Borrelia burgdorferi in Scottish patients with suspected Lyme borreliosis was introduced in 2018 to supplement the IgG testing already in situ. Results from 2018 to 2020 were assessed alongside available clinical data to evaluate the utility of IgM testing in serum. An estimated false positive rate of 25.5% was observed with IgM immunoblot vs 80.1% for IgM chemiluminescent immunoassay (CLIA). IgM testing can aid earlier diagnoses if used within a selective two-tier testing protocol: only patients with acute onset of symptoms should be tested for IgM CLIA but confirmation by immunoblot and consideration of clinical picture is necessary.Testing for IgM antibodies to  Borrelia burgdorferi sensu lato (hereafter B. burgdorferi) followed by IgG immunoblot [B. burgdorferi was introduced in 2018, followed by the introduction of IgM (and IgG) chemiluminescent immunoassay (CLIA) in 2020.Serological testing is recommended for all suspected cases of Lyme borreliosis (LB) other than those with clinically identified erythema migrans (EM) rash. Until recently, testing for LB in Scotland utilised a two-tier testing protocol: a screening enzyme-linked immunosorbent assay (ELISA) for the detection of IgG antibodies to munoblot . To aid munoblot , immunobB. burgdorferi lack sensitivity during early disease, and their persistence in serum can complicate interpretation [Methods to detect IgG antibodies to retation –8. Althoretation –11. IgM retation , 13.B. burgdorferi for the laboratory diagnosis of patients with acute LB.The aim of this study was to evaluate the benefits and limitations of both CLIA and immunoblot for the detection of IgM antibodies to B. burgdorferi antibodies from 1 June 2018 to 17 October 2020 were analysed:(i)Sera from 01/06/2018 to 14/04/2020 were tested by Enzygnost Lyme-link VlsE/IgG ELISA (Siemens) on the DS2 platform (Launch) following the manufacturer’s instructions. Equivocal or positive sera were subsequently tested by Borrelia recomLine IgG and IgM immunoblot (Mikrogen) on the CarL immunoblot platform (Mikrogen) and the results interpreted as per the manufacturer’s instructions. Samples that were IgM immunoblot positive and IgG immunoblot negative or equivocal were identified for further analyses.(ii)Sera from 15/04/2020 to 17/10/2020 were tested by DiaSorin Borrelia IgG and IgM Quant CLIA on the Liaison XL analyser following discontinuation of the Enzygnost ELISA. Any samples that were positive or equivocal by either assay were tested by IgG and IgM immunoblot as above. Samples that were IgG CLIA negative and IgM CLIA reactive , IgM immunoblot positive and IgG immunoblot negative or equivocal were identified for further analyses.Data for serum samples sent from throughout Scotland and tested at the Scottish Lyme Disease and Tick-Borne Infections Reference Laboratory (SLDTRL) for Clinical information from specimen request forms, additional information from questionnaires returned from the referring clinician and any data from subsequent samples were used to allocate individual patients with isolated IgM results into groups based on likelihood of acute LB Table .Table 1POf the 15,294 sera tested for LB for the period 1 June 2018 to 14 April 2020, 1304 (8.5%) were reactive by IgG ELISA and thus tested by IgG and IgM immunoblot. Of these, 188/1304 (14.4%) were IgM immunoblot positive and IgG negative or equivocal. These 188 sera came from 152 individual patients: 76 (50.0%) were classed as “Probable” acute LB, 34 (22.4%) as “Possible” and 30 (19.7%) as “Not consistent” with acute LB. Twelve (7.9%) patients had insufficient clinical details to assign a presumptive diagnosis  were reactive by IgG and/or IgM CLIA and subsequently tested by IgG and IgM immunoblot. Of these, 346 (52.3%) were reactive for IgM CLIA only: the majority of which (73.1%) did not confirm by immunoblot, the remaining 93 (26.9%) sera were positive for IgM immunoblot only. These were from 73 individual patients: 23 (31.5%) patients were classed as “Probable” acute LB, 24 (32.9%) as “Possible” and 20 (27.4%) as “Not consistent” with acute LB. Nine patients (12.3%) had insufficient clinical details to assign a presumptive diagnosis , following the introduction of IgM immunoblot, a total of 1304 IgM immunoblots were performed, representing an increase in laboratory consumables costs of £34,556 . During the second study period (6 months), following the introduction of IgM CLIA, 2895 specimens were tested by IgM CLIA at an additional cost of £10,595. An additional 346 sera were tested by immunoblot as they had a reactive IgM CLIA, resulting in additional immunoblot costs of £18,338. Thus, the increase in laboratory costs after the introduction of IgM CLIA could be extrapolated to £57,866 per year.This study has shown that IgM immunoblot is a valuable tool in the laboratory diagnosis of LB, allowing us to detect 110 patients with “Probable” or “Possible” acute LB over the initial 22.5-month study period that may otherwise have been missed with IgG immunoblot alone. Although false positive results were obtained with the IgM immunoblot, the estimated false positive rate of 48/188 (25.5%) was slightly lower than other recent studies , 15. IntIntroduction of the IgM CLIA produced a much higher false positive rate. Of the 346 sera with an isolated IgM CLIA result, 277 (80.1%) were potentially false positive as they either did not confirm by immunoblot or were assessed as “Not consistent” with acute LB. This highlights that IgM CLIA testing in sera should only be used as part of a robust two-tiered testing protocol with confirmatory testing. The high false positive rate obtained for the IgM CLIA meant that a much higher proportion of samples required immunoblot testing: 22.9% of sera tested by CLIA (April to October 2020) were reactive with IgG and/or IgM CLIA, in contrast with the 8.5% of sera that were reactive with the IgG ELISA in the previous study period. This put extra pressure on the laboratory staff and greatly increased test costs . It could be argued that the benefits of IgM CLIA are only marginal and perhaps not cost-efficient; however, 47 patients with probable or possible acute LB were detected, which may otherwise have been missed. Again, although unlikely, if all 47 were missed and progressed to disseminated LB/persisting symptoms, this could equate to 267,900 Euros.B. burgdorferi–specific antibodies exists in the population, over testing can lead to high false positive rates. The cost of misdiagnosing someone with acute LB based on false positive results, leading to their inappropriate, ineffective or even harmful treatment with antibiotics, and potentially delaying further investigations into the cause of their symptoms, should not be ignored.Our results show that there is a significant risk of reporting of inaccurate and misleading results if patients are diagnosed on the basis of an isolated IgM positive result without consideration of clinical details, disease duration and pre-test probability. Prior studies have found that the majority of patients tested for Lyme serology did not meet European or UK clinical case definitions, and recommend that pre-test probability of infection is considered , 6, 20. B. burgdorferi assays lack inter-assay consensus, particularly IgM assays [The authors concede that the categorisation of patients into “Probable” or “Possible” LB in this study was flawed as there was limited clinical information available. For this reason, assay sensitivity, specificity and positive predictive values could also not be assessed. Many of the samples tested were not accompanied with adequate clinical details such as symptoms and date of onset. The authors accept this may have influenced the study false positive rate and whilst this may indicate that our testing protocols are suboptimal, this is the real-world scenario for a large number of laboratories where demand for Lyme testing is high and illustrates the challenges faced when interpreting results. The authors also recognise that the study results may have been influenced by the actual assays utilised. It is widely recognised that M assays , 22. IntB. burgdorferi can be detected prior to or parallel to the formation of IgM antibodies and are more specific than IgM assays; thus, the use of VlsE/IgG screening assays is sufficient. However, the IgG CLIA used in this study, which contains the VlsE antigen, missed some cases of acute LB. Although complex to implement in laboratories with a high throughput of specimens, perhaps the use of selective testing protocols would be optimal, utilising IgM CLIA only for those patients with an acute onset of specific symptoms within a two-tier testing protocol.Due to the issues outlined above, some countries have, or are considering, stopping the use of IgM testing for LB. However, some cases of early disease may be missed and patient confidence in testing regimes will undoubtedly be affected, which could further fuel the controversy around testing. Some manufacturers claim that IgG antibodies to the VlsE antigen of


Conclusions: Our 3-month health program maintained improvements in oral and physical function in older women 1 year after completing the program.Background: The aim of this prospective cohort study was to clarify changes in physical and oral function in older adults after completing a 3-month health program combining physical and oral exercise, oral health instruction, and nutritional guidance. Methods: Subjects were 34 women aged at least 70 years (mean age 79.2 years) in Bungotakada City, Oita Prefecture, Japan. Physical and oral function was investigated on the first day (baseline), at the end of the program, and 6 and 12 months after completing the health program. Physical function was measured using handgrip strength test, timed up and go (TUG) test and one-leg standing time test. Oral diadochokinesis test and repetitive saliva swallowing test (RSST) were employed to assess oral function. Results: TUG scores were significantly lower at 6 and 12 months than at baseline in participants aged ≥70 and <80 years. The repetition rate of the monosyllables  A community-based integrated care system model has been introduced by the Japanese Ministry of Health, Labour and Welfare to ensure that lifestyle assistance, healthcare services, and nursing care are provided in accordance with older adults’ needs . This moSince 2015, the local government of Bungotakada City, Oita Prefecture, Japan, has been providing a combined health program, including oral health instruction, physical and oral exercise, and nutritional guidance to older adults living in local communities to promote healthy living . We haven = 1), leaving the region (n = 2), poor health (n = 6), or other personal reasons (n = 6)) during the 3-month participation period. Men (n = 7) were excluded from the analysis because of the low number of male participants. Additionally, participants aged ≥90 years (n = 2) were excluded because of the low number of people in this age group. This study therefore included 34 older women (mean age 79.2 years) for analysis. Three participants dropped out 12 months after completing the health program . None of the participants had taken part in any other health programs.The local government sent letters inviting older adults aged ≥65 years living in local communities to participate in a 3-month health program. A total of 68 older people participated in this health program from May 2019 to February 2021. The study design was approved by the Ethical Committee of Hiroshima University (no. E-1218). All participants signed an informed consent agreement. To exclude older people with a decline in activities of daily living (ADL), older people certified as requiring help or long-term support (n = 10) were excluded. Fifteen participants  dropped out for personal reasons unrelated to the health program  with a statistical power of 80%, a significance level of 5%, and an effect size of 0.5; the sample size was calculated to be 35 participants. Thus, the sample size was considered to be large enough to perform Wilcoxon signed-rank tests. Additionally, a post hoc power analysis was performed using G*Power with a significance level of 5% and an effect size of 0.5. The sample size achieved a statistical power of 0.79.A 3-month health program with a weekly intervention in community-dwelling older adults was implemented in this study. The details of the health program, including physical exercise, oral health, and nutritional guidance, were described in our previous study . On the Physical function was measured using a handgrip strength test , TUG tes/pa/, /ta/, and /ka/ as quickly as possible. Repetition of the syllable /pa/ reflects lip pressure [/ta/ and /ka/ is related to tongue pressure and tongue motor function, respectively [/pa/, /ta/, or /ka/ produced per second is less than six [An oral diadochokinesis test was used to evaluate oral motor function . Participressure . Repetitectively ,16. The than six .The RSST is a screening test for swallowing disorders. The participants were asked to swallow saliva as many times as possible over a 30 s period. Elevation of the larynx during swallowing was counted by the examiner. Fewer than three swallows within 30 s was considered to be a swallowing disorder .The Kihon checklist (KCL), developed by the Japanese Ministry of Health, Labour and Welfare, was employed to evaluate oral frailty. Answers to three questions about difficulty in chewing tough foods, choking or coughing when drinking tea or soup, and feelings of dry mouth and thirst were used to assess oral function . In lineThe number of oral bacteria was automatically counted using a bacterial counter  . Oral sa®, Scalar, Tokyo, Japan) [Oral moisture levels were assessed using an oral moisture checking device  . Three i, Japan) .p-values of less than 0.05 were regarded as statistically significant.The Mann–Whitney U test was used to evaluate significant differences in clinical factors and physical and oral parameters between the groups (participants aged in their 70s and 80s). Fisher’s exact test was employed to assess significant differences in clinical factors. The Friedman test or Cochran’s Q test were used for multiple comparisons to assess the differences in physical and oral parameters before and after the intervention. The Wilcoxon signed-rank test with Bonferroni correction was used to assess the differences in physical and oral parameters between baseline, the end of program, and 6 months and 12 months after completion of the program. SPSS software, version 24.0 , was employed for statistical analysis. p < 0.05 was considered statistically significant.Fisher’s exact test was used to evaluate significant differences in clinical factors between the groups. The Mann–Whitney U test was used to evaluate significant differences in clinical factors such as age, BMI, number of remaining teeth, oral bacterial numbers, and oral moisture level. p = 0.043, p = 0.006, p = 0.001, Mann–Whitney U test). For physical function at baseline, there were significant differences in handgrip strength, TUG scores and one-leg standing time with eyes open between the groups   (an test) . TUG scorection) . Howeverrection) . One-legrection) . There wrection) ./ta/ between the groups . The percentage of participants with a KCL score ≥2 was lower in participants aged ≥70 and <80 years at the end of program, at 6 months, and at 12 months when compared with baseline       . However90 years . Importarection) . Additiorection) . The reprection) , and therection) . Importame point .The DRACE score was maintained at less than 3  at the end of program and at 6 months and 12 months in participants aged ≥70 and <80 years, but this decrease was not significant . In contp = 0.04 and p = 0.03, respectively, Wilcoxon signed-rank test with Bonferroni correction)  in participants aged ≥70 and <80 years at the end of program and at 6 and 12 months, but this difference was not significant . In contrection) .p < 0.001, Friedman test). Oral bacterial numbers were lower in participants aged ≥70 and <80 years at 6 and 12 months when compared with baseline . Oral bacterial numbers were also lower at the end of the program and at 6 months and 12 months than at baseline in participants aged ≥80 and <90 years, but these differences were not significant . Participation in our health program may improve physical functions such as mobility and reduce the risk of falls even after completion of the health program in independent older adults. An individual personalized rehabilitation program over 7 weeks improved TUG scores in non-disabled older people . However/pa/ and /ta/ was at a normal level at 12 months in participants aged ≥80 and <90 years , indicating that a decline in lip motor function and tongue pressure can be improved gradually after completion of the program in the older group. Our health program is effective in improving lip motor function and tongue pressure even in adults aged ≥80 years. Repetition of the monosyllable /ka/ reached a normal level at 12 months in participants aged ≥70 and <80 years . However, the monosyllable /ka/ was below normal levels at 12 months in the older group. These results suggest that tongue motor function is more readily improved in the younger group. Therefore, intervention from a younger age  is required to improve tongue motor function in older people. In contrast, a previous study of older Japanese people with a risk of deterioration in oral health found that articulation of the monosyllables /pa/, /ta/, and /ka/ improved after participation in a 3-month health program [/pa/, /ta/, and /ka/ was more than 6 times/second  before the intervention [The tests for oral function revealed that repetition of the monosyllables The KCL scores indicated that the percentage of people with oral frailty was lower in participants aged ≥70 and <80 years after completing the health program, suggesting that the health program may be associated with improvements in chewing and swallowing ability. However, no such reduction in the oral frailty rate was evident in participants aged ≥80 and <90 years after completion of the health program. Individual oral health status  may also be related to oral function  in older adults. However, the relationship between oral health status and oral function could not be elucidated in this study. In addition to participation in the health program, proper dental care  should be recommended in accordance with each individual’s oral health status for effective improvement in oral function.The DRACE scores indicated that participants aged ≥80 and <90 years were at a high risk of dysphagia at baseline. Dysphagia is a serious problem in many community-dwelling older people because many age-related physiological changes increase the risk of dysphagia . A previOral bacterial numbers were lower at 12 months after completing the intervention than at baseline in participants aged ≥70 and <80 years and those aged ≥80 and <90 years in this study. These results suggest that the oral health intervention may have affected the participants’ oral hygiene status in both the younger and older groups. However, the participants’ plaque accumulation and periodontal health condition were not investigated in this study. A previous study found that the oral candida positive rate and the candida colony score were lower in older Japanese people after participation in a 3-month health program [Previous studies demonstrated that annual regular interventions improved oral and physical function and inhibited deterioration of such functions in older people ,34. In oOur results suggest that a 3-month combination program, including physical exercise, oral health instruction, and nutritional guidance, may contribute to the improvement and maintenance of oral and physical function in older women. However, one limitation of this study was that we did not include a control group that was not offered the intervention. To demonstrate the effectiveness of our health program, a comparison of physical and oral function between the intervention group and a control group is required. Further limitations were that the participants were independent older women and that the overall number of participants was small. Future research should investigate the program’s efficacy among a large cohort of older men and women.This preliminary prospective study revealed that participation in our 3-month health program improved a marker of physical and oral function at the end of program in independent older women aged ≥70 and <80 years. Improved oral function  and physical function  was maintained until 12 months after completing the program. Older women who completed our health program maintained their improved oral and physical function 1 year after the end of the program. For maintenance of improved oral and physical function in older people, regular participation in a health program should be considered.


Citrien Fund (CF) program eHealth; 29 eHealth projects with various subjects and themes were selected, supported, and evaluated. To determine the accomplishment of the 10 deliverables for the CF program eHealth and to contribute to the theory and practice of formative evaluation of eHealth in general, a comprehensive evaluation was deemed essential.A total of 8 Dutch university hospitals are at the forefront of contributing meaningfully to a future-proof health care system. To stimulate nationwide collaboration and knowledge-sharing on the topic of evidence-based eHealth, the Dutch university hospitals joined forces from 2016 to 2019 with the first CF program eHealth were accomplished. The second aim is to evaluate the progress of the 29 eHealth projects to determine the barriers to and facilitators of the development of the CF program eHealth projects.The first aim of this study is to evaluate whether the 10 deliverables of the To achieve the first aim of this study, an evaluation study was carried out using an adapted version of the Commonwealth Scientific and Industrial Research Organization framework. A mixed methods study, consisting of a 2-part questionnaire and semistructured interviews, was conducted to analyze the second aim of the study.CF program eHealth were successfully achieved. The program yielded 22 tangible eHealth solutions, and significant knowledge on the development and use of eHealth solutions. We have learned that the patient is enthusiastic about accessing and downloading their own medical data but the physicians are more cautious. It was not always possible to implement the Dutch set of standards for interoperability, owing to a lack of information technology (IT) capacities. In addition, more attention needed to be paid to patients with low eHealth skills, and education in such cases is important. The eHealth projects’ progress aspects such as planning, IT services, and legal played an important role in the success of the 29 projects. The in-depth interviews illustrated that a novel eHealth solution should fulfill a need, that partners already having the knowledge and means to accelerate development should be involved, that clear communication with IT developers and other stakeholders is crucial, and that having a dedicated project leader with sufficient time is of utmost importance for the success of a project.The 10 deliverables of the planning, IT services, and legal played an important role in the successful progress of the projects and should therefore be closely monitored when developing novel eHealth solutions.The 8 Dutch university hospitals were able to collaborate successfully and stimulate through a bottom-up approach, nationwide eHealth development and knowledge-sharing. In total, 22 tangible eHealth solutions were developed, and significant eHealth knowledge about their development and use was shared. The eHealth projects’ progress aspects such as RR2-10.1016/j.ceh.2020.12.002 The global population is increasing rapidly, and the number of people aged ≥60 years is expected to double by 2050 ,2. The deHealth may support the necessary reforms [fragmentation of eHealth initiation [Therefore, governments are increasingly debating which health care reforms are necessary to preserve the quality of our health care system and how to effectively deliver care from a distance. The concept of  reforms . By impl reforms -8. Moreo reforms ,10. In 2 reforms . The repitiation . In addiitiation  summarizitiation . Finallyitiation . They haCitrien Fund (CF) was established for the period of 2014 to 2018 by the government-funded Netherlands Organisation for Health Research and Development (in Dutch: ZonMw). The CF aims to contribute to a sustainable health care system by stimulating collaboration between 8 Dutch university hospitals, and between the university hospitals and other health care organizations. The CF supports 5 programs with different themes [CF program eHealth, which took place from 2016 until the beginning of 2019. This first nationwide university hospital eHealth collaboration mainly focused on the constitution of a strong collaborative framework to discuss present eHealth issues, on the development of a wide array of novel eHealth solutions—with the most successful being scaled in a subsequent program—and on sharing of eHealth knowledge. The overall aim of the CF program eHealth was to accomplish 11 predefined deliverables  to evaluate the progress of the 29 eHealth projects to determine the barriers to and facilitators of the development of the CF program eHealth projects.By conducting a comprehensive evaluation of the programs -19. SubsOne coordinating Dutch Federation of University Medical Centers vision on eHealth and eHealth road map .A virtual nationwide expertise center for eHealth.International positioning by promoting in journals and media and during the closure event.Conditions for downloading medical data described and, if possible, realized.Blueprint for interoperability between hospital information systems and electronic health records.Agreements and standards for data sharing between consumer and professional eHealth.A framework for regional collaboration for effective implementation of eHealth.Models that can strengthen the empowerment of the patient.A developed multidisciplinary infrastructure to stimulate the development of digital health.Development, evaluation, and implementation of eHealth instruments in collaboration with companies and start-ups.A blueprint for education in eHealth competencies and skills for health care professionals.CF program eHealth, each project leader drafted a detailed project plan describing which of the 10 program deliverables the project aimed to contribute, the project’s objectives, and a detailed timeline. The project plan was approved by the supervising steering committee, which consisted of 2 representatives of each university hospital. In a 3-month meeting, the steering committee monitored the progress of the projects and advised the project leaders. In addition, at the midterm (December 2017) and end-term (October 2018) of the program, the project leaders presented their projects’ progress to the steering committee, and a majority decision regarding the continuation of the project was made.As described in the previous study protocol, each of the 8 Dutch university hospitals was asked to propose 3 or 4 eHealth research projects to be carried out in their own university hospital. Although the university hospitals had a carte blanche for the projects they proposed, every project had to contribute to one or more of the 10 program deliverables. In total, 29 projects covering a wide array of eHealth themes were carried out from June 2016 to January 2019 [Commonwealth Scientific and Industrial Research Organization (CSIRO) framework for evaluating telehealth trials or programs  and part two at the end-term (55 questions) for each project. With this longitudinal aspect, we aimed to evaluate the change in magnitude of the eHealth project progress over time. The topics included respondent demographics and items related to eHealth project progress aspects. The questionnaire was completed using the web-based survey software SurveyMonkey  . The resCF program eHealth, one project leader from each university hospital was randomly selected by drawing lots and interviewed by the coordinating researcher (AR) for a more in-depth exploration of the role of the eHealth project progress aspects in their project. The semistructured interviews were held by telephone, following a previously composed interview guide , but physicians were more cautious, and it was not always possible to implement the Dutch set of standards for interoperability owing to a lack of information technology (IT) capacities (deliverable 5). We also learned that considerable attention should be paid to eHealth literacy when developing novel eHealth solutions (deliverable 4). Furthermore, the establishment of alternative communication infrastructures (deliverable 9) between the caregiver within the hospital and the patient outside the hospital was investigated and considered very relevant.All 10 deliverables of the Citrien Fund - mapping table. As shown in the  outcomes or evident benefits column, in 2 of the 4 cases, personnel matters were responsible for the insufficient progress, in one case there was an issue with the intraoperability of the proposed eHealth solution with the existing IT system and in the last case there was an IT freeze hospital-wide because of the implementation of a new electronic health record system.Owing to insufficient progress, one project was prematurely terminated by the steering committee after the midterm evaluation, and another 3 projects were prematurely terminated after the end-term evaluation. These projects are indicated with an asterisk (*) in the The 2-part questionnaire was completed by all the participating project leaders in November 2017 and October 2018. The first part was completed by 29 project leaders, and the second part was completed by 27 project leaders owing to the premature termination of 1 project and the early completion of another. CF program eHealth was to receive funding . However, publicity  and collaboration  were also important reasons. Of the 29 projects, 25 (86%) had ≥3 people internally involved, and in 23 (79%) projects, people from outside the hospital, such as general practitioners, patients, and software developers, were involved as well.The main reason for participating in the planning have been presented in The main results of the questions concerning policy or organization, technology, ethics, and legal. None of the topics was spared of inconvenience, with IT services and privacy issues representing the greatest shares in moderate to significant inconvenience.finance, 8 projects  received additional funding other than that from the CF program eHealth at the initiation of the project. Furthermore, at midterm, 8 project leaders  thought that they would need extra funding for the successful completion of their project. However, at the end of the study, 13 project leaders  stated that extra funding would be necessary for project completion. The funding received from the CF program eHealth was mostly insufficient to cover the personnel expenses and the implementation aims. After termination of the CF program eHealth, of the 27 projects, 13 (48%) still needed to find financial means to continue, while 4 (15%) already had the means and 10 (37%) did not need any.Regarding the aspect of In total, 8 project leaders were interviewed, representing the entire group of project leaders. After 7 interviews, saturation of information was reached. Three major themes, with subthemes, were identified . The maiSuccess factors for eHealth development and implementationFulfill a needOutsourceCommunicationPersonnelEssential third partiesInformation technology servicesMedical Ethical CommitteeLegislationFlexibilityProject planningConducting researchEffectiveness testingneed to fulfill, or problem to solve, when developing an eHealth solution, although conducting a needs assessment was not deemed necessary. Regarding outsourcing, it was crucial to find the right  partners that already had the knowledge and means to accelerate development. Clear communication with IT developers and other stakeholders about the development and other concerns, for instance, estimated changes in routine care, was essential. Successful development of an eHealth solution may depend on the availability and dedication of the personnel, including the project leader.While carrying out their eHealth projects, the project leaders encountered several relevant aspects that contributed to the success of their projects. In such cases, there should be an evident Owing to the immaturity and complexity of eHealth, several important topics related to its development and implementation have never been discussed before. Therefore, communication and close collaboration with third parties was of utmost importance.IT services, the project leaders indicated that communication was the number one pitfall in successful collaboration. It should also be emphasized that IT development costs time, capacity, and money. Medical ethical committees may find it difficult to take a position because of the unknown impact or burden of a novel eHealth solution. Moreover, one should be informed about the impact of legislation on their project. In addition, a privacy impact assessment is often obligatory, which may cause a delay in planning.Regarding Project planning is important in the initial stages. However, it should be possible in case of incidents to make timely adjustments.eHealth solutions are considered complex interventions with multiple interacting components. This required some level of flexibility when it came down to project planning, conducting research, and effectiveness testing. conducting research, there were varying responses to whether it was challenging to find study participants to evaluate the eHealth project. However, it seems that when an eHealth solution can solve a relevant problem, patients are willing to participate. Furthermore, the study end point was difficult to determine because of the novel character of eHealth and the resulting lack of literature. eHealth solutions should be evaluated in a study context where possible. Nevertheless, it was considered unnecessary to conduct a randomized controlled trial to prove effectiveness, because, for example, patients had already experienced significant benefits while using a novel eHealth solution. In addition, while clinical effectiveness may be obligatory, it does not tell anything about the effectiveness of the eHealth solution.Regarding CF program eHealth. In this study, we learned that patients are more enthusiastic about downloading their own medical data than physicians, that the lack of IT capacities plays a negative role in implementing the Dutch set of standards for interoperability, that considerable attention should be paid to patients with lower eHealth skills, and that establishing alternative communication infrastructures between caregivers and patients should be considered very important.The evaluation study targeted the first study aim. By systematically evaluating the accomplishment of 10 program deliverables, we were able to determine the successes and lessons of the CF program eHealth.The 29 different eHealth research projects delivered 22 tangible eHealth solutions and significant knowledge about the development and use of eHealth solutions. Strengthening the patient’s directing role was the most prominent theme of the CF program eHealth was able to bring the 8 Dutch university hospitals together and therewith significantly improve the fragmented eHealth landscape in the Netherlands.Through the formation of a new collaborative network, the planning, technology, and legal played an important role in successful development of the 29 projects. However, a lack of time with the individual project leaders, priorities other than implementing eHealth in IT services, and the never discussed before privacy issues, together with the relatively short CF program eHealth duration, caused project delays.The mixed methods study targeted the second study aim. The questionnaire helped us learn that the eHealth project progress aspects success factors for eHealth development and implementation, essential third parties, and flexibility, were identified as the 3 most important themes to pay attention to when carrying out an eHealth project.In the in-depth interviews, the themes: CF program eHealth could be compared.Although it seemed that the Netherlands was among the first countries to carry out a publicly funded university hospital eHealth program, there are other nationwide eHealth programs and initiatives with which the NHS digital [CF program eHealth encompasses all university hospitals of the Netherlands. Furthermore, as described by Astana et al [CF program eHealth used a bottom-up approach to search for innovative initiatives, controlled by the 8 university hospitals rather than the government itself. Owing to the high visibility of this program on the web and the co-operation with stakeholders and patients, many useful insights into nationwide eHealth development were gathered and disseminated directly.The National Health Service (NHS), the publicly funded health care system in England, holds an active and well-organized digital section, the  digital . One of na et al , the topna et al . In contPatient@home focused on rehabilitation and monitoring services to promote patient empowerment and support treatment at home [CF program eHealth, projects may have benefited from a structured innovation model with subsequent phases of development and implementation. Especially in the case of the 4 projects that were prematurely terminated, an evaluation of the first phase of innovation—need—which includes technology screening, could have been beneficial. However, the well-thought program structure, consisting of an obligatory project plan and a planning stage at the initiation of a project and 2 project progress evaluations along the way, might have overcome the lack of a structured innovation model.The Danish program  at home . In tota at home . In the planning, technology, and legal were important aspects in relation to successful progress of the projects. From an implementation perspective, comparable results were described by Schreiweis et al [The mixed methods study found that the eHealth project progress aspects is et al . After cis et al  studied Vedlūga and Mikulskienė  compiledCF program eHealth was the open and collaborative organization with a bottom-up approach. For example, one representative from each of the 8 Dutch university hospitals took place in the steering committee and was responsible for monitoring and mentoring local projects. A solid foundation was laid for successful program progress and the achievement of program deliverables.One of the major strengths of the Another strength was the wide array of subjects and studies in the 29 eHealth projects. Although this variation may have reduced comparison possibilities and thus the external validity of projects, many valuable insights that proved important across settings were gained. However, by creating a systematic overview of the projects’ findings in the evaluation study, their comparability was greatly enhanced. The combination of an evaluation study with a mixed methods study to evaluate the progress of eHealth projects in detail further strengthens our study findings.CF program eHealth deliverables were not formulated through the well-known Specific, Measurable, Attainable, Relevant, and Timely formats. Therefore, it might be debatable whether the 10 deliverables were truly completed. Another limitation regarding the achievement of the deliverables might be the finding that most of the project leaders indicated in the questionnaire that their project planning was no longer up to date at the end of the CF program eHealth. However, a not anymore up to date project plan did not necessarily mean project failure and, therefore, its failure to achieve deliverables. Project planning was relevant to the initial direction and evaluation progress but on-time completion of project planning was not compulsory when drawing the final conclusions about the results of a project.A study limitation was that the A limitation regarding the mixed methods study might have been the number of interviewed project leaders. However, saturation of information was accomplished after 7 interviews, and the interviewed project leaders were a representative sample of the whole group.A final limitation was that we used a self-developed questionnaire to assess the eHealth project progress aspects of the 29 projects. We decided to develop a questionnaire owing to the relatively small group of participants and the limited time frame. Although valuable insights were gained, methodologically, it would have been stronger if some level of content validity and construct validity was carried out.CF program eHealth, the most successful projects have now scaled up nationwide in a subsequent edition of the CF program eHealth, focusing on implantation and upscaling [pilotitis , might also be overcome with the sequel of CF program eHealth [After termination of the pscaling . The lac eHealth .The COVID-19 pandemic has accelerated the uptake and implementation of existing eHealth solutions ,42. AlthCF program eHealth has proven that nationwide collaboration on the theme of eHealth between the 8 Dutch university hospitals and related commercial parties is possible and diminishes eHealth fragmentation. To truly preserve and improve the quality of our health care system in the light of global aging, we should strive for the elimination of eHealth fragmentation and national and international eHealth collaborations, such as the CF program eHealth, should be stimulated by governments and the European Union.The planning, technology, and legal played an important role in successful progress of the projects and should therefore be closely monitored while developing novel eHealth solutions or when implementing existing solutions. To further counteract eHealth fragmentation and take the next step from development to upscaling, a subsequent CF program eHealth will be carried out.The 8 Dutch university hospitals were able to successfully collaborate and stimulate nationwide evidence-based eHealth development using a bottom-up approach. In total, 22 novel eHealth solutions with various subjects were developed, and significant knowledge about eHealth development and use was established. The aspects


Recently, recombinant monoclonal antibodies (mAbs) of three Ig isotypes  sharing the same anti-spike protein Fab region were developed; we evaluated their neutralizing abilities using a pseudo-typed lentivirus coated with the SARS-CoV-2 spike protein and ACE2-transfected Crandell–Rees feline kidney cells as the host cell line. Although each of the anti-SARS-CoV-2 mAbs was able to neutralize the spike-coated lentiviruses, IgM and IgA neutralized the viral particles at 225-fold and 125-fold lower concentrations, respectively, than that of IgG. Our finding that the neutralization ability of Igs with the same Fab domain was dramatically higher for IgM and IgA than IgG mAbs suggests a strategy for developing effective and affordable antibody therapies for COVID-19. The efficient neutralization conferred by IgM and IgA mAbs can be explained by their capacity to bind multiple virions. While several IgG mAbs have been approved as therapeutics by the FDA, there are currently no IgM or IgA mAbs available. We suggest that mAbs with multiple antigen-binding sites such as IgM and IgA could be developed as the new generation of therapy. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has caused the second pandemic of the 21st century, which so far has killed more than 2.5 million people and infected more than 130 million in 223 territories globally .Current clinical management procedures for coronavirus disease 2019 (COVID-19) include good hygiene practice, infection diagnosis, and supportive care such as supplemental oxygen and mechanical ventilatory support. The United States Food and Drug Administration (FDA) has approved one drug, remdesivir (Veklury), for the treatment of COVID-19; however, the World Health Organization does not currently recommend usage of remdesivir. Favipiravir, an approved drug to treat influenza, has also been administered to treat COVID-19, but its antiviral efficacy is still under debate [Antibodies collected from convalescent individuals can be used to treat infectious diseases. Approximately 90% of individuals with mild-to-moderate COVID-19 produce anti-SARS-CoV-2 antibodies. Immunoglobin (Ig) M and IgA are typically produced within 7 days , and IgGThe passive administration of monoclonal antibodies (mAbs) is a promising antiviral therapy for AIDS and COVID-19 ,8,9. SevThe mass production of mAbs is laborious and expensive. Thus, researchers are searching for ways to increase mAb potency and reduce the concentration of mAbs required for effective treatment. The five classes of Igs are IgM, IgD, IgG, IgA, and IgE. All Ig molecules contain a fragment antigen-binding (Fab) region, which recognizes antigens, and fragment crystallizable (Fc) regions, which mediate the effector functions of natural killer cells, macrophages and the complement system. IgG is monomeric, IgM is multimeric , and IgA exists in both monomeric and dimeric forms. The number of antigen molecules trapped by each Ig molecule can influence the effectiveness of virus neutralization .Recently, recombinant mAbs of three Ig isotypes  sharing the same anti-spike protein Fab region were developed; we evaluated their neutralizing abilities using a pseudo-typed lentivirus coated with the SARS-CoV-2 spike protein and ACE2-transfected Crandell–Rees feline kidney cells as the host cell line .Although each of the anti-SARS-CoV-2 mAbs was able to neutralize the spike-coated lentiviruses, IgM and IgA neutralized the viral particles at 225-fold and 125-fold lower concentrations, respectively, than that of IgG  Figure a. Our fiOnly the IgG type of mAbs has been clinically applied so far. The reasons could be ascribed to difficulty of IgM purification compared to IgG and the less-stable nature of IgM . But theWhile several IgG mAbs have been approved as therapeutics by the FDA, there are currently no IgM or IgA mAbs available. Our finding about efficacy of the polymerization of antibodies suggests to pharmaceutical companies that mAbs with multiple antigen-binding sites such as IgM and IgA could be developed as the new generation of therapy.


Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoters by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of the promoter regions. Our findings demonstrated the new roles of ARID1A and NSD2 in innate immunity, providing insight into the crosstalks of chromatin remodeling, histone modification, and transcription factors in the epigenetic regulation of antiviral innate immunity.Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity needs to be further identified. Here, we reported that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the  Ifn-I during innate immune response remains to be fully understood.Chromatin remodeling plays a critical role in regulating gene transcription , 2. EpigIfnb transcription upon viral infection [BAF complex (Brg/Brahma-associated factors), known in mammals as the mSWI/SNF (SWItch Sucrose non-fermentable) complex, is an evolutionarily conserved ATP-dependent chromatin remodeler . The mSWnfection . As anotnfection . HoweverIfn-I promoters and interact with the protein methyltransferase NSD2 which methylates H3K4 (H3K4Me3) and H3K36 (H3K36Me2) to facilitate chromatin accessibility at the Ifn-I promoters, resulting in the increased transcription of Ifn-I. Therefore, we demonstrated the interplay among the nuclear proteins including chromotin remodeler ARID1A, transcriptional factor IRF3, and histone modification protein NSD2 at the Ifn-I promoter regions which jointly regulate the production of IFN-I in innate immune cells upon virus infection. Our findings about the promotion of Ifn-I transcription by ARID1A during innate response provide new insight to the epigenetic regulation of innate immunity.In our study, we investigated the role of ARID1A in the antiviral innate response and found that ARID1A can selectively promote IFN-I production in macrophages. We revealed that, in response to viral infection, ARID1A can be recruited by IRF3 at the Arid1a expression was quite abundant in immune-related cells and tissues according to the BioGPS website (BioGPS.org). The higher expression level of Arid1a was verified in the spleen and lymph nodes of mice compared to other organs  was significantly decreased in Arid1a-silenced PMs after VSV infection  mice and control (Arid1af/f Lyz-Cre−) mice. Indeed, no difference was observed between the two groups with or without VSV infection  assay to examine the association between ARID1A and the promoter region of ion Fig. , suggestArid1a and Tbk1 plasmid. We discovered ARID1A significantly promoted the transcription of Ifnb reporter but not Tnfα or Il6 reporter  of ARID1A which could recruit ARID1A to the promoter regions of the given genes , 20. We Arid1a and truncated Irf3 plasmids revealed that deletion of the DNA binding domain  or the IRF association domain  of IRF3 abrogated its interaction with ARID1A  was identified as another ARID1A-associated protein , gastric cancer infected with Epstein Barr virus [Arid1a expression may be downregulated and involved in the immune escape and pathogenesis. In the current study, we utilized virus-infected macrophages as the cell model and found that the protein expression of ARID1A remains unchanged in these cells in response to acute infection with RNA or DNA viruses. The results indicated that ARID1A may have different responses to acute and chronic viral infections. More studies are further needed to explore the expression pattern and roles of ARID1A protein in infectious diseases and virus infection-related cancers.Pathogens have evolved a variety of epigenetic strategies for their survival and replication, such as induction of host protein and chromatin modifications to inhibit the expression of activators and enhance the expression of repressors in innate immunity , 40. Therr virus , epithelrr virus . These rIn conclusion, our study provides a mechanistic insight into the epigenetic regulation of antiviral innate immune response by integrating histone modification with chromatin remodeling. Our study may provide a potential target for the control of virus infectious diseases and other inflammatory diseases.Arid1a floxed mice [Arid1a gene. Arid1af/f Lyz-Cre+ mice were defined as Aird1a-deficient mice, Arid1af/f Lyz-Cre- littermate mice were used as control. Irf3-deficient mice were provided by Dr. T. Taniguchi from the University of Tokyo, Tokyo, Japan. All mice were genotyped by PCR before experimentation. The genotyping primers were Arid1a forward, 5’- TAAGTTCCAAGACAAGCAGAACC- 3’; Arid1a reverse, 5’- ACAGAATGGAGTGAAGACACGAT- 3’; lyz2- wt: 5’- TTACAGTCGGCCAGGCTGAC- 3’; lyz2-common: 5’- CTTGGGCTGCCAGAATTTCTC- 3’; lyz2-mutation: 5’- CCC AGAAATGCCAGATTACG- 3’.Animal experiments involved in this study were performed with the guidelines of the Institutional Animal Care, and the experimental design and process were approved by the animal ethics review (ACUC-A01-2018-018). The xed mice  and lyz2PMs were obtained from mice 3 days after intraperitoneal injection with thioglycolate, BMDMs were prepared by culturing in recombinant 50 ng/ml mouse M-CSF (Perprotech) for 7 days. HEK293T, RAW264.7, and Vero cells were obtained from American Type Culture Collection. Cells were all cultured in DMEM supplemented with 10% FBS.VSV (Indiana strain) and HSV-1 were amplified from Vero cells and SeV (Sendai virus) was amplified from chicken embryos as described previously .Arid1a (Invitrogen) and siRNAs of Nsd2 (Genepharma) and RNAi MAX reagent (Invitrogen) were utilized for RNA interference in PMs, and the interference efficiency was examined by qPCR. Sequences of siRNAs were listed as follows: Arid1a sense1, 5’-AGAUGUGGGUGGACCGGUATT-3’; Arid1a sense2, 5’-GAAUGAACAGGAAAACUCATT-3’; Nsd2 sense1, 5’-GCA AAGCUCAACUUUCUAATT-3’; Nsd2 sense2, 5’-GCA GAAAUUUAAUGGCCAUTT-3’. The detected primers for efficiency of RNA interference are: si Arid1a forward, 5’- GAACCCTATGGGTGCTGGAG-3’; si Arid1a reverse, 5’-CCCATCATGCCCCCTTGATT-3’; si Nsd2 forward, 5’- GGCCAGAACAAGCTCTTACAA-3’; si Nsd2 reverse, 5’-TGTGGGCTCCCATAA AAGCTC-3’.siRNAs of 7 pfu/g). Serum was collected for ELISA detection at indicated times. The RNA of the spleen, liver, lung, and PM cells were extracted by TRIzol (Invitrogen). The titer of VSV in cell lysates (0.1%Triton in PBS) of mouse organs was detected by TCID50. The lung lobes of mice were fixed with 4% paraformaldehyde. After embedding, sections were stained with hematoxylin and eosin, and observed with Pannoramic SCAN. For survival curve analysis, mice were intravenously injected with VSV (1 × 108 pfu/g), then generated and analyzed for statistical significance with GraphPad Prism 5.0.The mice were infected with VSV by tail vein injection  or RNAfast2000 kit (Fastagen). ReverTra Ace qPCR RT master mix (Toyobo) was used to synthesize cDNA.Quantitative PCR analysis was performed by Q7 (ABI) using the SYBR RT-PCR kit (TOYOBO). Sequences of the primers for qPCR were listed as follows: PMs plated on glass coverslips were infected with or without VSV for 8 hours and labeled with antibodies. Antibody to ARID1A (32761) was from Santa Cruz. Antibody to NSD2 (A7938) was from ABclonal. Antibody to Alexa488 (A1108) and Alexa594 (A11005) were from Invitrogen. Slides were subjected to microscopy analysis with Zeiss LSM780 confocal laser microscope.Expression vectors encoding ARID1A were obtained from Origene (MR224275) and cloned into PEF1a-V5-vector. FLAG-tagged-NSD2, FLAG-tagged-TBK1, Myc-tagged IRF3, and their mutants were cloned into pcDNA3.1 vector. All constructs were confirmed by DNA sequencing. HEK 293T cells were transfected with JetPEI reagents (PolyPlus). RAW246.7 cells were transfected with FuGENE HD (Promega), and BMDMs were transfected with Lipofectamine 3000 (Thermo) according to the manufacturer’s instructions.Immunoblot and immunoprecipitation assays were performed as described previously . CytoplaELISA kits (Biolegend and Ebioscience) were used for examining the concentrations of cytokines in cell supernatants or serum of mice according to the manufacturer’s instructions.Cell preparations and surface staining were performed as described previously . The dathttp://www.novogene.com/). Gene FPKMs were computed by summing the FPKMs of transcripts in each gene group. Transcripts with a P-adjust < 0.05 were assigned as differentially expressed. KOBAS software was used to test the statistical enrichment of differentially expressed genes in KEGG pathways.Total RNAs were isolated with TRIzol. Then RNA quantification and qualification were confirmed. Library construction and sequencing were performed on Illumina Novaseq 6000 -0h set to a value of 1. Sequences of the primers for qPCR are listed as follows: Ifnb promoter forward, 5’-TAACCCAGTACATAGCATATA- 3’; Ifnb promoter reverse, 5’-AGTGAGAATGATCTTCCTTCAT- 3’; Ifnα4 promoter forward, 5’-ATCCCA GACACAAGCAGAGAG- 3’; Ifnα4 promoter reverse, 5’-GGCTGTGGGTTTGAG TCTTCT- 3’; Tnf promoter forward, 5’-CAGCCACTGCTTGGCTAGAC; Tnf promoter reverse, 5’-CGGATCCCATGGACCAACTG- 3’; Il6 promoter forward, 5’-GCAGTGGGATCAGCACTAAC- 3’; Il6 promoter reverse, 5’-GGTGGGTAA AGTGGGTGAAG-3’.DNase I sensitivity assay was performed as described previously . In brieThe cells were treated as the instructions of the ChIP assay kit (Beyotime P2078). For each ChIP assay, antibodies were added to cell samples and incubated overnight at 4 °C. Antibody–chromatin complexes were pulled down by magnetic protein G beads (Invitrogen). DNA was eluted, purified, and subjected to qPCR. Antibodies to ARID1A (ab182560) and H3K4Me3 (ab8580) were from Abcam. Antibody to H3K36Me2 (39255) was from Active Motif. Sequences of the primers for qPCR are the same as the primers in DNase I Sensitivity Assay.Arid1a_/− and Nsd2+/− cells were generated by CRISPR/Cas9 system in the RAW264.7 cell line. Briefly, the Arid1a_/_ RAW264.7 cells were transfected with Cas9 and pGL3-U6-sgRNA plasmid, then added blasticidin S hydrochloride  and puromycin  after 24 h. Nsd2+/− RAW264.7 cells were transfected with sgRNAs–targeted-Cas9/green fluorescent protein (PGX458) plasmid. Single transfected cells were sorted. The clones were detected by PCR. The sequence of sgRNA are listed as follows: Arid1a- A1 up: 5’-CACCCTGGTTATAGTATGGAGTC-3’; Arid1a -B1 up: 5’-CACCCTGTTGTGTGGTGGACTGC-3’; Nsd2-AW1 up: 5’-CACCAAATCCTTGGCAGTGCAAA-3’; Nsd2- BW1 up: 5’- CACCACTAGGAGGAACAGGAAG-3’.For reporter assays, HEK293T cells were co-transfected with the reporter plasmid, pRL-TK-Renilla-luciferase plasmid, and other plasmids according to the experiment design and measured with the Dual-Luciferase Reporter Assay System Kit (Promega) according to the manufacturer’s protocols.t-test. *P < 0.05 were considered to be significant . For the mouse survival study, Kaplan–Meier survival curves were generated and analyzed for statistical significance with GraphPad Prism 5.0.Statistical significance between groups was determined by a two-tailed Student’s Supplementary MaterialSupplementary MaterialSupplementary MaterialSupplementary MaterialSupplementary MaterialSupplementary MaterialSupplementary MaterialSupplementary MaterialSupplementary Material


COVID-19 disrupted health care, causing a decline in the health of patients with chronic diseases and a need to reimagine diabetes care. With the advances in telehealth programs, there is a need to effectively implement programs that meet the needs of patients quickly.The aim of this paper was to create a virtual boot camp program for patients with diabetes, in 3 months, from project conception to the enrollment of our first patients. Our goal is to provide practical strategies for rapidly launching an effective virtual program to improve diabetes care.A multidisciplinary team of physicians, dieticians, and educators, with support from the telehealth team, created a virtual program for patients with diabetes. The program combined online diabetes data tracking with weekly telehealth visits over a 12-week period.Over 100 patients have been enrolled in the virtual diabetes boot camp. Preliminary data show an improvement of diabetes in 75% (n=75) of the patients who completed the program. Four principles were identified and developed to reflect the quick design and launch.The rapid launch of a virtual diabetes program is feasible. A coordinated, team-based, systematic approach will facilitate implementation and sustained adoption across a large multispecialty ambulatory health care organization. The COVID-19 crisis necessitated an abrupt adjustment to the delivery of outpatient care in order to protect vulnerable populations from avoidable exposure to the virus while providing continuity of care to patients with chronic health issues. One result of the crisis was that telemedicine use exploded worldwide, especially in patients with diabetes . In respUPMC Central Pennsylvania is a large, integrated, not-for-profit health care system with over 2900 physicians across 7 acute care hospitals and 200 ambulatory care sites, serving over 10 counties in central Pennsylvania. UPMC Central Pennsylvania established their telehealth program in 2013, when a telestroke initiative was launched. The telehealth department has since grown and is led by the chief medical information officer and supported by a director, analysts, clinical implementation consultants, and trainers. It is also supported by a dedicated patient phone and email hotline for telehealth and portal issues. UPMC Central Pennsylvania uses the Epic (Epic Systems Corporation) electronic health record (EHR), the accompanying MyChart patient portal, and the EHR-integrated telehealth platform Vidyo (Vidyo Inc). The platform offers audio and video calls, messaging, file sharing, and automatic vital sign reporting. The diabetes boot camp also uses the website Tidepool (Tidepool Project) [The all-virtual, holistic diabetes program was conceived and developed in less than 3 months and includes diabetes education, nutrition counseling, coping mechanisms, planned exercise, and medication adjustment via a team of physicians, registered dieticians, and diabetes educators. Patients meet virtually with a team member once a week, alternating between a diabetes educator and a dietician, and regularly interact with the Tidepool application. Follow-up HbA1c (glycated hemoglobin) values are obtained after the completion of the 3-month program.We started the program at selected pilot clinical sites, refining the program with input from all members of the team before adopting the program at the organizational level. Success was assessed by monitoring HbA1c improvement, weight and blood pressure control, and the number of patients completing the program. By using integrated workflows in the EHR and simplifying the process for both patients and providers, we were able to keep the changes minimal for most of those involved. Educating clinic staff to guide patients through enrollment and the use of the software was critical to the success of the program. Few studies have looked to described generalizable strategies to quickly design, launch, and implement a scalable virtual diabetes program across a large multispecialty ambulatory clinic group.UPMC Central Pennsylvania is comprised of multiple primary care offices consisting of 300 primary care physicians across 50 clinics and 3 endocrinology clinics across a 10-county region. We have a dedicated telehealth department that guides strategy, implements, and supports all virtual programs across the organization. In July 2020, due to the growing need from patients with diabetes to be seen virtually, a diverse group of clinical, operational, and telehealth leaders were engaged to support the launch of a new way of taking care of patients with diabetes who required frequent appointments. The virtual program was developed to alleviate the need for frequent in-person visits during the pandemic using previous and new lessons learned through the pandemic and serve a large geography of patients traveling as far as 1 hour to see their endocrinologist. A quick timeline was decided for the program, and bimonthly meetings were held to optimize the project due to the pandemic emergency and to improve the virtual access of patients with diabetes to doctors.We were able to embed the new virtual workflows into the Epic ambulatory EHR, facilitating ease of adoption and operational efficiency. A documentation template was created to guide diabetes educators through medication change-related decisions. We also created a unique electronic referral in the EHR for the virtual boot camp to identify it as a new clinical service and for tracking purposes. Both the dieticians and the nutritionist team could receive this referral from physicians. The Tidepool software was installed on provider, educator, and dietician computers. Tidepool provides a diabetes web-based data platform to view data from multiple patient devices and display it together on one timeline. Physicians and staff were trained on using the Tidepool software to download glucose monitoring home data. Our endocrinologists introduced primary care physicians to the program via virtual educational seminars.Using the endocrinology office as a pilot, a patient registry of patients with diabetes who had laboratory values of HbA1c>8% was generated from the EHR. The endocrinologists discussed the virtual boot camp program with these patients and initiated the referral process for interested patients. Administrative support personnel scheduled the virtual sessions and guided patients through the enrollment process. Patient education, including online instructions for downloading and uploading glucose data (using the Tidepool software), was delivered via the patient portal. If the patients had difficulty following the online instructions, the patient help desk or clinic staff engaged them via phone to guide them through the process.Each week, the patients met virtually for a 30-minute session, alternating weekly between a diabetes educator and a dietician, to review glucose monitoring data from their mobile app, diet, exercise plans, and lifestyle changes. The virtual meetings were also held to address other education and medication or therapy changes. Progress was followed closely, using real time blood glucose data. Weekly feedback showing improvements helped to keep the patients engaged and adherent to the program. We found that gamification of the process (by tracking the numbers closely and meeting target results) kept the patients motivated throughout the program. At the end of the 12-week program, HbA1c values were rechecked, and each patient had a follow-up telehealth visit with an endocrinologist. Our program’s success was assessed via changes in HbA1c levels, and by patient engagement as measured by the completion of the program. A survey assessed patient satisfaction with the virtual program. Following the launch at the pilot clinic site, the program was opened to patients with diabetes at primary care clinics. Education was provided by a lead endocrinologist champion to primary care clinics about the new virtual boot camp program, the patient criteria, its aim, and the referral process. This study was submitted for Institutional Review Board approval and was found to be exempt since it did not contain any patient-specific data.After the program’s launch and successful implementation at the pilot clinic site, it was extended to all 50 primary care clinics in the UPMC Central Pennsylvania network. Within 3 months of the September 2020 launch, we referred and quickly enrolled over 100 patients. Our strategies in 5 broad domains reflect an effort to expedite the launch while creating a sustainable program that can grow beyond the pandemic. Various approaches can be deployed to overcome barriers to implement a virtual program. Using the experience gained through our decades of implementing telehealth programs, we propose recommendations that can be deployed at the system-level for health care organizations to overcome barriers in a rapid time frame .P<.001), with a range percentage decrease of 0.7-3%. A survey after completion of the program showed that a majority  were very satisfied or satisfied with the virtual boot camp, while 76% (n=23) reported that they felt the virtual boot camp saved them time. A wide majority, 94% (n=28), would recommend the program to their family or friends.Of the 37 patients who completed the program, the mean age was 53 years, with the age range of 22-78 years, 62% (n=23) were female, and 38% (n=14) were male. Moreover, 81% (n=30) were White and 19% (n=7) were African American; 81% (n=30) of the patients had commercial health insurance, and 19% (n=7) were on government health insurance such as Medicaid . Of the We demonstrated a quick 3-month implementation of virtual diabetes boot camp with the enrollment of over 100 patients. Our program intervention made an improvement of diabetes in a majority of patients (75%) who completed the program. Our proposed practical steps on guiding strategies can be used for quick implementation solutions for digital health programs. Telehealth has been used in diabetes care since 2000. The IDEATel (Informatics for Diabetes Education and Telemedicine) project, a randomized trial conducted over 5 years in New York, compared usual care with telemedicine among older Medicare beneficiaries . StatistPrevious telehealth and diabetes care trials have studied the effectiveness of virtual nurse coaching and mobile health to improve physical activity , the impOur successful holistic interventions for patients with diabetes included a mobile app, diabetes education, nutrition guidelines, lifestyle intervention, therapy adjustment with integrated decision support system, and a dedicated telemedicine help desk phone for support and guidance. Though we faced a few challenges, specifically a quick timeline, we were able to use practical approaches to overcome them . Having Consistent barriers remain such as manual data entry by patients with diabetes, with automation and immediate feedback identified as enablers . The virThe virtual diabetes boot camp was launched to improve the overall health of our patients with diabetes and to reduce the need for in-person visits during the pandemic. We successfully launched the program within 3 months, with promising early clinical results and patient satisfaction. The program facilitated frequent engagement between the providers and the patients, decreased the burden for the providers, and increased communication between members of the provider team.We recommend aligning organizational goals to strategies  for the We launched the program quickly in the endocrinology clinics, but it took sustained educational and communication efforts by primary care clinics to improve adoption across the organization. Sustained effort is needed to successfully roll out a new virtual program and to engage physicians and patients in a multispecialty, large clinic organization. Frequently highlighting the program benefits and continuously monitoring progress is vital to adoption. We were able to use our dedicated patient telehealth help desk to support patients struggling with the telehealth platform. In our experience, a previsit education intervention led to an easier and more successful virtual visit by patients, as confirmed by others . We real


In this paper, we focus on why intraplate seismic initiation and migration occurs, which has widely been considered to be caused by static stress triggering caused by earthquakes, as well as post-seismic slips. To illustrate the mechanism underlying large earthquakes, in particular the migration caused by two key episodes that occurred after 1500 in the Bohai-Zhangjiakou Fault Zone (BZFZ) of North China, we developed a high-resolution three-dimensional viscoelastic finite element model that includes the active faults with vertical segmentation, their periodical locking, and the lithosphere heterogeneity. We used the birth and death of element groups to simulate stress intensity changes during the two episodes (named Episode I and II), with our results showing that the Tangshan earthquake was primarily triggered by the Sanhe-Pinggu M8.0 earthquake in 1679, whereas the Zhangbei M6.2 earthquake in 1998 was not triggered by earthquakes in Episode I. According to our work, the calculated stress changes in the different segments of the fault zone correspond to the magnitude of the triggered earthquakes. Further, the largest stress decrease was near the Sanhe-Pinggu fault and occurred the largest earthquake in Episode I, whereas the largest stress increase was near the Tangshan fault and occurred during the largest earthquake in Episode II. Given the above, we propose a model for seismic migration to describe the dynamic mechanisms of earthquake migration within the BZFZ and North China, in which the factors affecting both the seismic migration path and intensity primarily include the distance between the triggered active fault and the original fault, the coupling of the active faults, the location and scale of the low-velocity anomaly, its distance from the active fault, and the location and scale of the crustal thinning. Increasing amount of historical evidence regarding the intraplate earthquakes shows episodic seismicity and clustering seismic migration within some mid-continents, including North China and New Madrid ,2. SeismStatic stress triggering caused by earthquakes, as well as post-seismic slips, has widely been considered a cause of such intraplate seismic initiation and migration ,11,12. PThe Bohai-Zhangjiakou Fault Zone (BZFZ) underlies the capital region of China and several megalopolises. The BZFZ is an extremely active fault system and is arguably the most important intraplate seismic belt within the North China Craton since it has been dominated by moderate to strong earthquakes since 1500. Some of the largest earthquakes that have occurred include the Sanhe-Pinggu M8.0 earthquake in 1679, the Tangshan M7.8 earthquake in 1976, and the Zhangbei M6.2 earthquake in 1998 . To illuTherefore, in our work, we used a high-resolution three-dimensional viscoelastic FEM model that considers active faults with vertical segmentation, their periodic locking, and the lithosphere heterogeneity to illustrate the mechanism of large earthquake migrations in the BZFZ between the two key episodes after 1500, i.e., the Sanhe-Pinggu M8.0 earthquake in 1679 and the Zhangbei M6.2 earthquake in 1998.As shown in The earthquake catalog for the BZFZ and its adjacent areas, which appears to be complete for M6 events and greater from 1500 to 1998 , includeMost of the earthquakes in the BZFZ, especially those greater than M6.0, tended to cluster at the intersections of the NW-trending and NE-trending fault zones. Here, as shown in In Episode I, large earthquakes were concentrated in the middle segment, in particular the Sanhe-Pinggu M8.0 earthquake in 1679. In Episode II, large earthquakes were concentrated in the southwest and northwest segments, in particular the Tangshan M7.8 earthquake in 1976 and the Zhangbei M6.2 earthquake in 1998 . ResearcTo study the mechanism underlying earthquake migration within the BZFZ, we developed a three-dimensional viscoelastic FEM model that includes all active faults, vertical segmentations, and lithospheric heterogeneity.We constructed the FEM using the ANSYS 14.5 (University Version) finite element software package. Our model domain extends from 113°E to 120°E longitude and from 37°N to 42°N latitude, covering a depth of 100 km. As shown in We modeled the lithosphere using a layered rheology structure that includes four types of rock; as summarized in In the above viscoelastic model, Young’s modulus E and Poisson’s ratio ν can be calculated using the following equations, which essentially define Hooke’s law in three dimensions ,51:Vp= are defined to be up to an order of magnitude less than that of the surrounding upper crust . To studKey in our model, we use the birth–death elements for the locking segments of faults to simulate the re-opening of locking segments after large earthquakes. Note that the stiffness of the birth–death element can be reduced without changing the properties of the other elements.We applied the boundary conditions based on GPS data and the inverse method ,30 as foBy comparing the simulation results of different models with various loading of the observation GPS, we analyzed the influence of the uncertainty in different boundary condition and verified the reliable of the forward model. Here we use average dispersion D to measure the fitness between the GPS observation results and calculated results in different models .D=1m∑i=For the models given in Given the above three-dimensional viscoelastic heterogeneous model and boundary conditions, we applied a GPS-based displacement field at the edges of the model. We then obtained the maximum principal compressive stress trajectory map of the study area, which we present in http://www.eq-icd.cn/webgis/index.htm) for comparison and validation. The calculated trajectories of the horizontal maximum principal compressive stress σHmax fit well with the observed data, which comprised NEE–SWW-trending trajectories, as depicted in To illustrate the reliability of the calculated stress field, we used horizontal maximum principal compressive stress σHmax from the observed data, which includes collapse data of boreholes, fault slip monitoring, hydraulic fracturing, and the focal mechanism   induced by large earthquakes and their triggering effect to subsequent earthquakes have caught wide spread attention in recent years ,18,46. TIn conclusion, we found that episodic seismicity and clustering seismic migrations in mid-continents result from the adjustment of regional stress fields after large earthquakes and active fault openings, as well as coupling between deep and shallow geological processes. In our future work, our model of earthquake migration could be considered in the long-term seismic hazard assessment within North China and other mid-continents.S1 FileAll earthquakes used in the papers are listed.(EQT)Click here for additional data file.S2 FileBoundary loading data used in the papers are listed.(TXT)Click here for additional data file.