant who has only taken Step 2 CK.Of those involved in the interview process (n = 10) were leadership decisions made at the medical school, departmental, or institutional level, uncertainty in evaluating the quality of training that osteopathic students receive, and a perception that matching osteopathic students would reflect poorly on their program.On thematic qualitative analysis of subjective responses, the most common responses for programs not ranking or matching osteopathic applicants  revealed the following barriers: the already large number of allopathic U.S. applicants, unfamiliarity with the quality of the foreign educational process, departmental or institutional policies, and visa complications.Thematic qualitative analysis of the subjective responses of those who do not consider IMGs for a residency position at their program (Most respondents (80.2% [73.4–88.0]) attempt to coordinate interview dates for matching couples and will communicate with the PD of the other program regarding the matching couple (76.2% [67.9–84.5]). Many respondents (43.6% [33.9–53.2]) reported moving an applicant’s position on their rank list because they were matching with an applicant in another program. Also, 88.1% [81.8–94.4] report that their program will consider matching an EM-EM couple.Just over half of respondents involved in the interview process (53.5% [43.8–63.2]) had interviewed a student who had failed USMLE Step 1 in the past 3 years. In the past 3 years, the majority of respondents sometimes (5–15% of interviews) or frequently (> 15% of interviews) interviewed applicants with a below-average USMLE Step 1 . For applicants with a below-average USMLE Step 1 score, an available USMLE Step 2 CK score during initial application review increased the likelihood of respondents offering an interview, with 56.0% [46.3–65.7] more likely to interview with an average Step 2 CK score and 44.0% [34.3–53.7] with an above-average Step 2 CK.Respondents involved in the interview process rated the frequency in the last 3 years with which they considered applicants with other common application red flags Table .Table 4When asked about advising applicants who plan to reenter the match to pursue an EM residency position, respondents rated different options for the year leading up to the re-application cycle as well as preferred disciplines through the Supplemental Offer and Acceptance Program (SOAP) Fig. a and b.Thematic qualitative analysis of the subjective responses indicated respondents had reservations advising students to take a categorical position with the intent of leaving after a year, considering the potential effect on the program. Respondents also underscored the recommendation that reapplicants pursue EM exposure in the interval to maintain skills and obtain additional recommendation letters.n = 13) reported considering applicants for both their dual-accreditation and categorical EM programs.Respondents involved in the interview process who have a categorical EM program only were asked how they view EM applicants who have also applied for a dual-accreditation program. Most stated it does not affect their ranking (82.4% [74.6–90.2]) while 17.6% [9.8–25.4] would be less likely to rank a dual applicant. All respondents with a dual-accreditation program  did not know if they had the resources available to them to advise students through the military match process and 19.4% [11.6–27.2] reported they did not have any resources available. Many reported being more likely to interview a military applicant with similar competitiveness to a traditional applicant .Our survey uncovered previously unreported data regarding advising and residency selection practices for special applicant groups. It provides data that can foster discussions about aligning how students are being advised with how students should be advised, enabling applicants and their advisors to approach the application process better informed.The SLOE is an important component of the EM-bound student’s residency application and directly impacts interview and ranking decisions , 5, 17. A common reason applicants risk an unsuccessful match is below-average performance on medical licensing examinations . We knowFor the average EM applicant, our data also support at least one published study that found 95% of programs did not require USMLE Step 2 CK to grant interviews to average applicants . In 2018Despite recently published data that demonstrate correlation between USMLE and COMLEX performance, our survey data show that osteopathic applicants are considered at the greatest number of ACGME programs if they have completed both USMLE Step 1 and Step 2 CK , 21. RecQuality advising regarding the number of applications to submit can make a successful match more likely while also saving students time and money . The 201Many special population applicants face barriers beyond their control in the residency application process. Discrimination against IMGs in the context of the residency application process has been published and our study confirms that expectations for osteopathic and IMG applicants varies from those of US MD applicants . The numWhile the aforementioned barriers may not be modifiable, the survey responses do offer some tangible suggestions for IMG and osteopathic applicants. They should focus on taking licensing examinations early and obtaining an audition elective at an institution where they would like to match. IMG applicants should strive to master the English language, as it was listed as a top reason to consider IMG applicants, and may want to spend less time on pursuing research. These results can also provide guidance for when to consider applying to another specialty as a backup plan.According to the NRMP, U.S. senior couples match at the same rate as their peers . When reIt is important for an individual applying to dual programs to consider the impact of this revelation to the non dual-accreditation programs to which s/he is applying considering 17.6% stated they would be less likely to rank this applicant.We found no prior data that suggest the best use of time following a non-match in EM. In the 2019 NRMP applicant survey, U.S. seniors in this position stated they would be most likely to participate in the SOAP, first in their preferred specialty, followed by a preliminary year position, then a less competitive backup specialty . In our Our data highlight numerous other potential areas where advisors can help their unmatched or at-risk students better strategize. For example, medical school course or clerkship failures, academic misconduct, and legal problems were significantly more disqualifying than board performance . As suchMilitary applicants are outliers among the special population groups, as respondents were more likely to interview those with similar competitiveness to a traditional applicant. The uncertainty of most respondents about the military match illustrates the importance of developing evidence-based advising resources for EM special applicant populations.Our respondents (104) compared to the total number of ACGME-accredited EM residency programs (231) was limited. The survey may have captured multiple respondents from individual institutions, further lowering the response rate; we did not apply a limit of 1 response per institution in order to encourage honest reporting and maintain blinding of the results. Also multiple people of differing roles  often contribute to both advising and the residency application process within a single institution; by limiting responses to just one of these roles, we would miss perspectives from important stakeholders in the advising and residency selection process. As a result, geographical variations in responses is not known. Also, those educators who chose to respond may differ from those who did not with respect to their advising and interviewing practices. We also recognize that although our data reflect current advising strategies, identifying the best strategy for a particular applicant requires an individualized approach.This survey adds to the existing literature by providing much-needed data to inform advising an increasingly diverse applicant population. The trends we identified suggest that evidence-based advising is much more nuanced than previously known, and those advising EM-bound students can leverage our findings to the maximal benefit of the students. This information is important for all stakeholders in the EM residency advising and interviewing processes.Additional file 1.