In the homeless population, barriers to housing and supportive services include a lack of control or access to data. Disparate data formats and storage across multiple organizations hinder up-to-date intersystem access to records and a unified view of an individual’s health and documentation history. The utility of blockchain to solve interoperability in health care is supported in recent literature, but the technology has yet to be tested in real-life conditions encompassing the complex regulatory standards in the health sector.This study aimed to test the feasibility and performance of a blockchain system in a homeless community to securely store and share data across a system of providers in the health care ecosystem.We performed a series of platform demonstrations and open-ended qualitative feedback interviews to determine the key needs and barriers to user and stakeholder adoption. Account creation and data transactions promoting organizational efficiency and improved health outcomes in this population were tested with homeless users and service providers.Persons experiencing homelessness and care organizations could successfully create accounts, grant and revoke data sharing permissions, and transmit documents across a distributed network of providers. However, there were issues regarding the security of shared data, user experience and adoption, and organizational preparedness for service providers as end users. We tested a set of assumptions related to these problems within the project time frame and contractual obligations with an existing blockchain-based platform.Blockchain technology provides decentralized data sharing, validation, immutability, traceability, and integration. These core features enable a secure system for the management and distribution of sensitive information. This study presents a concrete evaluation of the effectiveness of blockchain through an existing platform while revealing limitations from the perspectives of user adoption, cost-effectiveness, scalability, and regulatory frameworks. According to Austin’s Ending Community Homelessness Coalition (ECHO), more than 7100 people in Austin experienced homelessness and needed housing and other supportive services in 2016 [The Mayor’s Challenge Competition, sponsored by Bloomberg Philanthropies, is designed to facilitate innovative and scalable solutions for city leaders to tackle urgent local challenges. Austin, Texas, was one of the 35 cities selected to prototype and test their ideas over 6 months with a grant support of US $100,000. Through a partnership between Dell Medical School, the City of Austin government, Austin Travis County Emergency Medical Services, and community organizations, a pilot study was conducted to test the first use of blockchain technology to validate identities and improve access to services for the PEH in the country.transaction identity, we previously proposed the use of distributed ledger technology (DLT), or blockchain technology, to provide a validated, immutable identity and record of service transactions [economic passport for the homeless, working toward the goal of ending homelessness. This technology was chosen as a solution over other methods of storing and sharing information such as a digital wallet or a relational database because its features met the requirements of our use case. We have continued this study, and here, we provide results from our testing of the deployment of this approach.To solve these problems of sactions . The litsactions -9. BlockBlockchain is a technology for shared databases used by multiple writers in which each organization’s entries must be verified and cannot be modified by an outside party. When transactions from one entity are needed by another to provide a service or verify a document, storing transactions in a single shared database promotes expedient exchange of information. A regular shared database can reliably manage the permissioning of multiple authorized users to view data. However, a relational database system in which various entities update and write information can result in unrecoverable errors. Maintenance of a health and social service information system involves backup storage services, recovery mechanisms, and updating information . In the Blockchains organize data so that secure transactions are approved and recorded through consensus from entities on the chain ,11, provpublic blockchain is completely decentralized, and transactions depend on consensus from a majority of nodes. In a private blockchain, users are granted access by permission from the owner of the blockchain [A ockchain . For senockchain . A privaockchain . The onlockchain ,16-18.Lack of interoperability between service providers arises from nonuniform data formats and storage methods . BlockchIn this study, we describe the results of a pilot test using a blockchain solution to mitigate the current challenges in service access for the homeless and data exchange between providers. The potential for blockchain in various health care settings has been examined in several studies ,14,20,21Austin, Texas, was 1 of the 35 cities selected by the 2018 Mayor’s Challenge Competition, sponsored by Bloomberg Philanthropies. The competition was designed to facilitate innovative and scalable solutions for city leaders to tackle urgent local challenges. Each Champion City selected in the Mayor’s Challenge Competition was to prototype and test their ideas over 6 months. Through a partnership between Dell Medical School, the City of Austin’s Office of Technology Innovation, Austin Travis County Emergency Medical Services, and community organizations, a pilot study was conducted to test the use of blockchain technology to validate identities for the homeless.Participation in the Mayor’s Challenge Competition required a series of steps to design and implement testing. First, we identified assumptions underlying the idea, which will be required for stakeholder participation. We found that the following set of assumptions must be tested and shown to be valid for the successful implementation of our solution see : (1) ourSecond, we identified markers for what constitutes an appropriate test of a platform based on blockchain technology see . To be eBefore testing our assumptions, initial engagement with the homeless population was performed to determine their needs and concerns. Two-hour meetings were held biweekly over a period of 12 months. Attendees included 20 homeless individuals in the City of Austin and 1 to 2 staff members from the City of Austin Office of Innovation who regularly interacted with the homeless population. The homeless participants were rotated monthly to include a larger subset of the population, and each participant was compensated for their time at a rate of US $20 per hour. Meetings consisted of open-ended questions regarding difficulties those with lived experience of homelessness face in daily life, interacting with service providers, maintaining documents, and filling out applications.On the basis of these discussions and the answers we received to the questions in As can be seen, the documents required for identity verification varied across types of organizations. Every organization, though, needed an official photo ID; yet, about one-third of clients lacked such a basic identity document when first entering the system. Replacing a photo ID is a time-intensive effort. Approximately half of the presenting users lacked insurance cards, which were required by many organizations. Looking at the entirety of the figure, though, it becomes clear that managing identity involves managing a significant number of identity documents across a wide audience of service organizations.As some of the assumptions had overlapping aspects, we describe our methodology in testing all 7 assumptions in the subgroups below.Given that our blockchain platform is modified from a pre-existing platform for refugees, the use case of refugees must be nominally equivalent to the use case of people experiencing homelessnessTo gain user participation, people experiencing homelessness must understand the functionality and features of the platform, and consent to participate.Stakeholder participation requires providers to access, accept, and trust information shared through the blockchain network.Blockchain is necessary to meet our goals.Privacy and confidentiality of personal data needs to be protected.Enabling access to information facilitates service transactions.The technology enables a shared data standard and governance that increases inter-organizational efficiency.Assumptions 1 and 5 regarding the viability of an existing private, permissioned blockchain platform for our use case and the security and privacy of data were tested in 2 sessions on June 14, 2018, and July 13, 2018. In the first session, our testing plan was for the homeless clients to set up an account, upload a document onto the blockchain, deny a request to connect from an organization, accept a request to connect from an organization, and participate in a 3-party transaction between the client and 2 service providers. All tests were performed with platform provider staff, our team members, and 2 homeless individuals. Members of our team created mock provider accounts before testing with our homeless participants. For our second testing session, we modified the user interface so that an account profile contained the user’s picture and name with categories for general profile information, identity documents, medical documents, and dependents or emergency contacts.We tested our assumption regarding user participation (assumption 2) at 2 pop-up resource clinics, where the homeless could access multiple health, social, and other service interventions. Our group of 8 city officials and 5 individuals from our team engaged a total of 34 homeless residents. Of the 34 homeless residents, 15 agreed to participate, 11 indicated interest when more information and a working platform were available, and 8 either declined to participate or did not finish the discussion.Attendees were offered the opportunity to discuss and provide feedback on a technology designed to securely store and share their documents. In our discussions with homeless participants, we used 3 different prototypes of our platform with increasing levels of fidelity to a real-life DLT platform. At the lowest level, to explain the concept of DLT in a nontechnical manner, we created a prototype of the platform using several journals with a lock and key . Each joIncreasing the fidelity of the prototypes, we next showed screenshots of the platform prototype with sample transactions, and then, at the highest fidelity level, a digital prototype on a mobile phone with uploaded data was presented. These 2 prototypes were used to further explain the technology and platform concepts. The static screenshot-based prototype showed prospective categories  for the different types of documents. We also showed screenshots of a request from a provider for permission to see a user’s data, accepting and giving the provider permission to view specific documents, and a transaction history showing that a document was shared with a provider.At this stage in our project, the high-fidelity prototype platform was then used to demonstrate uploading and viewing a picture of a driver’s license via the platform. The prototype platform for refugees had not been modified at all for our use case. Thus, our demonstration was performed in a sandbox or in a closed, nonlive testing environment to safely experiment with Web or software projects. We additionally decided to conduct further tests with sample documents until the technology was fully configured and free of errors.Understanding and acceptance of metrics were measured with participation consent forms and qualitative feedback through open-ended questions.We tested assumptions 3, 6, and 7 regarding stakeholder participation and organizational and data standards through interview questions with representatives of the Downtown Austin Community Court, Central Health, and ECHO who interact with and provide services to PEH regularly . The parAs was clear in the Methods section, multiple assumptions were tested in each of the approaches. As such, we note which assumption(s) was being tested, where appropriate. In particular, note that assumption 6 about data availability facilitating service transactions permeates most aspects of the testing process. The assumptions are listed in In testing assumptions 1 and 5, both of our homeless participants were able to set up a user account, accept a connection request, deny and accept a provider connection request, and exchange transactions to and from providers. Specific observations, difficulties encountered, and their relevance to our project and testing assumptions are displayed in Overall, users on the platform were able to accomplish the tasks expected of them even if guidance was required, but there were definite issues that need to be solved. Trying to use an existing platform developed to assist refugees without modification did not translate to the use case of working with those experiencing homelessness. Furthermore, privacy and security did indeed turn out to be of paramount importance to end users.The results of our tests showed that the homeless can understand the platform and its potential benefits, and a majority of individuals consented to participate immediately or at a later date. Feedback from our PEH test participants included the need for a wider variety of documents that can be validated and authenticated on the platform, leading us to consider possibilities for future expansion, such as involving state or federal institutions. We also planned to create benchmark documents facilitating services such as housing, disability benefits, Supplemental Nutrition Assistance Program (SNAP), medical, court documents, and insurance. Each benchmark document would consist of validation from multiple providers that the documents necessary for a service have been obtained and authenticated, increasing efficiency for service providers and improving access to services for their homeless clients.The results showed that providers will accept data shared through the blockchain platform, but permissible document fidelity varies across organizations. Specifically, the requirements of what would be considered a certified document varied see . TransacThe need for interorganizational records or documents from clients also varied. Many providers kept internal digital copies of client records and provided services to the homeless without proof of identity because of flexible policies for this population. Identification documents are unnecessary for social security, disability benefits, transitional housing, or rehabilitation services, but the lack of identification documents can delay medical care at hospitals. These providers envisioned a role for a distributed ledger system when clients did not grant permission for document storage and for time-sensitive documents such as a current utility bill needed to prove residency. In these cases, system-level efficiency could be improved if provider employees knew what type of documents were available and if documents of interest could easily be located without looking through extraneous information.Potential changes in the organizational workflow to accommodate a new system, such as our platform, was another area of friction. The HMIS provided by the US Department of Housing and Urban Development (HUD) is already widely used across the country as a centralized database to confidentially aggregate data on the homeless and housing provisions provided to these individuals. Copies of documents and IDs can be stored via HMIS, and organizations funded by HUD are required to use HMIS for client data. From the service provider perspective, blockchain is most useful for documents not currently stored in the HMIS database or for client personal use to keep track of future appointments and pending documents needed for services. This showed that the blockchain platform may, for the time being, work complementary to other existing databases or information systems, adding new features that are difficult to establish using legacy systems.Technological concerns included the privacy and confidentiality of indelible and immutable client data for a service that might not be successful in the long term. Providers agreed that the technology showed value for the nonhomeless population as well, but opinions on whether the technological barriers were surmountable for the homeless were mixed. The most vulnerable members of the homeless population struggle to keep a phone and remember their email IDs and passwords, complicating platform access and use. There will always be a level of tension between ease of use and privacy/security concerns. However, adequately addressing the latter may help facilitate more practical solutions for the former. The readiness to overcome any specific requirements for the use of the solution by PEH seemed to be determined by how many of their problems were being solved effectively by using such a platform.Analysis of interview feedback elucidated the requirement of clearly defined roles for each organization. Not all providers wanted responsibility or additional work processes of account creation, document validation, and resolution of transactional or account legitimacy. Legal issues and worries regarding Health Insurance Portability and Accountability Act (HIPAA) compliance to share personal health information and other client data between organizations were further constraints on stakeholder roles, participation, and interorganizational efficiency. The questions around governance and standardized processes for onboarding and managing roles remained unresolved. It was not clear whether the City of Austin had the capacity to manage a blockchain platform or if there was another organization in the city, which had the capacity and trust of all other stakeholders and general citizens, including the PEH.The results of our tests demonstrated that the platform we had chosen to use lacked core functionality and configuration specifically needed for our particular use case. The user experience was time consuming and not intuitive for tasks such as account creation and sharing of data, which will likely hinder client and provider understanding, acceptance, and adoption of the platform. Validated data could not be securely shared while protecting privacy and confidentiality; thus, data transactions on the blockchain platform cannot facilitate services or increase interorganizational efficiency. The nature of sharing and transacting data on this platform was specific to the original use case of small farmers and refugees and was not suitable for our purpose of securely sharing and storing documentation. As our contract with the platform provider was constrained to limited modifications because of the time frame and budget of the project, we were unable to make the necessary changes to continue testing this platform for our use case. Given these findings, testing assumption 4 on the equivalence of the 2 platform use cases was invalidated.Secure, fast, and reliable sharing of validated health and identity data is crucial to improve the quality of life and health outcomes of the general population, particularly vulnerable populations such as those experiencing homelessness. Our project tested whether a blockchain-based platform had the functionality to manage permissioned access and distribution of data while empowering patients with control over their own records. This study also showed the need to address challenges in establishing and operationalizing a blockchain system before trial or full-scale production.Although broader and timely access to health and identity records can be achieved through blockchain, there are costs in transferring to a new system and training professionals and patients on the best methods of use to improve efficiency and outcomes. In the underserved populations, initial adoption depends on a user-friendly interface and an end user experience accounting for varying levels of technological access and ability. Unfamiliarity with blockchain technology and usage also creates challenges in adoption for service providers. Understanding the basic principles of blockchain technology is necessary to confer trust in the system and allow changes in workflow, promoting organizational efficiency and preventing the burden of additional verification of authorized documentation. Institutions participating in a blockchain system must also mutually agree upon the size of data that may be stored or transferred on the blockchain to maximize system performance ,12.Our research showed that a blockchain can be used to manage personal and health data by facilitating interoperability, patient control of documents, and a record of consented document access while maintaining data privacy and security. A validated, immutable, and decentralized ledger promotes system and transactional trustworthiness but cannot guarantee the absence of falsifications or errors from the point of origin. These mistakes are perpetuated in the blockchain without a manual content verification procedure ,22,23. OTimeline and budgetary constraints from the Mayor’s Challenge Project limited our ability to fully modify the platform for our use case. We were unable to develop an end user experience promoting homeless client adoption or develop changes in workflow, policy, and data sharing agreements for the best use of blockchain technology. The significant security and usability issues with our original platform prevented large-scale implementation in an empirical setting.Further research is required to compare the efficacy and costs of an approach based on blockchain technology with other alternative approaches. Although the research presented here shows the potential of a blockchain-based approach, we need to better understand the comparative benefits and costs. For example, the City of Austin could have created a central database to which all partners and collaborators would agree to add their data. Questions on whether all participants would adopt the use of standard data types and a centralized, city-owned database would need to be addressed. Experience has shown that not all advocacy groups or people experiencing homelessness fully trust the city government, for example. The purpose here, however, was to show whether a blockchain-based approach could work, and it was not to address the question of comparative effectiveness.Several studies to date have explored the potential applications of blockchain to solve key issues in the health care sector. This study demonstrates a methodology and rigor that may be needed to test if a blockchain can be used to securely store and track verified documentation, promote client ownership of data, and improve interoperability by facilitating permission-based data sharing. This study paves the way for future studies by detailing specific organizational, logistical, and system considerations for successful and scalable implementation.Blockchain may provide a means for consented access to validated personal and health data, thus increasing interoperability without compromising the security or privacy of data ,24. Exis


The site has updated information supposed to be useful for nuclear physics researchers in the region, such as in terms of job opportunities.The Asian Nuclear Physics Association (ANPhA) was established in 2008. It represents nuclear physics in the Asia Pacific region. It also plays a role as the Division of Nuclear Physics (DNP) of AAPPS. Because of COVID-19 situations, its regular activities are limited. For example, the annual board meeting scheduled in December will be organized virtually by the University of Hong Kong (HKU). From the year 2020, Prof. Weiping Liu from China served as the ANPhA chair, succeeding Prof. Tanaka from Japan, who has made great contributions to the activities. Maintenance of the ANPhA website was moved from RIKEN in Japan to CIAE in China , APLAT 2020 symposium organized online by KEK, NuSYS summer school 2021 in Beijing, and APFB2020 scheduled to be held in the city of Kanazawa in 2021. Thanks to the AAPPS supports, together with the budgets collected in previous years, ANPhA/DNP awards were granted to young scientists in Asia on the occasions of some of the ANPhA-supported symposiums.A report on ANPhA activities for these 10 years was published in NuPECC’s Nuclear Physics News, entitled “Ten Years of the Asian Nuclear Physics Association (ANPhA) and Major Accelerator Facilities for Nuclear Physics in the Asia Pacific Region” .(2) Agenda of the second part of the 44th Council Meeting was adopted as prepared by the president.(3) Youngah Park, the chair of the Women-in-Physics Working Group of AAPPS (AAPPS-WIP) reported on recent activities. She first introduced the history of AAPPS-WIP and its current members. The working group was established after the approval of the 16th AAPPS council meeting held in Osaka, Japan, in April 2006. The first workshop on AAPPS-WIP was held at APPC10 in 2007, and the most recent workshop was held at APPC14 in Sarawak, Malaysia, in November, 2019. Seven talks were delivered in the AAPPS-WIP session of APPC14, and extended working group members had a luncheon meeting after the session. The working group recently made a AAPPS-WIP homepage for networking. Park acknowledged support from AAPPS and APCTP. Park explained that the International Conference on Women in Physics (ICWIP2020), which had originally been planned to take place in Melbourne, Australia, in July 2020, was postponed to July 2021 due to the Covid-19 pandemic. The conference will be held virtually, as it will take some time to make the new vaccines globally available. The best and easiest platform to be used is under exploration. The IOP Journal of Physics: D is planning to publish 2021 Women in Applied Physics Roadmap. From 18 to 20 pieces of short reviews on every aspect of applied physics will be contributed by all the female authors.Furthermore, Park introduced the activities of Gender Equality Promotion Committee in JPS. The activities were initiated and conducted based on large-scale survey for the last twenty years by the Japan Inter-Society Liaison Association Committee for Promoting Equal Participation of Men and Women in Science and Engineering. A new award for young female scientists after the name of Prof. Fumiko Yonezawa was recently established in JPS. Summer camps for high-school girls, which were held for 15 years since 2005, are very successful. The camp was held online this year. The committee has been organizing symposiums and luncheon meetings in annual JPS meetings every year since 2002. They also provide daycare services for participants’ children in JPS meetings since 2010.Park also reported on the activities of the Women in Physics Committee in Korea. The number of women is approximately 20 % of the total number of the KPS members. The committee was established in the year 2002 in Busan, Korea. Since 2002, the committee organizes physics camps for high-school girls, site visits, and special sessions in KPS meetings. The surveys were conducted in 2005, 2010, and 2014, and the female ratio is found to be continuously improving. Nevertheless, there are still concerns, such as only 20 % of the female scholars have children and women feel more pressure for parenting than men. The standing of Korea in the index of gender inequality is 17th out of 152 countries. Yokoyama suggested to share the presentation slide to which Park agreed.(4) Hiroyuki Nojiri explained the preparation status for the formation of the Division of Condensed Matter Physics (DCMP) as a regular division. A preparation for the foundation and a round table were held on December 4 and 5, 2020. He summarized the purpose, core areas, and core starting members for the division. The division will form an executive committee (EXCO), consisting of two representatives from each of the five founding societies and one or two representatives from each of the newly participating societies depending upon size. The division sets the status of an observer (not participating but having interest to receive information) by the bylaws. Prof. Je-Geum Park is the candidate division chair and Nojiri will be a vice chair. The selection of another vice chair and auditors are under progress. The membership will be given to regular members of Ph.Ds. or equivalent degree holders as well as to associate members including students. Registration will be completed on personal basis; Anyone belonging to the participating societies of AAPPS can join. The division will also accept exceptional cases, such as a researcher who lives in an area where no AAPPS society exists. The division defines the codes of conduct. Article 6 declares gender equality in composition and activities. Nojiri explained the schedule toward the foundation. The bylaws have been circulated for the formal signing by 30 founding members from the five societies. Finalization of the bylaws and nomination of the second vice chair will be completed by December 20, 2020. The founding documentation will be further circulated to call for participation to the division. The web site is presently under preparation and will be complete in March 2021. The first division meeting is planned to be held in November 2021 in Korea as a hybrid conference. Yokoyama stated that he was impressed by the sophisticated bylaws of DCMP. S.P. Kim commented that minimized simple bylaws are better, and to let the division work functionally is important. Yokoyama responded that respective divisions go its own way and amendment can be made at any time whenever it becomes necessary.Tao Xiang asked whether the list includes full members. Nojiri answered that it is only a part of the list of 30 founding members. Choi asked how one can join the division. Nojiri responded that the division not only asked five founding societies to nominate six representatives, but also will call for initial members other than the representatives. S.P. Kim asked how EXCO members are nominated from each society. He suggested steps along the line of AAPPS philosophy, such as recommendation from the president of each society for an EXCO member. Akira Yamada asked about the membership fee, and Nojiri answered that membership is free. Nojiri expects that the division does not need a large financial source at the beginning and handling assets is too complicated at the time of foundation. Jodie Bradby mentioned that there is no separate condensed matter group in Australia and New Zealand but is part of the AIP groupings. Yokoyama asked Bradby to announce the foundation of DCMP to Australian community and to encourage them to join. Rajadeep Singh Rawat stated that in Singapore, the condensed matter society is not very large while the material science community is rich and huge. He asked if DCMP has a plan to establish a legal entity status. Nojiri answered the division plans for transfer to this status in six years, and the transfer is intended only as a technical measure to treat financial issues. S.P. Kim added that even after DPP was legalized, the division is not independent of AAPPS and is called AAPPS-DPP.S.P. Kim proposed to build up a systematic divisional website at the AAPPS headquarter, i.e., at APCTP, so that one could see contents of all divisions at once. Yokoyama stated that all division websites are already linked from the AAPPS main page. Nojiri explained that the domain name of DCMP has not yet registered. Yokoyama stated that it is possible to have more than two domain names for a single website, and suggested Nojiri to specify the second name under the AAPPS domain name from a systematic point of view for the readership. Fu-Jen Kao voiced that JSAP is the largest society and seems to run one of the most successful condensed-matter related conferences in the Asia Pacific region. Therefore, cohosting a member-society’s annual conference with the division meeting seems to be very efficient and interesting. S.P. Kim also hoped JSAP to join DCMP, as JSAP and JPS are two independent member societies of AAPPS. Yokoyama summarized that active participation from JSAP is strongly encouraged.Meng-Fan Luo stated that although the Physical Society located in Taipei does not have many participating members at present, more members will attend in future. In Taiwan, they have recently established a new division of particles and fields, and biophysics and computational physics divisions will be established in coming future. The condensed matter group covers a large area, and it is separated into several smaller divisions.Xiang stated that six core members participating to DCMP are from CPS. Each division of CPS, associated with condensed matter, has a representative. Xiang explained that CPS organizes annual meetings of condensed matter in July each year. There is a possibility to combine this with the division meeting as a joint meeting.(5) President Yokoyama proposed a motion to vote for the approval of the establishment of DCMP in AAPPS. The motion was unanimously agreed. Yokoyama congratulated Nojiri. For the next formal process, approval from not less than four member societies is required according to the bylaw.(6) Treasurer Kim reported the financial status of AAPPS. He explained that in 2019 we started with a carry-over of KRW 52,000,000 and the balance as of December 15, 2020 was KRW 63,000,000  which is a surplus. The Leo Koguan Foundation has USD 36,500 after USD 10,000 has been excluded for AAPPS Bulletin (AB). The major income comes from AAPPS’s membership fees, which are USD 500 for each society. The major expenses are the certificate case and shipping costs for AAPPS activities. Yokoyama expressed concern that the number of societies paying the membership fees is continuously decreasing. Bradby mentioned that the invoice may be missed at the time of transition to the new staff members [*]. Five societies are donating USD 5,000 each as AB contribution. The support from APCTP is USD 358,050 since 2004, and DACG covers the “aapps org” domain fee for the next five years. [*Note added: this was subsequently resolved by the treasurers and the AIP did actually pay their invoice].(7) Kao, the chair of the CN Yang Award selection committee reported on the current situation and future perspective of the CN Yang Award. He explained about the timeline of the 2020 Awards and the selection process of the awardees. The call started on February 3, 2020, and nominations were closed on April 15. After initial screening to check the eligibility, the selection committee was formed. Reviewers were appointed by the committee and the evaluation reports were prepared by the reviewers approximately till the end of May. The exchange of opinions and online meetings were started five weeks later so that the committee members could have enough time to think carefully. Each winner delivered a talk at the award ceremony held on November 5, 2020. Among 23 nominees in nine categories, those in three categories covered by the AAPPS divisions were pre-screened by each division while others were evaluated by reviewers. The committee received written evaluation reports and selected 11 candidates (maximum three from each category), based on the scrutinization of the reports and discussion. Afterwards, five semifinalists were chosen by voting and finally three winners were chosen by voting. The voting was conducted by committee members excluding the chair.There are some feedbacks from the last-year meetings. The main issues are i) lack of basic statistics regarding a candidate as a reference, ii) insufficient criticalness in review report to qualify the candidate, and iii) many do not know that an individual can nominate. Kao proposed minor amendments in the evaluation form.In the current rule, the selection committee consists of members chosen from three categories, i.e., AAPPS council, AAPPS divisions and APCTP science council, and the number of members from each category is set to be equal. The number of divisions will soon become five. The increase in number # may lead to expansion in the size of the committee, thus may cause difficulty in coordination. Therefore, Kao proposed to limit the number of the committee members up to 12 provided that the chair is not counted in. In the maximum case, (8-#), #, and four committee members will be allocated to AAPPS council, AAPPS divisions, and APCTP science council, respectively. S.P. Kim asked how to strike a balance between societies. Kao answered that the role of each society is to nominate, and selection is made by the committee.Gui-Lu Long proposed routine of the subjects in the CN Yang Awards, in order to protect some minority subjects from disciplines having many recipients. Kao responded that the committee selects the best candidates each year and the relative impact and standing of nominees in his/her category really count. Yokoyama mentioned that we should try to cover all the fields of physics as much as possible in a long run. Long suggested to set subjects of the two recipients rotating and the remaining one free, among three recipients. Kao said this would be a very good consideration and will become a consensus rather than a written rule. Long agreed to this point.Subsequently, Kao voiced that considering the foundation of new division(s), in particular the huge areas covered by DCMP, we shall relax the rule for pre-screening to allow maximum three nominees from each division rather than one in the current rule. This opinion was seconded by Luo and S.P. Kim. Yokoyama once again clarified the current process: We call for nominations to member societies and participants of APPC. For nominees those who have been classified to corresponding divisions, their application forms are sent to the division chair. The division chair forms a sort of sub-selection committee inside the division for pre-screening, afterwards, one candidate is chosen from the division. The number of pre-screened candidate(s) might be changed from one to three, considering the new division formation.Kurunathan Ratnavelu asked whether the number of committee members will be 12 or remain 9 next year. Yokoyama responded that it will be 12 if the current rules are applied and the new division, DCMP, is included. Finally, Kao proposed to limit the maximum number of selection committee members up to 12. The motion was unanimously agreed. Yokoyama added that we need to consult with APCTP as well. Written amendments of rules will be circulated by the next council meeting and the rules should be fixed by April, 2021.(8) Keun-Young Kim reported on the progress of the establishment of the Division of Particles and Fields (DPF). The first discussion started after the banquet of APPC14 in 2019. He introduced the list of representatives from five societies, i.e., AIP, CPS, JPS, KPS, and the Physical Society located in Taipei. After two meetings, a small working group was formed. The first working group meeting will take place soon, after Christmas or in the new year. Yokoyama asked about the possibility of participation from India.(9) In 2017 under the leadership of the former president Long, AAPPS determined the rules on the sponsorship, co-sponsorship, and endorsement of AAPPS activities. The only case applied to the sponsorship or co-sponsorship so far is APPC without any problem. Yokoyama proposed to amend the application due date for endorsement, which is four months in advance in the original rule. As approval in email communications does not need a long time, the proposed deadline is three weeks before the desired notification date. The amendment was approved by the council members. Yokoyama introduced Article 3 on the criteria, which must be satisfied to be sponsored, co-sponsored, or endorsed. DACG and DCMP incorporated these terms in their bylaws as codes of conduct. Yokoyama hopes other divisions to do so as well.(10) President Yokoyama presented the list of his activities following the 43rd Council Meeting. He personally attended the JPS meeting held online, as the president, he attended the Meeting of the Physical Society of Philippines held online in October, the DPP annual meeting, CN Yang Award ceremony, the joint meeting of KPS and JPS in November, and DACG’s first online conference in November 2020. At the 43rd Council Meeting, he proposed to establish a joint award between AAPPS and each member society. He is collecting information from each society about the type of awards being provided, especially for young researchers. He is sometimes asked about merit of being an AAPPS member. Establishment of such an award may help to answer this question. He hopes to provide joint presentation awards at the 4th Meeting of the Physical Society located in Taipei as a pilot case. He calls for other societies if interested in such a joint award.(11) President Yokoyama summarized the last meeting, i.e., 44th Council Meeting, Part I. There were reports from division chairs on division activities. Progresses toward the formation of DCMP and the Division of Computational Physics (DCP) were reported. Yokoyama attended the preparation meeting for the division of computational physics inside JPS, and introduced possible activities of AAPPS next year. Any progress on AB will be reported by email. Status of a legal entity is difficult to achieve in a short time. We will continue discussion on APPC15 and will have a council meeting in March, 2021. Yokoyama added that the forthcoming APPC will be a much larger conference than Choi presently anticipates, and suggested possibility of 4.5 or up to 5 days for the sessions.(12) President Yokoyama announced that the next council meeting will be scheduled in March 2021, and closed the meeting.


To understand the advantages and disadvantages of imaging techniques in identifying aetiology and mechanisms of mitral and aortic regurgitation.To understand the key echocardiographic methods of quantifying severity of mitral regurgitation (MR) and aortic regurgitation (AR), and their advantages and limitations.To be aware of the relative advantages and disadvantages of cardiac magnetic resonance in quantifying severity of MR and AR.Valvular heart disease (VHD) affects 1 in 50 of the general population and 1 in 3 of the over 65s, and is associated with increased morbidity and premature mortality.The severity of regurgitation through the MV and AV is governed by the Gorlin formula, which states that flow through an orifice varies by the square root of the pressure gradient across the orifice, the duration of flow and a discharge coefficient.Access to echocardiography is critical for diagnosis of valve disease.Once regurgitation has been detected, the key step is to determine the cause. This is particularly the case in the patient with MR, as the natural history, classification of severity and treatment choices all depend on whether regurgitation is ‘primary’, due to a fault in the valve apparatus, or ‘secondary’, due to disease of the LV . Most caIdentifying structural abnormalities leading to MR requires imaging of the leaflets, chordae, papillary muscles and annulus at high temporal and spatial resolution. 2D TTE is the main method to define leaflet thickening , leaflet mobility  or restricted), degree of leaflet coaptation, as well as extent and location of calcification . 3D TTE is of incremental value in identifying the lesion, leaflet involved and the specific valve segments affected, with an accuracy similar to multiplane 2D TOE.Visualisation of primary and secondary chordae requires good quality 2D TTE imaging in a modified apical two-chamber view to define location, length and thickening, with the transgastric long-axis view on 2D TOE also useful to perform these measurements and define interpapillary muscle distance. 3D TOE can improve on these measures but is mainly used to measure annulus size and detect annular remodelling that can be specific to a disease process, for example, to myxomatous or ischaemic MR.In the anatomical assessment of AR, 2D (and to some extent 3D) TTE remain the first step in the assessment of leaflet mobility, thickening and calcification required to determine mechanism and aetiology. When TTE provides inadequate visualisation of structures, or when high spatial and temporal resolution imaging is required to assess suitability for intervention, for example, with highly eccentric jets and when repair is considered, 2D and 3D TOEs provide incremental accuracy.When quantifying severity of a regurgitant lesion, it is important to consider the appearance of (1) the valve morphology and (2) the size, shape and function of the ventricle. For example, if the mitral valve leaflets are flail, it is highly likely there is severe regurgitation but if you do not think it is severe, make sure you have done all you can to be certain. Likewise, if the LV is dilated with spherical remodelling, if you are going to call any AR moderate, make sure you have done all you can to be certain.Good quality TTE with Doppler can provide all the core information required for evaluation of regurgitation severity but requires an experienced, motivated echocardiographer able to perform the necessary integrated assessment of multiple qualitative and quantitative parameters, in the knowledge that single measures are subject to variabilityLVOT–SVol MV) is subject to large interobserver variability.The assessment of AR severity with echocardiography is more challenging than that of MR. On TTE, the AR jet is seen with the highest resolution in the parasternal long-axis view, which can be used to measure vena contracta and jet width relative to the left ventricular outflow tract. In this view however, the PISA in AR is perpendicular to the angle of insonation (and therefore unreliable), and in the apical window it is in the far field and is often too small to measure reliably. In addition, the pulse Doppler method used to calculate stroke volumes across the mitral valve and left ventricular outflow tract  and flow quantification (for CMR) to identify the cause and mechanism of regurgitation, severity, and haemodynamic impact on ventricular and atrial remodelling, as well as the effect on pulmonary pressure. Transthoracic echocardiography remains the workhorse but requires careful integration of multiple parameters that vary in sensitivity and specificity, particularly when the aetiology is ischaemic, and the skill to use 3D regularly. Where data are conflicting, imaging is suboptimal or when intervention is under consideration, either transoesophageal echocardiography or CMR can be used, with 3D an integral component for complete TOE assessment.All imaging assessments in mitral or aortic regurgitation should include a statement on the quality of the scan, the size of the patient  and haemodynamic status .Transthoracic echocardiography remains the first-line imaging modality to determine cause and mechanism of regurgitation, quantify severity using multiple parameters, and impact of regurgitation on atrial and ventricular size and function.In cases where the above information is incomplete or is contradictory, transoesophageal echocardiography using 2D and 3D is the usual next step for detailed assessment of valve anatomy and helps with quantification.In those cases where regurgitation severity and the effects of regurgitation on chamber size and function are the primary source of concern, cardiovascular magnetic resonance (CMR) may be a better, less invasive alternative.Grading of severity by echocardiography and CMR differ, with thresholds for intervention lower using CMR, although there is a lack of data using these to guide intervention.Multislice CT is currently used mainly to image specific subsets of patients before intervention, such as those for percutaneous valve intervention and those requiring concomitant aortic surgery.Education in Heart articles are accredited for CME by various providers. To answer the accompanying multiple choice questions (MCQs) and obtain your credits, click on the 'Take the Test' link on the online version of the article. The MCQs are hosted on BMJ Learning. All users must complete a one-time registration on BMJ Learning and subsequently log in on every visit using their username and password to access modules and their CME record. Accreditation is only valid for 2 years from the date of publication. Printable CME certificates are available to users that achieve the minimum pass mark.10.1136/heartjnl-2019-316216.supp1Supplementary data


Recent developments in the understanding of the relationship between the microbiota and its host have provided evidence regarding the therapeutic potential of selected microorganisms to prevent or treat disease. According to Directive 2001/83/EC, in the European Union (EU), any product intended to prevent or treat disease is defined as a medicinal product and requires a marketing authorization by competent authorities prior to commercialization. Even if the pharmaceutical regulatory framework is harmonized at the EU level, obtaining marketing authorisations for medicinal products remains very challenging for Live Biotherapeutic Products (LBPs). Compared to other medicinal products currently on the market, safety assessment of LBPs represents a real challenge because of their specific characteristics and mode of action. Indeed, LBPs are not intended to reach the systemic circulation targeting distant organs, tissues, or receptors, but rather exert their effect through direct interactions with the complex native microbiota and/or the modulation of complex host-microbiota relation, indirectly leading to distant biological effects within the host. Hence, developers must rely on a thorough risk analysis, and pharmaceutical guidelines for other biological products should be taken into account in order to design relevant non-clinical and clinical development programmes. Here we aim at providing a roadmap for a risk analysis that takes into account the specificities of LBPs. We describe the different risks associated with these products and their interactions with the patient. Then, from that risk assessment, we propose solutions to design non-clinical programmes and First in Human (FIH) early clinical trials appropriate to assess LBP safety. The development of molecular methods in recent decades has enabled the detection of non-cultivable microorganisms in different environments, including human and animal ecosystems, and has shifted the perception that most microorganisms are threatening, to a greater understanding of the importance of balanced microbial ecosystems in human and animal health. Consequently, new therapeutic approaches have emerged, aiming at re-establishing the necessary balance between the microbiome and its host in several pathologies. When such interventions are intended to prevent or treat diseases, in the European Union (EU) they fall under the definition of a medicinal product according to the Directive 2001/83/EC  contains live organisms, such as bacteria; (2) is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and (3) is not a vaccine” by the FDA, and as “medicinal products containing live micro-organisms (bacteria or yeasts) for human use” by the Ph. Eur . As for all biological medicinal products, LBPs represent a regulatory efficacy and safety challenge due to the live characteristics of the product and the often multifactorial mode of action (MOA).Medicinal products for which the active substance is a living microorganism, are currently being developed for multiple indications and are referred to by both the Food and Drug Administration (FDA) and the European Pharmacopeia (Ph. Eur.) as Live Biotherapeutic Products (LBPs) , 3. ThisThe present review intends to provide an overview of the existing guidelines in the field of biological medicinal products, and to document how these guidelines can be used as a set of tools to assist in the design of an LBP development programme. At the same time we are proposing a road map that integrates crucial concepts laid down in existing documents directly or indirectly related to LBP-adapted safety assessment, in the absence of specific EU guidelines. Focus will be on how new techniques developed for discovery might allow more appropriate risk documentation and therefore better risk management in early clinical trials.Complex microbial ecosystems inhabiting the human body are composed of bacteria, archaea, fungi, protozoa, and viruses, which altogether are known as “microbiota.” The term “microbiome” refers to the entire habitat of the microbiota, including the microorganisms, their genomes, and the surrounding environmental conditions . This gaIn order to design appropriate development programmes for this type of medicinal product it is important to understand how the microbiome is involved in the maintenance of human health and how LBPs may exert their beneficial effect. As mentioned, LBPs do not exert their biological effects by reaching distant organs, tissues or receptors, and, in most cases, do not act directly on a known target, but are thought to exert their effect by modulating the host microbiota, e.g., by inhibiting pathogens , produciunlike a rainforest or river ecosystem, the microbiome is not only driven from the bottom up by species interactions, but the host is under strong natural selection to shape the microbiota from the top down and foster a community that is beneficial”  is also an important parameter and has a large impact on the composition of the microbiota . Given tThe first mention of the LBP category at the European level was in the Ph. Eur. Monograph on LBPs published in 2019, which discusses the quality requirements for this type of products . In the early clinical development of human medicinal products has an intrinsic element of uncertainty in relation to both the possible benefits and risks of a novel drug candidate. Uncertainty may arise from particular knowledge, or lack thereof, regarding the MOA, the presence or absence of biomarkers, the nature of the target, the relevance of available animal models and/or findings in non-clinical safety studies”  Guideline on general considerations for Clinical Trials (ICHE8) , the Comstudies” . These uategies” . Indeed,nt plan” .For this purpose, risk analysis for LBPs should consider any risk intrinsic to the strain(s), as well as any information originating from the literature or the sponsor's data on the use of the strain(s) in different models or individuals  and information on potential risks related to the particular characteristics of the intended population. The risks posed by the administration of LBPs may depend on the origin of the cells, the manufacturing process , the specific characteristics of the strain(s) , and on the intended treatment population . Consequently, LBP developers should undertake a thorough risk analysis at a very early stage in development as it may guide the design of the non-clinical and clinical programmes, the outcomes to be monitored in the clinical trials, the definition of the risk management plan, and the contingency plan in case of severe adverse events in the intended population.This section propose a risk analysis generally applicable to all LBPs, taking into account the microorganisms themselves and the characteristics of the intended population. Afterward, we will define and propose adapted tools for a non-clinical safety assessment of LBPs, allowing to subsequently improve the clinical programme designs.The potential safety issues associated with the administration of living microorganisms have been addressed in the past by different stakeholders, and identification and characterization at strain level has always been considered critical. However, research on microorganisms intended for food applications has shown that many safety-related aspects may be common at the species level . This prin silico analysis for potential intrinsic risks  in food, is not sufficient. Indeed, in Europe, post-market surveillance is not generally required for conventional foods and food supplements and adverse events in patient populations may not be systematically reported. In addition, in a 2011 report made by the US Agency for Healthcare Research and Quality , the autWithout any doubt, the antimicrobial sensitivity profile of the strain(s) present in the LBP is of the highest importance. There have to be sufficient options left for the patient to be treated with effective antibiotics in the event of an unexpected infection or allergy with the LBP. Combined approaches for the evaluation of the antimicrobial sensitivity profile should be considered taking into account the specificities of the intended population (including disease-specific characteristics as well as concomitant therapies) so as to optimize the assessment of the product's sensitivity to a relevant list of antimicrobials, considering the patient's pathology and relevant standards of care.The EFSA regulatory framework therefore does not represents the right benchmark for sensitivity evaluation in patients.For antibiotic sensitivity testing, it is recommended to complement molecular methods with culture-based methods. Also, a combination of different antimicrobial resistance databases should preferably be used in order to identify relevant antimicrobial resistance genes , 30: ResIn relation to the culture-based antimicrobial sensitivity profiles, the FDA regulatory guideline for LBPs  requiresin silico and in vitro MIC determination , or defensive . Microorganisms acquire these factors often through vertical or horizontal gene transfer.in silico searches of the annotated genome sequence using relevant databases . FDA considers the assessment of the translocation potential as part of the characterization of the strain and recommends the use of a reproducible translocation assay, preferably in an appropriate animal model, such as germ-free mice . AssessmEnterococcus faecium SF68, a strain contained in an LBP registered nationally in Switzerland since 1979  that were challenged with enterotoxigenic Escherichia coli (ETEC). Additionally, when immuno-compromised mice received persistent exposure to large intravenous doses of SF68 no traces could be detected in liver, kidney or heart after plating individual homogenized organs.Examples of more global approaches for this challenging assessment can be found in the literature which will help LBP developers in their efforts to document their strain(s). In regards to the assays developed for the evaluation of both abilities mentioned above , examples are provided by Holzapfel et al. on nce 1979 . SF68 waDaniel et al. also used marked strains from food or infection sources and administered these to healthy mice without any consequence. When administered to animals with a damaged mucosal barrier, induced by the administration of TNBS , only strains from infection sources were found to translocate to the different organs in the mice, while food-derived strains did not . This exThe full understanding of the MOA of a living microorganism used as an LBP is not (yet) a requirement for its registration as a medicinal product if quality, safety and efficacy have been demonstrated and documented through appropriate clinical trials. However, bearing in mind the recent trend to also apply drug quality standards to the production of biological medicinal products, knowledge or partial understanding, of the MOA may become a prerequisite . Indeed,It is also commonly accepted that living microorganisms may exert their biological effect (positive or negative) through several, potentially simultaneous, direct or indirect MOAs which may depend on the specific host environment. While this complexity represents a challenge for LBP developers, understanding the potential capabilities of the strain(s) and their MOA remains highly valuable as it may further help to document the risks and benefits by identifying the potential negative or positive secondary pharmacodynamic effects (MOA and/or effects of a substance not related to its desired therapeutic target).To illustrate the importance of understanding the MOA in terms of safety, we can mention the case of biogenic amines (BAs) and drug-metabolizing enzymes, which are intrinsic characteristics of the strains, and should be documented as a risk pertaining to potential drug-drug interactions.in situations of polypharmacy, such as in severe acute diseases , complex chronic diseases , and in elderly individuals. In order to improve the value of a specific dossier, an approach similar to a “drug-drug interaction” investigation could be used to test LBP impact on relevant drugs or known biological markers of a specific disease. In cases where such potential is expected, monitoring of the kinetics of the drug during the first human trials would allow for the definition of appropriate risk management measures.Human commensal bacteria are now known to be capable of metabolizing drugs and/or drug metabolites affecting the pharmacokinetics of the drug. This phenomenon, known as “pharmacomicrobiomics,” is considered to play a major role in the efficacy and toxicity assessment of drugs –58. ZimmBAs, such as histamine and tyramine, are low molecular weight organic molecules with one or more amine groups, commonly detected in many foods and beverages. Exogenous BAs can be formed by enzymes in plants and animals, but can also be generated in significant concentrations by certain microorganisms through the activity of amino acid decarboxylases . EndogenWhile strains from different Gram negative and Gram positive genera harbor the capacity to decarboxylate amino acids and produce BAs, lactic acid bacteria are the main producers . BAs placonventional approaches to toxicity testing of pharmaceuticals may not be appropriate for biopharmaceuticals due to the unique and diverse structural and biological properties of the latter that may include species specificity, and unpredicted pleiotropic activities.” In the microbiota field as well, developers have to be innovative in their approach for risk documentation, and therefore safety and toxicity assessment. The main challenge is the limited relevance and poor predictability of in vivo animal models (As mentioned in the ICHS6(R1) guideline, “l models , 62, 63,l models , 19 any We therefore believe that it is important for developers and competent authorities to address LBP safety through a combined approach. As highlighted in the work of the EU reference Laboratory for alternatives to animal testing (EURL ECVAM) regarding alternative methods on toxicity testing for chemicals , integraAbove all, the usefulness of any model for toxicity and safety testing, should be evaluated in terms of their suitability in line with the MOA and the associated risks, their reproducibility, as well as their predictability in terms of safety in the intended population. If mammalian models are used as part of an integrative safety documentation approach, their selection should be based on a deep understanding of the relationship between the targeted host and his/her microbiota. This includes knowledge on the pathophysiology of the targeted (patient) population, the MOA of the LBP, and knowledge about the degree of similarity of the microbiota between the animal model and the intended host in terms of composition and function, as well as the potential conservation of the LBP target.biological activity may be evaluated using in vitro assays to determine which effect of the product may be related to clinical activity.” The guideline also refers to the “examination of direct effects of the product on cellular phenotype and proliferation through the use of cell lines and/or primary cell cultures” (According to ICHS6(R1), “ultures” . In the ultures”  or Kang ultures” , should ultures” , could aex-vivo models have been recently reviewed for products intended for topical applications  or Caenorhabditis elegans (nematode worm) might be helpful in, e.g., deciphering pathways within the host. As reviewed by Gerbara et al. , studies in non-relevant species may give rise to misinterpretation and are discouraged,” and the CHMP guideline on human cell-based medicinal product, mentioning “if relevant animal models cannot be developed, in vitro studies may replace animal studies”   which ststudies” .An important aspect of non-clinical studies is the assessment of the potential risks associated with the dosage regimen. These programmes should be designed in order to provide information on the dose to be used in clinical trials, the route of administration, the administration schedule, the duration of exposure and the duration of the follow up period during which adverse reactions are to be tracked.Biodistribution is key information when addressing the question of the dosage for LBPs and the potential risk estimation associated with the behavior of the strain once administered. Studies should monitor the effective presence of the strain(s) at the site of action, assess potential engraftment (at the site of action or in other locations), as well as the elimination after administration has ended.studies should be carried out to demonstrate distribution, viability, trafficking, growth, phenotype and any alteration of phenotype due to factors in the new environment.”LBPs are not expected to reach the systemic circulation, therefore, conventional Absorption, Distribution and Metabolism (ADM) studies are not relevant for these products. Once again, LBPs share similarities with human cell-based medicinal products, for which the guideline  does not®  and the TIM®  models.When efficacy is mediated by indirect mechanisms of action, e.g., by impacting unidentified microbiota components at the site of action, the dosage of the product might be partly disconnected from the level of efficacy and safety, and may depend on the individual's physiology  and ecosystem composition and complexity. The assessment should therefore include models taking into account the patient's characteristics and his/her physiology. Gut indications are the most challenging in this context as animal models may be poor predictors of the actual behavior of LBP's in the human Gastrointestinal Tract (GIT), and because the monitoring of their presence at the site of action requires rather invasive methods. Artificial models of the human GIT have, however, been optimized and validated for microbiota research and represent an interesting alternative. Some examples of currently available systems are the SHIME® and  under different conditions   in the GIT under different (patient-like) conditions and with different formulations, as well as the evaluation of their influence on the human microbiota as published , 85 for ® and  for the nditions , as wellnditions . In caseThis information could help developers to narrow down their Optimal Effective Dose Range (OEDR), defined as the largest dose range required to obtain the intended effect based on the clinical results for efficacy and tolerability, before Phase I/II clinical trials.If animals are chosen for biodistribution studies, their suitability should be accompanied by the documented rationale that supports the translation and extrapolation of the dosage from animals to humans.In conclusion, non-clinical studies are inherently part of an LBP development cycle where, in comparison to traditional pharmacodynamic and pharmacokinetics studies, many adaptations will have to be made. Harmonized guidelines at this level may be useful in guiding developers in their risk analysis and in the design of non-clinical studies which will then provide a picture as complete as possible of the safety profile of their LBPs.To discuss the acceptability of these innovative models, developers should seek scientific advice from competent authorities.It can be expected that the information on LBPs' safety will often be provided mainly by early clinical trials as they are the only way to test the products in the target environment where the complex interactions between the host and his-her co-evolved microbiota are present.Phase I/II studies should be designed to identify the Minimal Effective Dose, the lowest dose to obtain the intended effect, or an Optimal Effective Dose Range. If possible, also a Safe Maximal Dose, defined as the maximal dose which could be administered on the basis of clinical safety studies without acceptable adverse effect, should be investigated”  isolated from healthy humans, it can be expected that some healthy volunteers might carry, if not the same, at least some representative strain(s) from the same species in their native ecosystem, or carry strains that provide functional redundancy , 89. ConFor LBPs, it is also important to take into account the influence of other confounding factors, such as environment, diet, medications and (other) nutraceuticals, food products containing living microorganisms or prebiotics, genetic background, and geographical location, all of which could have an influence on the composition and/or function of the microbiome. Tolerability studies with placebo-controlled cross-over designs should be considered as an option to exclude the influence of such extrinsic and intrinsic factors, as patients become their own controls. In such designs, however, blinding will be important and the “wash-out” period will have to be carefully considered. Moreover, interventions designed to, e.g., (permanently) correct a dysbiosis cannot use this type of cross-over set-up, as a return to the base line is by definition no longer possible.For long-term use of LBPs, patients consenting may benefit from the biobanking of their samples obtained during the different clinical phases, as they could be valuable for future assessments of long-term effects that might not have been anticipated at the time of trial. These samples might therefore allow to further optimize individual treatment strategies, to design future studies directed toward obtaining a better understanding of the mechanisms involved, as required under the pharmacovigilance rules, or assist in clarifying subgroups of, e.g., responders and non-responders.Finally, as specified in the CHMP guideline on strategies to identify and mitigate risks for FIH studies and early clinical trials with investigational medicinal products , risk miPotential metabolic activities of the strain(s) are important parameters to consider in the case of strain(s) presenting a strong potential for the production of BAs, bloating, diarrhea and stomach pain should be commonly monitored for LBPs with gut indications.On the other hand, the potential metabolism of non-related drugs by the microbiota is also becoming a topic of concern , 95 as tSimilarly, the microbiota may impact the metabolism of different hormones  thereby Nevertheless, the main risk identified for all LBPs, regardless of indication or site of action, is the potential for translocation, migration, and infection of distant organs as discussed above. This risk highly depends on the host and the monitoring is of paramount importance in instances of poor barrier integrity, or if the patients present an impaired gut motility  or are immunocompromised (YOPI). Clinical outcomes relating to such risks, like routine body temperature recording, could allow for early detection and early mitigation, including an immediate stop of the administration and/or the treatment with an appropriate antimicrobial for which the LBP had been proven sensitive during the non-clinical characterization phase of the development.Overall, the body of knowledge acquired during non-clinical programmes, pertaining to potential risks associated with the strain(s), the product, or the intended population, should guide developers while designing early clinical trials and the appropriate management and contingency plans.In the absence of any EU guideline on the development of LBPs, developers are strongly advised to discuss the development process with regulatory authorities, especially as this field is rather new. In the EU this can be performed via the so-called Scientific Advice Procedure. This should include proposals for the most suitable studies guaranteeing sufficient quality and (pre)clinical safety, and it should help developing protocols to demonstrate efficacy. These products represent a real challenge, because their MOA does not rely on their absorption in the systemic circulation nor on a simple direct liaison between a ligand and a receptor, but is rather related to an impact on the local ecosystem and the local host cells, involving various direct and indirect mechanisms. Thus, existing CHMP and ICH guidelines , 52, 69 As new products are being developed, we hope that this review will improve the understanding by all stakeholders, including government and regulatory agencies, and advance the regulatory harmonization, resulting in the development of dedicated and specific guidelines and recommendations for LBP-specific drug and microbiome-based medicinal product development programmes. This will increase consistency in LBP development and encourage investment/funding for developers, offering new and promising microbiome-based therapeutics for various diseases and many patients in the future.AR contributed to the drafting of the manuscript as first author. SB, AB, IC, HC, HG, AH, SL, SM, MP, BP, and CS equally contributed to the discussions and the drafting of the manuscript and are equally considered as second authors of the manuscript. WA, CB, SB-D, CC, SC, BH, CH, CJ, BL, GM, LM, CM, NN, MO, JS, LS, AV, and FV equally contributed to the discussions and provided some input along the drafting of the manuscript. MC-S contributed to the discussions and to the drafting of the manuscript as last author and corresponding author.The opinions expressed herein, and the conclusions of this publication are those of the PRI and authors alone and do not necessarily represent the views of their member companies. SB is employed by the company MRM Health NV. AB is employed by the company Lallemand SAS. IC is employed by the company YUN Probiotherapy. HC is employed by the company Accelsiors CRO. HG and CJ are employed by the company Biose. AH and GM are employed by the company ADM Protexin. SL is employed by the company Biofortis Mérieux NutriScience. SM is employed by the company PharmaBiome AG. BP is employed by the company Yakult Europe BV Science Department. CS is employed by the company Johnson & Johnson Consumer Services EAME Ltd. WA was employed by the company NIZO Food Research B.V. CB is employed by the company IPSEN Pharma. SC is employed by the company LNC Therapeutics. BH is employed by the company Exeliom Biosciences. CH is employed by the company Chr. Hansen A/S. BL and CM are employed by the company Metabogen. MP and LM are employed by the company Probiotical Research. NN is employed by the company Astel Medica. MO is employed by the company Lactosan. JS and LS are employed by the company Caelus Health. AV is employed by the company Pilèje. FV is employed by the company 5QBD-Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The security and socioeconomic development of China’s border areas are of great significance to the nation and the wider world. Using census, statistical, digital elevation model (DEM) and network data, this paper employs visual analysis to capture population distribution patterns in China’s 131 border counties from 1982 to 2010. Multiple stepwise regression is carried out to identify the influencing factors of population dynamics in border regions. The main findings include: China’s most heavily populated border areas are primarily in the northeast, northwest, and the Guangxi-Yunnan region, while rapid growth of population is found in western Inner Mongolia, southwest Xinjiang, northwest Tibet, and southern Yunnan. Given the increasingly market-oriented migration mechanism, the national reclamation policy has been no longer effective in population attraction in the new century. Education has significantly lowered and will continuously lower the fertility rate in remote border areas. The factors influencing population growth show a remarkable regional heterogeneity along China’s long border. The cmportant ,11. The mportant ,13. The mportant .However, this is accompanied by a series of border issues, such as illegal immigration, cultural conflicts, and so on –18. Due People are the carriers of all economic activities and the basic force of social and economic development . As the Given the shortcomings of existing research, this paper selects the county unit as the research object based on census data from 1982, 1990, 2000, and 2010, as well as each county’s statistical yearbook. The first aim is to examine population patterns in different counties and districts along the nation’s borders over a long period of time. The second goal is to analyze the factors affecting population changes in the state as a whole and regionally. Finally, the paper provides suggestions and references to develop population policies.The novelty of this study lies in two aspects. First, the choice of the research scope: border areas. Data from eight 131 borderland counties, provinces, and regions are used for the analysis, and we added three dummy variables related to border policy, so that we can highlight the particularity of border areas. The differences between various borderland zones are effectively distinguished so that regional variations can reflect their unique characteristics. Furthermore, distinct orientations and directions can be identified in economic and social expansion to guide actively and effectively the characteristic development of each borderland area. Second, we carry out regression analysis of the factors affecting population change and the main elements are identified; such information can lead to more precise policy recommendations for healthy growth in border regions. The spatial heterogeneity in factors is also discussed by mapping the factors and comparing them with population geography.The paper explores existing research on population distribution, population change, and border areas. Then, it introduces the general context of the research area, data selection and processing, and research methods. After presenting the study’s findings, the paper offers suggestions for the growth of border counties in different regions.Border and boundary are two different concepts. A border divides national territories, whereas a boundary encompasses specific distances on both sides of the border . Ratti . Given that massive internal migrants have not changed their household registration, resident population can better reflect the real population of places than registered population in China. Census data are the only reliable source of information about the resident population at the county level. This is also the main reason for our selection of the four years when the latest four rounds of national censuses were conducted to do this research.By reviewing relevant studies on population distribution, the factors affecting regional population distribution are identified. These include natural conditions, economic aspects, public services, science and education, and social elements. Therefore, data on traffic, the Average growth rate per annum of GDP, illiteracy, and employment in border counties and districts are collected to determine the elements that drive changes in population distribution. In addition, we also collected data related to national policies, such as the presence of border ports, border economic cooperation zones, and reclamation and border defense.All information was obtained using county statistical yearbooks, 2010 road vector data, and digital elevation model (DEM) data either directly or through calculation.Using 1982, 1990, 2000, and 2010 census data, this study illustrates population size, density, and shifts, as well as the absolute population change in border counties compared to local cities. The census results are visualized using ArcGIS software to analyze the spatial distribution patterns of China’s border communities. To identify the spatial distribution patterns in these locales, these census data are employed to contrast shifts in the absolute and relative populations in the 131 border counties. Comparisons with each border county’s population change are included, as well as that of the city in which the border county is located.Absolute change in population:A1 represents population growth rate, Pi+1 indicates the border county population at the end of the period, and Pi refers to the border county population at the beginning of the period. If A1>1, there was population growth. If A1<1, the population decreased. If A1 = 1, there was no change.Relative change in population:B1 signifies the relative change in population, Pi+1 represents the final border county population, and Pi signals the initial border county population. Di+1 refers to the population of prefecture-level cities at the end of the period, and Di indicates the population of such cities at the beginning of the period. If B1>1, there was relative population growth. If B1<1, there was a relative population decrease. If B1 = 1, the relative population remained the same.To examine the main factors affecting the changing spatial patterns of population in China’s border counties, we firstly use multiple regression including all variables that are theoretically or practically expected to have effects. Multiple stepwise regression is then introduced to identify the key variables. This technique establishes the quantitative relationship between multiple variables in linear or nonlinear mathematical models and analyzes them with sample data. This paper examines the relationship between population change and natural conditions and economic factors; hence, this approach was chosen.The process of variable selection by stepwise regression includes two basic stages: (1) Remove the tested insignificant variables from the regression model; and (2) Introduce new variables into the regression model.1, X2…, XP, respectively make them and the dependent variable Y to establish the regression model with one variableStep 1: For the p regression, for regression variables XF(1). If Calculate variable Xi. The corresponding regression coefficients of F are the values of the test statistics i1, X1},…}, {Xi1, Xi1-1, 1} {Xi1, Xi1 +,…{Xi1,Xp} is established ; The number is p-1. Calculate the regression coefficient variable, which is the statistical value of the F test. Remember 2:Step 2: The binary regression model of dependent variable Y and independent variable subset {Xi2 variables are introduced into the regression model. Otherwise, terminate the variable introduction process.For a given level of significance of alpha, whereby the corresponding threshold for F (2) and i1, Xi2, Xik} and repeat Step 2.Step 3: Consider the regression of the dependent variable to the variable subset {XAccording to this method, one of the independent variables that has never been introduced into the regression model is selected each time until no variable is introduced after the test.Because the issue we studied involve many independent variables, it is difficult to determine that all the pre-selected independent variables have significant influence on the dependent variables, and there is no guarantee that all the independent variables are independent of each other. Therefore, in the establishment of multiple linear regression equation, variables should be screened according to the contribution of each variable to the dependent variable, and those independent variables with small contribution and close relationship with other independent variables should be eliminated, so as to obtain a concise and stable regression equation. Therefore, stepwise regression analysis method is selected in this paper.By conducting multiple stepwise regression analysis of the elements that drive population change in border areas using SPSS software, the factors affecting the absolute population change in each county are identified.The literature review points to the components that impact population shifts in border zones, which include the natural environment, economic development, geographic conditions, infrastructure construction, culture, education, and national macro policies.As for the influence of natural conditions, we choose the index of average altitude, which represents the terrain conditions. The annual growth rate of GDP indicates the region’s economic performance. In terms of location, the distance from a prefecture-level city and a provincial capital city is selected to represent the degree of traffic access in the region. The average proportion of the minorities in 2000 and 2010 is selected to represent the ethnic structure in the county . The chaBorder area is crucial for national security for its frontier location and ethnic diversity. To guarantee the border security and social stability, national policies are often introduced to stimulate economic development in the border area, leading to population growth. Three dummy variables are included in our model to investigate the effect of these policies, namely whether the border county has a border port, whether it is a border economic cooperation zone, and whether it has the national policy of reclamation and border defense.According to the national census, The Numbers obtained by dividing the population at the end of the period and the population at the beginning of the period in each county reflect the change of the population during this period. There is a large difference between the population change and the distribution pattern . From 19Each border county’s demographic shifts are compared to those of their corresponding cities for the 2000–2010 period. Next, the counties’ relative population changes are estimated. In Results of the regression model including all variables are shown in Effects of national preferential policies are notable and complex. The policy of reclamation and border defense is significant and negative associated with population density. It is reasonable because it is the less populated places that have the demand for such a migration policy to safeguard the territory security. However, the effectiveness of this policy has totally disappeared in the new century as indicated by the results. Migration in contemporary China is determined mainly by economic factors rather than political forces. Those who migrated to border regions for political reasons are re-migrating back to their hometown or other cities, which has led to a more severe condition of emigration in the border counties that historically experienced the reclamation and border defense policy. The border ports have not attracted immigrants in border areas over the study period. The positive relationship between population density and the establishment of border economic cooperation zones largely represent the locational preferences of the latter rather than its effectiveness in population attraction. This conclusion is proven by its insignificant association with population growth.Multiple stepwise regression is then conducted to identify the key influencing factors of population flow in border counties. We can see from the result that the time to the prefecture-level city, illiteracy rate change from 2000 to 2010 and whether the county has the national policy of reclamation and border defense have significant effect on population change in border counties . Travel Result of the regression models indicates limited explanatory power of many independent variables. Nevertheless, it does not mean that these factors are not important in shaping the geography of China’s border population. When we compare the maps of changing population distribution with those of influencing factors shown in During the research period, the population growth rate in northeast China was lower than the national average and kept slowing down. It is the case especially after entering the new century and will be continuing for a long time if not forever. The spatial distribution of the population change is uneven and the counties with a population decrease are obviously more than those with a population increase.China’s northeast border refers to the northeastern border areas of Liaoning, Jilin, Heilongjiang, and the eastern Inner Mongolia Autonomous Region. The region is located in the northeast of China, adjacent to the DPRK, the Russian Far East and Mongolia. The northeast border area has many neighboring countries, making it convenient for developing economic ties with surrounding countries and overseas regions. In addition, the trade system and trade ports in the northeast border area are optimal, with dense cities and better traffic conditions. The topographic conditions, traffic, and the proportion of the minority population in each county in this region are similar; therefore, these factors have a small effect on population shifts. The changes in GDP and the illiteracy rate  have a great impact on population shifts in this region. The main reason for the population decrease in northeast China is migration; compared with other border areas, the traffic conditions in northeast China are more developed, and people can move out more easily. To stabilize the population, corresponding measures should be taken to slow down the population emigration and attract the migrants.In the border areas of Inner Mongolia, the population of most counties increased, the economic growth rate was relatively high in most counties, and the proportion of the ethnic minorities was not much different across counties. Therefore, these factors have no significant influence on the spatial variation of population change. However, the difference in altitude is large, which has a deep effect on regional population changes. Variations in traffic and education also have a considerable influence on the regional geography of population change.Looking at the counties with declining populations, most of them have poor natural conditions and traffic conditions, such as Prairie Chenbarhu banner, which has Hulunbuir Sandy Land in its county area and only one national highway. The loss of population was exacerbated by the poor environmental and infrastructure conditions. In contrast, there was a marked increase in population in Manzhouli and Erenhot. These two counties are the main port cities of Inner Mongolia, with perfect transportation systems and foreign trade systems.The population increased in most border counties in the northwest. The proportion of the ethnic minorities in the region does not vary much; also, the illiteracy rate has significantly reduced but is relatively balanced in the region. Therefore, these factors have no substantial effect on population shifts. The altitude of each county varies greatly and the level of economic development is clearly different. Hence, topographic conditions and economic growth have an influence on population changes in border counties. Traffic varies greatly. Also, due to the regressive development of prefecture-level cities in the region, traffic access between the region and provincial capitals has a deep impact on population change. These counties have the national policy of reclamation and border defense, which is expected to help them in regional development and population attraction. However, the regression results show that such an relationship may not exist and the changing population geography may have little to do with this policy.We can see that the populations of almost all border counties in Tibet increased in the study period. China has proposed many special preferential policies in Tibet, including migration of cadres, investment in infrastructures and social welfares, and all types of economic stimulation policies. These national polices have direct and indirect effects on population changes in Tibet. For example, the degree of traffic access has important influence on regional population change. The opening of the Qinghai-Tibet Railway and Nyingchi airport, Ali Airport, and Xigaze Airport have laid a strong foundation for the development of border counties in Tibet, which is convenient for them to develop border tourism. In recent years, tourism has become an important industry in Nyingchi, Shannan, Xigaze, and Ali. Moreover, the unique cultural, religious and linguistic barriers between Tibetan and Han people have also hindered emigration of Tibetan. All these factors contribute to population concentration and growth in Tibetan border counties.In the past decade, the economic development of this region has lagged slightly behind the overall level of the border; but the difference is not significant. In other words, economic growth in this region is relatively balanced; thus, the impact of economic aspects on the region’s population is not apparent. Due to the region’s dense population, the area of border counties here is considerably smaller than that in other regions and they often have a higher degree of traffic access to the prefecture-level cities in which they are located. Hence, the traffic access to the prefecture-level city greatly influences population changes in this region. In addition, border trade and tourism are industries with special advantages in border counties in this region, which is an important factor to attract labor force. The populations of Ruili, Dongxing, and other border port cities and tourist cities have increased significantly in recent decades.In terms of population distribution and change in border areas, from 1982 to 2010, the population distribution of China’s border counties did not vary much. Counties with large populations are generally located in three provinces in northeast China, i.e., Xinjiang, Guangxi, and Yunnan (autonomous regions), while Tibet has a smaller population. There are great variations between population shifts and distribution patterns. The border populations of Inner Mongolia, Xinjiang, and Tibet continued to rise. The growth rate of populations in border areas during each period is higher than the national average, while the growth rate of the populations in Inner Mongolia and Tibet is higher. The population growth rate of border counties in the three northeastern provinces from 1990 to 2010 is lower than the national average.Given the increasingly market-oriented migration mechanism, the national reclamation policy has been no longer effective in population attraction in the new century. Education has significantly lowered and will continuously lower the fertility rate in remote border areas. In addition, factors influencing population growth show a remarkable regional heterogeneity along China’s long border. For example, emigration are important in the population change of border counties in the northeast, just like traffic and education in the north, topographic conditions and traffic in the northwest, national political and financial support in the southwest and border trade and tourism in the south.According to the different population distribution patterns and changes in the border areas, as well as the analysis of the factors affecting population distribution in these locales, the following suggestions are put forward.Migration as the main reason of population change has been dominantly determined by market forces rather than political ones in current China. In this sense, investment and economic development should be viewed as the key measure to prevent population decline and promote population growth in border counties. The level of economic development in border areas lags behind that of the national average. It may indicate a possibly higher return of investment. But the state should continuously improve the traffic and infrastructures in these remote areas and propose more open economic and trade policies to guarantee such a high return. Moreover, direct financial support on social welfares of residents in border areas is also important because these social resources are key for preventing population outflow and attracting people from the outside.To be specific, the following financial and policy support are highly recommended. Taking advantage of opportunities such as the Belt and Road Initiative, Western development strategies and other regional strategies that are closely related to border areas should be integrated more deeply into the national opening up strategy. Port cities should be developed, and large urban centers should be built with nodes for international exchanges. Border zones’ special geographic advantages should be exploited to foster trade between these areas and neighboring states. It is necessary to continuously improve infrastructure in border areas and raise the level of public services in border areas, such as transportation, medical and health care, and science, education and culture. In this way, the living standard of residents in border areas can be improved, and meanwhile, human and material resources in border areas can be ensured to flow rapidly and resources can be fully mobilized.Current research still has some weaknesses. Due to limited data availability, the selection of independent variables is one-sided. For example, change in the illiteracy rate is only used to represent improvement in the regional level of culture, science, and education. Furthermore, the impact of regional development policies and public service level on population change is insufficient. At the same time, due to a lack of data, there is no information on shifts in Tibet’s annual GDP rate from 2000 to 2010, so it is impossible to analyze the effect of economic development on population changes in this region’s border counties.