To work with seldom heard groups of mothers, their families, and health workers to identify unanswered research questions for maternal and newborn health in villages and health facilities in rural UgandaTo establish locally responsive research questions for maternal and newborn health that could be prioritised together with the public in UgandaTo support the case for locally responsive research in maternal and newborn health by the ministry of health, academic researchers and funding bodies in Uganda.Maternal and newborn deaths and ill health are relatively common in low income countries, but can adequately be addressed through locally, collaboratively designed, and responsive research. This has the potential to enable the affected women, their families and health workers themselves to explore ‘why maternal and newborn adverse outcomes continue to occur. The objectives of the study include;The present study will follow the James Lind Alliance (JLA) Priority Setting Partnership (PSP) methodology. The project was initiated by an academic research group and will be managed by a research team at the Sanyu Africa Research Institute on a day to day basis. A steering group with a separate lay mothers’ group and partners’ group  will be recruited. The PSP will be initiated by launch meetings, then a face-to-face initial survey for the collection of raw unanswered questions; followed by data collation. A face-to-face interim prioritisation survey will then be performed to choose questions before the three separate final prioritisation workshops.The PSP will involve many participants from an illiterate, non-internet population in rural eastern Uganda, but all with an interest in strategies to avert maternal and newborn deaths or morbidities in rural eastern Uganda. This includes local rural women, their families, health and social workers, and relevant local groups or organisations.We will generate a top 10 list of maternal and newborn health research priorities from a group with no prior experience in setting a research agenda in rural eastern Uganda.The current protocol elaborates the JLA methods for application with a new topic and in a new setting translating the JLA principles not just into the local language, but into a rural, vulnerable, illiterate, and non-internet population in Uganda. The face-to-face human interaction is powerful in eliciting what exactly matters to individuals in this particular context as opposed to online surveys.This will be the first time that mothers and lay public with current or previous experience of maternal or neonatal adverse outcomes will have the opportunity to identify and prioritise research questions that matter to them in Uganda. We will be able to compare how the public would prioritise maternal health research questions over newborn health in this setting. There is increasing recognition for public involvement in research. It ensures that research is relevant to the needs of the end-users. However, currently, research ideas arise mainly from academics and health professionals without the involvement of those who directly experience the problem or conditions. This is especially important in rural low-income settings where there are often huge cultural and economic differences between researchers and the population. We, therefore, aim to work with seldom-heard groups of mothers, their families, social and health workers in rural eastern Uganda. We will identify the unanswered research questions on pregnancy, childbirth, and newborn care that are considered important to the women and their families who receive such care.Maternal and newborn health exist together as a public health priority at international, national, regional, and local levels . StillbiIn Uganda, there are approximately 38 perinatal deaths per 1000 pregnancies , 27 neonatal deaths per 1000 live births, 336 maternal deaths per 100,000 live births but these vary from one area to another .Poor pregnant women are intensely vulnerable to illness, disability, and even death or any other costs incurred during childbirth. Perinatal mortality is twice in women with no education (45 deaths per 1000 pregnancies) compared to women with more than a secondary education in Uganda . These mHowever, the health research prioritisation for maternal and newborn health has mostly occurred at the highest international levels and in developed countries, . Where rThere is a considerable variation in approaches, tools, and methods used for setting priorities in health research , but theWe are working in association with the James Lind Alliance to set up a maternal and newborn health priority setting partnership in rural eastern Uganda (MNH-UG PSP). The study article aims to present this research prioritization process to identify unanswered questions on pregnancy, childbirth and newborn care considered most important to the women and their families, health workers, and social workers in rural Uganda. We will consider effective ways of applying the James Lind Alliance process in a rural and vulnerable population in Africa. The study will provide substantial new learning for ensuring the voices of seldom heard and complex rural populations in sub-Saharan Africa are heard to form the research agenda.The PSP will take place in the districts of Mbale and Budaka, a rural setting in eastern Uganda. We will specifically recruit from four health facilities, namely Mbale regional referral hospital at health centre level 6, three community health centres at level 4 and 3, social services centres and the surrounding 10 villages. We will choose a facility in a central area with some urban population, follow compass bearings visually aligned to the main road outlets of Mbale town to map out community health facilities  with a largely rural population. We will map out villages around each facility using the sub-county Maps, from which 2 villages will be selected to participate in the study.Fig. ). Maternal and newborn health are integrated. This scope covers conditions or aspects of care during pregnancy, the intrapartum period, the immediate postpartum period, the neonatal period, and the management of complications that develop during this period [Preliminary discussions via zoom, email, and one-day meetings were undertaken by the academic research group about the scope of the project. This informed the steering group discussion to have a broad scope, integrating both maternal and newborn health , National Institute of Health Research (NIHR), Bill and Melinda Gates Foundation, Global Fund, as well as any other major research funding bodies.The PSP will open and last for 12–18 months of implementation. The outbreak of COVID-19 pandemic and the lockdown restrictions in Uganda have subsequently affected our timelines. The study is expected to complete in August 2021  priority setting partnership (PSP) method, well described in a freely available on-line manual . This ise-based” , 16. TheThe present PSP is underpinned by a socio-ecological model (SEM) , 19, a sIn October 2016, the academic research group (the University of Liverpool and Sanyu Africa Research Institute) contacted JLA via an email expressing interest to set up a PSP for maternal health in Uganda as part of a Ph.D. training proposal. The academic research group made an initial enquiry with JLA to initiate and develop the process for priority setting.JLA shared the PSP information for guidance including a readiness questionnaire and found us not ready to start due to lack of funding. However, we continued to develop the idea.Upon confirmation of funding for the Ph.D. training in 2017, the potential for a PSP was discussed again with JLA in November 2017, and a half-day meeting in London in June 2018. The attendees represented the University of Liverpool, University College London, University of Leicester, University of Leicester, the James Lind Alliance, and the Sanyu Africa Research Institute in Uganda. The meeting discussions included the scope, which initially included gynaecological conditions; a discussion of a grant application for the PSP. We later submitted a grant application to MRC, Health systems Research initiative foundation call, which was not funded, with a notification in October 2018.The academic research group submitted a similar application with the scope of maternal and newborn health as part of the BabyGel trial grant application to the European and Developing Countries Clinical Trials Partnership (EDCTP). This was funded and commenced in February 2019. The Academic research team immediately engaged JLA again via zoom to discuss the readiness to implement the PSP, its implementation modalities for academic training purposes, and agree on the JLA chair.The PSP is set up primarily for academic training purposes, with the leadership and management team of four groups, namely; academic research group, steering group, lay mothers’ group, and partners’ group.The academic research group consists of the academic faculty (supervisors) of the University of Liverpool and Makerere University, the student, and the research team.www.safri.ac.ug). The institute will serve as the local coordinating organisation for this PSP with the research team.This group formed after registration for Ph.D. training with the University of Liverpool as an offsite student based at the Sanyu Africa Research Institute. This is a research institute in rural Uganda that uses research and innovations to improve outcomes for mothers and newborns  led by the student . This will form the secretariat responsible for managing the PSP on a day to day basis in Mbale. The research team members will have a background in medical, nursing, midwifery, and or social sciences, basic skills in qualitative research methods, and be fluent in any one local language . They will be trained in the PSP and JLA method. They will coordinate, administer, and manage the overall process in Mbale including organising meetings and workshops, collecting, managing, and analysing data.steering group includes membership of mothers, carers, health, and social workers with experience or interest in pregnancy, childbirth, and newborn health. This will be a diverse group of 15 members, to be recruited by the academic research group , and teen mothers with regards to their experience in pregnancy, childbirth, postnatal care, and newborn care. We too intend to hear from the traditional herbalists or witch doctors and traditional birth attendants and how they influence or would wish to influence maternal and newborn health in this setting.Table The details of the population at each socio-ecological level are described in The individual will be eligible to participate in the PSP if s/he meets any of the 4 broad criteria, aligned to the SEM.TableWe will involve participants described in We will purposively select participants at each SEM level with current or previous experience in pregnancy or childbirth. We will purposively select vulnerable and marginalised groups including sex workers, women with disabilities, carers of newborns with anomalies and teenagers, traditional herbalists, and traditional birth attendants. The purposive sampling techniques will ensure the representation of voices from vulnerable and marginalised groups of people at each stage of the PSP. A further exponential non-discriminative snowball sampling will be used to sample mothers or families that have experienced any death of the mother or baby or severe morbidity to participate in the PSP.Recruitment into the PSP will largely be face to face. The research team will physically visit antenatal care clinics, labour suites, postnatal wards, high dependency units, young child clinics, family planning, and immunisation clinics, and gynaecologic wards in community health facilities. They will too visit homes, churches, villages, places of work , and organisations or attend meetings or workshops to recruit participants. Three research members will walk, take motorcycles (Boda-boda) and or taxi to visit each health facility or organisation, meet the institutional representative for introduction and orientation to the staff and clients or participants, will check that the survey launch poster is pinned on the notice boards or offices. In the health facility, the research team will participate in the clinical care of pregnant and postnatal mothers before starting recruitment. Unlike the UK’s online surveys , 23–27, Further, some local members of the Steering group (SG) will identify potential participants and recruit them directly into the study. While representatives of partner organisations will encourage their clients to participate in the prioritisation exercise.During the face to face recruitment, the research team member will present study information to the participant, obtain informed consent from each participant, and then administer the questions during the surveys.We will also upload initial and interim prioritisation questions online on the PSP microsite to potentially reach persons with access to the internet in some parts of Mbale. The link to surveys will be sent to WhatsApp groups.The research team will directly contact social groups and leaders of institutions, inform and invite them to participate in the PSP. The research team will present the surveys to the partners’ group during the launch meeting and introduction meeting at each organisation or group. The partners’ group will place survey launch poster Fig. , with inStep Broadcasting media (SBC), a local radio station in Mbale with a coverage of up to 4 million people.The research team will share PSP information to the general public via twitter @maternal_jlapsp and a microsite. The research team together with members of the steering group will hold a launch promotional radio talk show at, The members of the steering group and the partners’ group will be encouraged to promote the PSP through their social groups, WhatsApp groups, departmental or village meetings. The research team will create a WhatsApp group to continuously engage and update steering Group members with the PSP recruitment progress.Initial surveyTable 2.Interim prioritisationWe will recruit 320 participants in the initial survey. The target sample is 120 (100–140) seldom-heard participants (mothers and their families), 20 (10–30) wider stakeholders, and 80 (60–100) health and social care professionals) for face to face data collection. The survey will also be uploaded online, and we expect to reach about 100 persons with access to the internet. Though this is a small sample size for the initial survey compared to previous JLA PSPs –27, 29, 3.Final priority setting workshopWe aim to reach a sample of 200 participants for interim prioritisation. Though this sample size is not based on the average of the previous JLA studies –27 for tAn average sample size of 27 participants will be invited by the steering group to take part in a one-day workshop. The JLA method recommends a minimum of 12 and a maximum of 30 patients, caregivers, and clinicians . PreviouParticipants’ characteristics have been described in Additional file The research team plans to reimburse participants for travel and time for any PSP meeting away from their homes. We will invite motorcyclists, and sex workers to the research office for data collection and will pay cash for their time and travel.Mothers involved in priority setting workshops will be encouraged to move with their babysitters who too will receive a modest allowance and a meal. There will be a designated room for breastfeeding mothers during the meetings, but in our settings, these mothers are too allowed to breastfeed freely in the meeting venue.We will train mothers and other lay members of the public joining the steering group and partners on principles of public involvement, and award them with a certificate of participation at the end of the PSP. We will allow time for the lay public and mothers to offer their voice during the priority setting workshop and any other PSP meeting.The research group will develop the initial questions iteratively with women, mothers, carers, and professionals in Mbale via individual face to face interviews.The draft questions will be presented to and reviewed by the partners’ group, and lay mothers’ group in separate half-day group meetings. We will then pilot the questions in Mbale via face to face individual interviews with 10 participants  to improve the design and clarity of questions.The Steering Group will review and approve the final initial survey tool . The research team member fluent in a particular local language will directly translate and ask the questions to the participants who neither speak nor understand English. At the end of the interview, each participant will be asked to confirm their willingness to participate in the interim and priority setting workshop.The JLA adviser will observe at least two face to face interviews with the participants via the zoom video meeting facility. The student will review each completed form against the audio-record at the end of each field day and the survey.The student will export data from the ODK system as a CSV file with the raw questions every two weeks, which will serve as a data handling excel file. We will perform ongoing cleaning of the data while the survey is still open, and an interim sub-analysis of participants’ demographics to identify under-represented study population in the preliminary responses and set a schedule for purposive recruitment.The student will prepare a complete clean dataset at the end of the initial survey, to categorise and summarise, while maintaining an audit trail. Each participant entry into the data handling excel file will be checked against the consent form, enrolment log and audio recording.We will double-check each participant’s entries against the audio recording to prevent the research team bias of entering questions based on their technical jargon and losing the lay context. The student or another separate research member will listen to audio recording per participant while comparing with the entered questions to check for consistency of participant’s questions. Any question phrased differently in the data file will be changed to the participant’s phrases in the audio recordings. We will enter the lay questions directly replacing those phrased or entered by the research team member. The cleaning will also involve removing duplicate identification (ID) numbers to participants, assigning new IDs to participants with missing IDs in the dataset.If the person listening to the audio doesn’t understand the language, then a language expert will be invited to interpret the audio to the research team. We will submit all local names for specific words or herbs during the interviews to a language translator. We also will take pictures of herbs being mentioned in local names by participants and submit them to the research team to confirm the English or botanical name. For the dataset with missing audios, we will contact the participant directly via phone calls to confirm the nature of the questions.Organise and code the responses.The student will keep a clean dataset as final on file, share it with the research team and research group, then create a new data file labelled “coded data set”, and will use this to code initial survey responses. The coding process will include removing participant’s initials, names, phone numbers, any blank responses, splitting questions that have multiple sub-questions, giving each question a unique identifier, while maintaining the link to the participant.The student will code 60% of the participants’ data while each of the two research members will code 20%. The student will review 50% of the data coded by research members while each research member will review 30% of the data coded by the student.Identify out-of-scope questions.The student with the research team members will continue to code the dataset. This will involve creating a column in the dataset for in-scope or out-of-scope with its reason and checking each question against the agreed PSP scope, as defined earlier in this protocol. The research team will hold a zoom meeting with the JLA adviser and the academic research group to check the exact interpretation of the scope.We will analyse out-of-scope questions separately from the in-scope questions and generate tables for review by academic research and steering group members. The research team will prepare frequently asked questions (FAQ) document for the questions of information and advice, which will be shared with antenatal care units, health facilities, district health offices, and the ministry of health.Sort into themes and summarise in-scope questions.The research team will sort out all in-scope questions into overall original themes, namely; pregnancy and its complications, labour and its complications, diagnosis, prevention, and treatment.The student will export the in-scope questions or data into NVivo 10 software, to generate emerging themes following the principles of the thematic content approach for analysis . AnotherThe research team will code questions asked only once as single questions with the emerging theme. However, they will group similar in-scope questions, which are asked at least twice, to form an indicative question representing all these questions in terms of the language and context.Discuss and agree on questions with the steering group.The research team will present the list of indicative questions to the lay mothers’ group in a 3-h face to face meeting at a central place and check whether they agree with how the questions have been categorised and summarised.The research team will organise a steering group meeting, in which members will review, comment, and confirm themes, indicative in-scope questions, single in-scope questions, and out-of-scope questions.Evidence check for research questions.The student will check each indicative question against existing literature or systematic reviews through a rapid review of the literature. An independent librarian at Busitema University in Uganda will do a separate literature search using a predefined systematic criterion and the search results will be shared with the student to double-check the search results. Any discrepancies will be resolved by another search by the librarian at the University of Liverpool. We will apply the GRADE system for rating the quality of a body of evidence as a guideline wherever evidence is not clear . The stuThe research team will perform the following for any answered question;Provide summary evidence against each question, including s as appropriate,Review all the questions with the steering group.Following the evidence review, the steering group will agree which questions are to be removed as already being answered.Where questions are partially answered by research, they will be amended to include the un-answered part of the question.The remaining indicative questions and any single questions as agreed by the steering group will form the final long list of unanswered questions by research.Number of unanswered research questions.The research team will group questions for maternal health alone, newborn health alone, and later combine maternal and newborn health to form three separate long lists of questions.A one-off face-to-face steering group meeting will be held to discuss the three long lists of questions and agree on the number of questions on each list to go forward for interim prioritisation. In this PSP, we will consider up to 70 questions for maternal health alone, 70 for newborn health alone, and 70 for both maternal and newborn health together. Previous PSPs have considered an average of 65 (range 40–114) research questions on the long list.The following criteria will be used to reduce the large list of indicative questions to the proposed number.The question based on a submission by utmost two participants will be prioritised lower than questions from several participants in the initial survey.The question based on submission from one socio-ecological model level or group will be prioritised lower than questions from more SEM levels.The removed questions will be checked to ensure that questions known to be coming from ‘seldom heard’ persons are retained.The research team will conduct face to face data collection largely through verbal interactions with each participant at each SEM level.The research team will arrange the three agreed longlist of questions separately in a better format for visualisation on the paper version or the mobile smartphone.The research team will administer the questions to individual participants in a chronological order starting with the longlist for both maternal and newborn health combined, followed by a long list for maternal health alone, and will end with the longlist for newborn health alone. There will be a resting period between the second and last long list.Each participant will read or be read the long list of questions in random order from the phone or the paper version. The research team member will then ask each participant to choose any 10 most important questions on each of the three-long list of questions separately and have the responses entered into the questionnaire, following the JLA approach.Based on the experience of the JLA adviser, asking people to rank their top 10 questions does not add much to the value of the data, hence they will only be asked to choose and not rank. There are examples of PSPs that have applied this ranking approach .In the process, ‘we will simply ask each participant to choose her/his most important questions’, which will take approximately 90 min to complete.We will hold three steering group meetings to discuss and agree on an overall shortlist of 20–30 top questions from each longlist to be taken forward to the final priority setting workshops.This is planned to take 12 weeks.This will be a face-to-face group priority setting workshop using participatory mixed methods. The research team will hold three priority setting workshops on three separate dates with three separate groups of participants. The participants will have similar characteristics across the three groups.The first priority setting workshop will be for the combined maternal and newborn health priorities, while the second priority setting workshop will be for the maternal health questions alone, and the third priority setting workshop will be for the newborn health questions alone.Each priority setting workshop will occur in a central meeting place for all participants. We will follow the standard JLA approach. The process will encourage open discussion and involvement of all group members guided by an independent JLA chair and assisted by the research team and observed by the academic research group.The ranking exercises will be based on nominal group techniques .All participants will be made aware of the purpose of the workshop at the beginning, to generate the top 10 research priorities representing the views of all those who participated. The workshop will begin with small-group debate and discussion to challenge and explore the final questions on the shortlist before the final plenary ranking session.The JLA adviser will facilitate this process and ensure transparency, accountability, and fairness and ensuring that the views of the vulnerable and marginalised population are considered. Participants will be expected to declare their interests in advance of this meeting.The present study commenced in January 2020. Participants are currently being recruited to the study. The outbreak of the COVID-19 pandemic and the lockdown restrictions in Uganda subsequently affected our timelines. Data collection for the initial survey will be completed once the COVID-19 lockdown restrictions are lifted, possibly in October 2020. Recruitment for the interim prioritisation will be finalised in May 2021 and priority setting workshops in August 2021.We will generate research topics, themes, or areas and questions and compare how people chose maternal health questions over newborn health questions in this setting. The original research questions for all the three long lists will be maintained non-technical to avoid missing context and value around these questions from the non-researchers.The Academic research group plans to translate the questions into technical focussed research questions with a specific structure, i.e. the Population, Intervention, Comparator, Outcome (PICO) format.For purposes of reporting, Table The research team will track and report on PPI processes within this research including the experiences and impact of public involvement from the perspectives of the steering group members, partners, and participants.We will use an activity log to record PPI outcomes during any meeting or workshop . EDCTP has no part in the execution of the study and write-up. The James Lind Alliance provided partial contribution towards the JLA adviser’s time. The University of Liverpool offered a Ph.D. tuition waiver for the student while the Sanyu Africa Research Institute paid the student’s stipend during the project period. The budget for the PSP project alone is estimated at €28,000.The PSP is financially supported by the EDCTP through a grant to the BabyGel cluster randomised trial All steering group members and priority setting workshop members will declare their interests at the start of the project and workshop respectively.The maternal and newborn PSP in Uganda is translating the JLA principles not just into the local language, but into the local setting. The current protocol elaborates JLA methods for use with a new topic and in a new setting. This PSP challenges the usual process of PSPs in western settings, where participants are generally literate and informed of their condition, where there are existing support and professional networks for the condition, and digital technologies are in common use. We anticipate the findings could be rapidly incorporated into the future World Health Organization and other international research priorities.This study will, for the first time in rural Uganda, provide new learning for ensuring the voices of seldom heard and under-represented complex populations in rural villages and health facilities are heard to form the research agenda in pregnancy, childbirth, and newborn health.The PSP provides the steps that necessary for an academic research group to follow while setting up a priority setting partnership for purely academic training purposes at postgraduate level.Unlike other PSPs, this one will adopt a face to face collection of questions from the participants. It will be a non-internet-based approach; there is hardly any internet access in the villages of Uganda and any efforts to use the internet to collect questions from the lay public would not yield the locally appropriate responses. Further, the Corona virus disease 2019 pandemic creates a new challenge. We therefore will demonstrate the feasibility of using phone calls to consent and collect raw questions from participants in this setting while adhering to the COVID-19 national guidelines for conduct of research in Uganda .Unique with this PSP is the formation of a sub-group of lay mothers as part of the steering group. This is a group of mothers who are not English speaking and will represent views of the majority of the rural women who will be participating in the surveys.The steering group agreed on a broad remit for this PSP of maternal and newborn health. The scope is further subdivided to explicitly include first and third trimesters This aims at exploring the critical questions during this period, especially in rural Uganda where first-time mothers are exposed to traditional practices with unknown effectiveness. We too included the immediate postpartum period due to the high risk for maternal and neonatal mortality during this period , 34.The study will inform the establishment of a protocol for research prioritisation of Maternal and Newborn Health (MNH) in Uganda. If proven effective and appropriate in MNH, this methodology will ultimately be adopted as one of the methodologies in identifying research priorities for other disease conditions in Uganda or any LMICs.The results of this study will inform the design of studies out of women’s voices or seldom heard population. The study findings will guide the Ministry of Health Uganda and current funders in resource allocation, as well as the Royal College of Obstetricians and Gynaecologists (RCOG) global health division and other researchers in the research agenda development. We anticipate the findings could be rapidly incorporated into the future WHO research priorities and or prioritisation exercise .The Maternal and Newborn Health Priority Setting Partnership in Uganda will, for the first time, identify the most pressing unanswered questions about the pregnancy, childbirth, and after childbirth in under-served populations in villages and health facilities within the rural settings of Uganda. This will ensure that future research can be prioritized according to the local needs of mothers, carers, families, and professionals with interest in strategies to avoid maternal and newborn morbidities and mortalities.Additional file 1. Characteristics of governance team and participants.Additional file 2. PPI Activity log for recording JLA PSP Meetings.Additional file 3. Initial survey data tool.


The most used families were Leguminosae, Asteraceae, Malvaceae, Euphorbiaceae, and Lamiaceae. Medicines were commonly prepared as a decoction and administered through oral ingestion, with roots reported to be the preferred plant part for medication. The Maasai preference for roots compared to other plant parts may be unsustainable and could threaten species availability in the future.The use of medicinal plants for treatment of humans and animals is entrenched in the Maasai culture and traditional knowledge related to it is passed on from one generation to the next. A handful of researchers have in the past decades documented this knowledge. No single study has documented medicinal plant uses of the Maasai community as a whole. This review provides a consolidated database of the diversity and uses of medicinal plants among the Maasai in Kenya. The study will help conserve traditional medicinal plant knowledge that is valuable for the development of modern medicine. Relevant information on medicinal plants used by the Maasai of Kenya was extracted from journals, books, M.Sc., and Ph.D. dissertations. We found evidence of 289 plant species used by the Maasai of Kenya in traditional medicine. Most species were used to treat health conditions in the categories  All humans depend on plants for food, medicine, firewood, and more . The usePeople around the world have different cultures and lifestyle which influence medicinal use patterns and practices. The parts of the plants used and the preparation methods could also be influenced by species availability and traditional knowledge of use. To understand diversity of medicinal plants, all these factors should be considered.Traditional knowledge of medicinal plants held by different communities has provided baseline data for selection of species for screening of active compounds in search of new drugs ,8. NeverThe Maasai live as pastoralists in Kenya and Tanzania, and their population is estimated to be about 1 million. The Maasai keep cattle as their main source of wealth and food . In KenyIn the Maasai community, traditional use of plants for curative purposes is a cultural practice that has been inherited from their ancestors over many generations . For exaDue to strong cultural beliefs, an expensive government and private healthcare system, and long distances to available facilities, a majority of the Maasai, especially those in rural areas, prefer to use medicinal plants for their health care needs and for those of their livestock. Gastrointestinal disorders, parasitic infections, tuberculosis, brucellosis, sexually transmitted diseases, and wounds are the main diseases that affects the Maasai . Some ofNevertheless, the Maasai’s traditional way of life is rapidly changing due to the introduction of western education, increasing access to government healthcare facilities, climate change, and urbanization, among other factors, which all lead to the loss of this important knowledge and of the associated plant resource base . A recenThe available research on medicinal plants of the Maasai of Kenya is highly fragmented, encompassing single villages in different geographical areas of the Maasai land. A consolidated account and analysis of the uses and use pattern of medicinal plants among the Maasai community as a whole is not available. Therefore, there is need for a comprehensive analysis and compilation of the available scientific literature concerning medicinal plants practices and use patterns of the Maasai people in Kenya. It is also important to understand whether medicinal plant knowledge is shared in different areas occupied by the Maasai in Kenya.Such a compilation will aid in medicinal plant conservation, and could be used as a basis for subsequent studies on the pharmacology and phytochemistry of the highlighted plants for future development of drugs.In our analysis, we describe and evaluate the diversity and use patterns of medicinal plants in the Maasai community of Kenya, specifically, we ask the following: (1) How many medicinal plant species have been documented for the Maasai community in Kenya, which plant species are most used for medicinal purposes, and which plant families do they belong to? (2) What are the ethnopharmacological uses of medicinal plants with high use reports, and which medicinal use categories do they belong to? (3) What parts of the plants are used, and how are the plant-derived medicines prepared and administered? (4) How homogenous is the use of medicinal plants among the Maasai of Kenya?Data on medicinal plants used by the Maasai community were gathered from journals, books, published M.Sc. and Ph.D. theses, and in different electronic databases including science direct, Medline, Google scholar, Web of Science, AJOL, in local Kenyan university websites, the University of Nairobi, and Aarhus University libraries. We searched for relevant information using the key words “medicinal”, “plants of the Maasai”, “Maasai of Kenya”, “ethnobotany of the Maasai”, “traditional medicinal plants of the Maasai”, “indigenous knowledge of the Maasai”, and “local knowledge of medicinal plants of the Maasai”. In total we identified 15 articles, two theses (M.Sc. and Ph.D.) and two books, all published between 1994 and 2018 ,29,30,31Before including the data in the database, it was traced to the original sources. We consolidated a database, organized in Excel, with columns for the scientific name of the plants, the reference from which data was obtained, counties where original research was conducted, villages and study sites when available, original use reports, parts of the plants used, preparation methods, route of administration, and classification of the condition treated.We excluded use reports for plants that were not referred to by their scientific names. Plants that were referred to by their genus names only were also excluded, as it was not possible to know the exact species being referred to.In this analysis, “use report” refers to the local uses of medicinal plants as reported in the primary reference . So, a “The Plant List [Scientific names from primary sources were verified and updated to current accepted names according to ant List . Medicinant List .In the cases where the names given in the primary references were listed as a synonym in the plant list, we databased them under their accepted names.We found 177 use reports under synonyms and 1200 misspelled names in the primary sources which were then updated to the current accepted scientific name.Some reported more than one plant part, for example, stem and roots, as ingredient in medicine. In such cases, we recorded the entry as multiple parts. When the used plant part was not provided in the primary sources, we recorded it as unspecified. When the whole plant was used, we recorded it as whole plant.To determine common species used and homogeneity of use in different localities, we calculated the number of use reports per species and Informant Consensus Factor (ICF) , respect shared) ,37. In tWe found information about 289 medicinal plant species used by the Kenya Maasai which together had 1844 use reports . Thirteeand Respiratory system disorders   . Most usts; 14%) . Nine dits; 14%) .About two thirds of the primary sources analyzed mentioned which part of the plants that was used, but only 342 (19%) of the use reports mentioned how the plants were prepared before being used and their route of administration. Roots were the most frequently used plant part, followed by “multiple parts” . DecoctiThe use report data originated from two groups of the Maasai occupying Narok and Kajiado counties. Metabolic disorders, social problems, gastrointestinal, respiratory, and musculoskeletal disorders had the highest ICF values. The rest of the categories had low ICF . The catThe use of plant-based medicine among the Maasai is still an important component of their culture. This is demonstrated by the high number of use reports in the primary references . It is aFrom the 1844 use reports gathered from the 19 references included in the analysis, 289 species were identified as belonging to 70 families. It was noted that all the data accrued from documented research were conducted in Narok and Kajiado counties suggesting that medicinal plant uses in other places such as Laikipia and Baringo counties have not yet been documented, published or the data is not available online or in hard print.Out of the 289 species, 51 (18%) had ten or more medicinal use reports and 76 species had a single use report. Medicinal species with high numbers of use reports might be much more effective in treatments or could be more easily accessible compared to those with few use reports. On the contrary, those with single use reports could still be effective in traditional treatments but may not be easily available in the surrounding environments.Leguminosae, Asteraceae, Malvaceae, Lamiaceae, and Euphorbiaceae were the plant families with most species used for medicinal purposes. Our findings partly agree with research conducted in Tanzania which reported Leguminosae, Lamiaceae, and Asteraceae to be dominant families . The comThe most common category of health conditions treated with medicinal plants by the Maasai of Kenya was gastrointestinal disorders. More than half of all recorded medicinal species (59%) were used to treat gastrointestinal disorders which contributed 27% of the total use reports. The category had a high informant consensus factor of 0.66 indicating that the knowledge of use of medicinal plants is largely shared among the Maasai of Kenya occupying different localities. Kajiado and Narok counties are classified as arid and semi-arid counties with little or no access to clean water. Gastrointestinal disorders such as diarrhea are therefore common. Diarrhea is a common disease in Africa and is reported to cause death in children. Similar results were recorded in a study on medicinal uses of African palms .Respiratory disorders were the second most common disorder treated with medicinal plants and had a high informant consensus value (0.64) and about 14% of use reports were classified into this category. In Ethiopia, 16% of the reported medicinal plants species were used to treat respiratory disorders .Muscular-system disorders were the third common disorders that were treated with medicinal plants by the Maasai. This could be a result of the Maasai way of life which entails trekking long distances in search of pasture and water for their livestock. The long walks in the forest and savannas may result in body discomfort such as body pain, muscle aches, and rheumatism.Malaria was the fourth disorder treated with medicinal plants. Malaria is caused by parasitic protozoa and is reported to cause over a million deaths in Sub-Saharan Africa . We expeUrological, gynecological, and skin disorders had only two species with more than five use reports and a low informant consensus factor of 0.47, 0.46, and 0.33 respectively. Neurological and toothache disorders also showed lower intracultural consensus due to few use reports. This suggests that the knowledge of medicinal plants in the five categories is not shared across geographical locations or within the Maasai groups. The difference in the use of medicinal plants in the studied counties could be a result of the ease of availability and ecological factors ,49. SimiThe Maasai used many different plant parts for preparing medicine. We found reports for the use of eight different plant parts  but manyDifferent methods of preparation of medicinal plants are used in various parts of the world. For the Maasai people in Kenya, we found that decoction was the most frequently used method of preparation. This is consistent with studies conducted elsewhere that reported decoction to be the most commonly used method for preparation ,57,59. DThe Maasai’s common route of administering the plant derived medicine was oral by drinking, which is the same as found in many other studies ,61,62. EMetabolic disorders, social problems, gastrointestinal, respiratory, and musculoskeletal disorders had the highest ICF values, indicating that the plant species used for treatment in these categories were shared by informants ,37. The The study gives an overview of medicinal plants used by the Maasai of Kenya, disease categories treated with medicinal plants, and their ethnopharmacological uses. Most of the encountered 289 medicinal species were used to treat health disorders in the categories gastrointestinal disorders and respiratory system disorders. This means the two are either the most common health disorders among the Maasai of Kenya or the Maasai community prefers to use traditional medicinal plants to treat disorders in these two categories.The 289 species encountered in the 19 references were from the Maasai community living in Narok and Kajiado counties in Kenya. No information was available on medicinal plants of the Iljamus and the Laikipia Maasai who inhabit Baringo and Laikipia counties respectively. We also found that medicinal plant knowledge was localized and only shared in part between the counties studied. This implies that people might have developed new knowledge based on the available medicinal plants in their surrounding environments as dictated by ecological and other factors. Based on these findings, it is important to document medicinal plants knowledge in additional villages and counties for knowledge conservation. Therefore, additional research on Maasai medicinal plants from the so far not studied counties is needed to document the ethnomedicinal uses of plants to safeguard their knowledge from extinction. Also, research should be conducted to understand the factors that influence the selection of medicinal plants for treatment.The Maasai preference for roots compared to other plant parts for medication may be unsustainable and could threaten species availability in the future. To ensure sustainable utilization of plant resources, the community should be encouraged to cultivate medicinal plants. This recommendation would have been meaningless some years ago when the Maasai moved from place to place to feed their cattle, but now that they are becoming more sedentary the suggestion could be relevant. Alternatively, the Maasai could consider the use of other parts of the plant such as the fruits and leaves which may be more sustainable to harvest. In addition, it is necessary to find new ways to harvest and prepare the medicine to protect medicinal plants resources obtained largely from the wild.Phytochemical and pharmacological analysis should be directed towards the highlighted medicinal species with more than five use reports in each disorder category to understand the rationale for usage. The discovery of more and new medicinal plants could lead to the discovery of new drugs in the future.


Integrated care has been suggested as a promising solution to the disparities in access and sustained high quality long-term care emerging in Europe’s ageing population. We aim to gain a better understanding of context-specific barriers to and facilitators of implementation of integrated care by doing a retrospective assessment of seven years of Embrace. This Dutch integrated person-centred health service for older adults was based on two evidence-based models (the Chronic Care Model and the Kaiser Permanente Triangle). Despite successful deployment the programme ended in 2018. In this case study we assess the impact of the programme based on past evaluations, reflect on why it ended, lessons learned and ideas to take forward.The majority of health outcomes were positive and the perceived quality of care improved, albeit no clear-cut savings were observed, and the costs were not balanced across stakeholders. The Embrace payment model did not support the integration of health services, despite reforms in long-term care in 2015.Enabling policy and funding are crucial to the sustained implementation of integrated person-centred health services. The payment model should incentivize the integration of care before the necessary changes can be made at organizational and clinical levels towards providing proactive and preventive health services. Throughout Europe, communities and entire societies have to face the challenges that come with ageing populations. As the number of people with chronic diseases and multi-morbidity increases, the need for long-term care will rise to a point where budgets become limitative and disparities in access to high-quality care will occur. This is considered a growing public health concern .According to the World Health Organization (WHO), person centred integrated care services provide promising solutions to these challenges since they have the potential to enhance the quality of and access to healthcare, thus improving clinical outcomes and patient satisfaction while reducing cost . These p2Although systematic literature reviews have identified numerous elements, factors, barriers to and facilitators of successful implementation at the micro, meso and macro level 67, inter6To assess and address the challenges of implementing integrated care in the context of the Dutch healthcare system, we will examine Embrace, a combination of the evidence-based Chronic Care Model (CCM)  and a poWe have examined the integrated care programme Embrace, from its start in 2012 until it ended in 2018. In this paper, we describe the initial goals and contextual changes, and summarise the impact of the programme based on past evaluations. In addition, we reflect on why the programme ended and the legacy it left behind. Finally, we present lessons learned and conclude with prospects for the revival of the programme.We used a mixed-methods case study design  to retroData for this case study were collected in multiple ways, as summarized in Table 15Semi-structured interviews were conducted with three Embrace programme coordinators to gain a deeper understanding of three topics: (1) integrated care characteristics, (2) evaluation and implementation and (3) sustainability and the payment model. The same researcher (SH) conducted the interviews, which lasted approximately 90 minutes, using an interview guide. The interviews were audio-recorded and transcribed afterwards.Part of the data collected originated from the ACT@Scale project  in which Embrace participated as a case study of scaling up integrated care . This ACThematic analyses   was usedThis study did not require the participation of human subjects, nor actual patient data. The information collected with the semi-structured interviews was anonymous and non-identifiable information or data related to individuals were collected or accessible. As such, this retrospective assessment was considered “service evaluation” and therefore beyond the scope of the local UMCG Research Ethics Committee. The latter only applies to experimental studies on human subjects.Embrace has previously been described in great detail 20. In brThe clinical information system consisted of a Digital Elderly Record that was accessible for the members of the Elderly Care Team. It included personal data, the results of the questionnaires, the anamnesis, the advanced care plan and information on issues to be discussed in the Elderly Care Team meetings. The providers’ staff received intensive training in using the protocol and the clinical information system for over seven days in total. They were coached during the Elderly Care Team meetings for over two years and received peer-to-peer support.Embrace was preceded by two pilot studies on case management for older adults 2008–2011) and started as an integrated care service in 2012 in three municipalities in the eastern part of the province of Groningen. Embrace started in the province of Drenthe in 2014. The history of Embrace is shown in Figure 1 and staA multidisciplinary team from University Medical Centre Groningen initially developed the programme together with a health insurer and a health care provider. After the pilot studies, regional steering committees were installed in which multiple stakeholders participated, such as providers, payers and elderly representatives. The multidisciplinary team from University Medical Centre Groningen, among which were programme coordinators, advised and supported the steering committee and the local Elderly Care Teams. Furthermore, they monitored and evaluated the programme. Older adults and representatives’ organizations participated in regional Sounding Boards. Daily coordination of care was done by the Elderly Care Teams.The Netherlands has a statutory health insurance system which is universal and mandatory . Health Primary care is provided by group practices, two-person practices or GPs working solo. In primary care, 75% of the payment is a mix of capitation and fee-for-service for core activities. There are also bundled payments for programmatic multidisciplinary care for chronic conditions and pay-for-performance contracts.Not included under social health insurance are prevention and social support. These are funded by municipalities with funds from general taxation. This arrangement has been in place since the long-term care provision and financing reforms in 2015 15 which aiThese reforms were intended to keep health care and social support accessible and affordable in the long run. The aim was to enable older adults to live at home for as long as is possible and desirable, and to bring the responsibility and decision-making closer to citizens, i.e. in the municipalities. Informal care and the local community were intended to provide more support. However, the reforms led to problems in both coordination and procurement. Intensive home care, community nursing and social care and support now have different purchasers each with their own separate budgets and responsibilities that do not align. Great difficulties emerged in the coordination of services the anticipated improvements in efficiency were therefore not achieved. Moreover, perverse and non-aligned incentives led to unanticipated cost-shifting between the schemes .Various funding sources, mostly grants, were used for the development, implementation and evaluation of Embrace. This was necessary, since elements of the intervention were not reimbursable at that time under various funding schemes .Text 1.Table The outcomes of Embrace were evaluated in terms of the Triple Aim outcomes in multiple studies: a Randomised Controlled Trial (RCT), several pretest-posttest studies and qualitative studies. The RCT of 12 months of Embrace was done in the province of Groningen (2011–2013) . In a loThe Embrace intervention improved the quality of care as perceived by both older adults and professionals . Also, pAfter twelve months it was not possible to demonstrate any clear benefits for health, wellbeing and self-management for all the risk profiles, compared to the control group, in a Randomized Clinical Trial . However2122Table 3.The cost-effectiveness study (RCT) revealed that Embrace was more effective, but also more expensive compared with the care-as-usual group in the first 12 months after implementation (n = 1.131) . The lonThe summarized results would, at first glance, appear to render the programme futile; however, we now expand on the circumstances and issues that divert and absorb focus and effectiveness.The ‘innovation reimbursement agreement’ of Embrace, granted by the Dutch Healthcare Authority for the Health Insurance Act, ended in July 2017. This agreement made it possible for Embrace to assess the long-term results, and if they were deemed positive, to have the intervention reimbursed on a permanent basis under the Health Insurance Act. The basis for this grant was a multi-stakeholder agreement, in which the intension and aim were embedded to scale up when Triple Aim outcomes were positive. One of the programme coordinators summarised what happened when the agreement ended: “The health insurer withdrew as a result from the evaluation of long-term outcomes. The main cause was that expected cost savings were not realised. For many stakeholders, this came by surprise. Municipalities were not planning on taking this over, financially. The largest health care provider had financial and organisational challenges itself.”When the innovation reimbursement agreement ended, there was no alternative payment model. Embrace was halted in the province of Groningen in 2017 and in the province of Drenthe in 2018.The reforms in long-term care (2015) had major consequences for the development of a payment model after the agreement ended in 2017. The reimbursement of health care and social support for older adults participating in Embrace were divided over two funding schemes . Under these funding schemes, important elements of Embrace that were covered by the innovation reimbursement agreement until July 2017, could however not be reimbursed: the screening activities and risk stratification, the Electronic Elderly Record, and the self-management support and prevention programme. For municipalities and health insurers it was not appealing to invest in such preventive activities, as any potential cost savings would fall under another funding scheme (i.e. the Long-Term Care Act). Furthermore, the regional procurement offices were not risk-bearing for this scheme, and therefore not incentivised to invest and save costs 30.One of the factors that influenced the outcomes of Embrace, was the lack of fidelity to the protocol. For example, not all older adults who had the risk profile ‘frail’ based on the risk assessment, received case management in accordance with the intervention protocol. In practise nearly half of these older adults were no longer receiving case management after a while and their risk profile was adjusted to ‘robust’ .One of the reasons for the lack of fidelity might have been that the case managers caseloads in the Elderly Care Team increased since the start of Embrace. That is what the programme coordinators observed. The case managers were more or less urged to stop contacting the older adults if no imminent or urgent need for care or support was identified (or such needs ceased). Short term financial results of organizations outweighed long term impact, and daily issues required immediate attention. Or as one programme coordinator remarked: “during meetings we ask: are you only extinguishing fires or are you pro-actively and systematically screening the elderly?”.In search for local implementation sites, program coordinators experienced that some GP practices did not fully share the Embrace vision and preferred more case-finding approach of including participants. One of the program coordinators described this challenge:“When you try to implement and normalise in practise the [integrated care] vision that has a scientific foundation, minor derivations happen during the process. Then you think: they are taking the strength out of the intervention. The strategy is to stratify all older adults aged 75 years and older. One GP practice says, “let try that” and really is willing to do so. The other GP practise says, “I don’t believe in this approach”. That’s what you are navigating in between”.Whether this lack of shared values influenced the fidelity to the protocol of participating GP practices, was not evaluated.It was clear that the implementation of Embrace had impact on the management of the GP practise, the clinical information system, and required certain skills and capacity of staff. The intervention therefore had to fit the long-term vision and strategy of a GP practice and of the other local organizations in the primary, secondary and social care sector. This alignment is not always custom, as one of the programme coordinators remarked: “Implementing such a programme [Embrace], that is about managing a GP practise and about expertise, means examining where to connect. […]. Some GP’s say to me: why does it matter to me this region deals with a declining and ageing population. I have 1500 patients and together with my GP assistant, I will manage to sit it out. Why should I think about effective health care in this region?”.Although Embrace ultimately ended in 2018, there still are prospects for the revival of the programme. One of the Embrace programme coordinators has been asked by the Ministry of Health, Welfare and Sports to start developing a national framework for integrated people-centred health services for older adults. This framework will be based on the experiences of Embrace and similar programmes in the Netherlands and will be in line with the World Health Organization’s global strategy on integrated person-centred health services [strengthening governance & accountability and creating an enabling environment are therefore now explicitly included in the new national framework. In this way, future integrated care programmes for older adults should be better aligned and gain more support than Embrace had, to achieve the transformation as intended.The barriers that Embrace encountered in the quest for sustainable implementation were mainly at an organizational and policy level. The WHO strategic goals of Furthermore, a revised integrated care programme for older adults started in 2017 in the Province of Drenthe, based on the building blocks of Embrace and on previous experiences of integrated care programmes in the region.From the start of Embrace, the Triple Aim outcomes were monitored and evaluated at the request of the health insurer. The long-term economic evaluation made it clear that the costs and benefits ended up accruing to different stakeholders and payers. Although the 2015 reforms aimed at more efficient coordination and procurement of services in long-term care, they produced new financial disincentives. From the perspective of individual organizations, it is not surprising that they acted in their own financial interests, as tends to happen in a healthcare system with managed competition . We belienabling environment that the World Health Organization envisages [3334To create the nvisages , in our nvisages . Paymentnvisages 333435. Iages 3334. The evaages 3334. JoiningOne example in the Netherlands of a bundled payment model of this kind for an integrated care programme is to be found in the Care Chain Frail Elderly programme . The intexperience of providing care as an important aim of the programme, and monitor it, the Triple Aim would need to be expanded to a Quadruple Aim [During the years when Embrace was funded by grants or based on temporary financial agreements, most prerequisites seemed in place at the level of governance of the programme and communication : particiuple Aim .The key lessons from Embrace are clearly not limited to the (Northern) Netherlands and are worth sharing internationally. In our opinion, multiple frameworks and methods would be useful to provide a better understanding of the complexity of the sustained implementation of current and future integrated care services. First, prior to large-scale implementation, an evaluation framework such as the Consolidated Framework for Implementation Research (CFIR) could help to identify critical barriers, as used by Warner et al. (2018) for an online frailty tool . Secondl414243Although we have collected and analysed data on Embrace in multiple ways, the semi-structured interviews were limited to programme coordinators. This might have led to an over-emphasis on the main barriers from their perspectives.One of the factors that might have influenced the effectiveness, yet not included in this paper, is the interoperability of the Elderly Care Record with the IT systems of health care providers. To this date, within the Dutch primary care sector such interoperability issues occur, however we did not assess these issues or identified them in the data analysed.This retrospective assessment of Embrace (2012–2018) underscores the importance of an enabling context, including a payment model that truly incentivizes the integration of health and social care services. These prerequisites are crucial to transforming health services at an organizational and clinical level, from being reactive and problem-solving to becoming proactive and preventive. Without the right incentives, monitoring, training and support, and shared values and understanding, this transformation will not last. However, with a new national framework for integrated person-centred health services for older adults in sight, there are still prospects for revival of Embrace.The additional files for this article can be found as follows:10.5334/ijic.5434.s1Supplementary Text 1.Details of the Embrace payment model.10.5334/ijic.5434.s2Supplementary Table 1.Details of the Embrace payment model.10.5334/ijic.5434.s3Supplementary Table 2.Overview of publications on Embrace included in this study.10.5334/ijic.5434.s4Supplementary Table 3.Change in costs per risk profile*, compared to baseline.


Medicine can be broadly divided into two fields: clinical medicine that aims to save existing patients and basic medical research that aims to save the lives of future patients. In terms of disseminating basic medical research, medical journals play a vital role for physicians and scientists, as they enable them to share experiences. The author, who has been serving as an Associate Editor of the Brazilian journal Acta Cirurgica Brasileira over a long period of time, wishes to encourage physicians and researchers to submit their papers to medical journals. As we currently face the difficult battle against COVID-19 pandemic, physicians worldwide must team up and fight the virus for the safety of our future generations. Currently, the COVID-19 pandemic has not only negatively affected the lives of infected patients, their families, and health care professionals but has also brought the world and its economy to a halt. Medical science can be broadly divided into practice that is oriented towards the treatment of current patients and research about future medical issues. In terms of the latter, international medical journals offer a means to share research findings.I am Eiji Kobayashi, a Japanese surgeon and a researcher specializing in organ transplantation and regenerative medicine. I am also involved in the research and development of state-of-the-art medical devices. Ever since accepting an offer from Professor Edna Montero, I have been serving as an Associate Editor of the journal Acta Cirúrgica Brasileira for over 20 years, and to date, I am the only Japanese Associate Editor. Meanwhile, Acta Cirurgica Brasileira has grown to be an internationally recognized journal, and its impact factor has been gradually increasing, reaching almost 1.0 recentlyA large number of scientists who are currently engaged in fighting the novel coronavirus may be finding their research activities significantly restricted. To protect ourselves from getting infected, we may need to publish our research findings by submitting our papers to journals while staying at home, and not while working at our affiliated institutions.Brazil and Japan have a long history of interactions, such as cultural exchanges. In the context of surgeons, we must not forget Professor Masayuki Okumura who performed clinical small bowel transplantation at the University of Sao Paulo when organ transplantation therapy was in its early stagesTo many people, however, one of the most famous common aspects of our cultures may be soccer. In the old days, Kazuyoshi Miura, a soccer player who is still active in Japan, travelled alone to Brazil at the age of fifteen to become a professional soccer player there. Recently, a Japanese soccer player Keisuke Honda, who was born and raised in Japan, was reported to have joined a Brazilian club.I have had opportunities to interact with Professor Edna Montero through the International Society for Experimental Microsurgery (ISEM) over the years. At the Conference of the Brazilian Society for the Development of Surgical Research (SOBRADPEC) held in Natal in 2005 , I propoTo increase the journal's readership and to ensure its international success, I believe that we, the editors, are required to make every effort to review the submitted manuscripts carefully, to publish logically sound papers, and also to publish reviews that aim to describe the future of surgical medicine.I sincerely hope that young surgeons of the next generation will make advances by submitting their manuscripts to our journal and become scientists who can think globally. Finally, I would like to suggest that we, the health care professionals, along with the patients affected by the severe COVID-19 and their family members, must team up and strive to fight against the virus.


The world is experiencing an unprecedented global pandemic of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2). Development of new vaccines and therapeutics are important to achieve long-term prevention and control of the virus. Experience gained in the development of vaccines for Ebola virus disease provide important lessons in the regulatory, clinical, and manufacturing process that can be applied to SARS-CoV-2 and other epidemic pathogens. This report outlines the main lessons learned by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) during development of an Ebola Zaire vaccine (ERVEBO®) and looks ahead to critical lessons beyond vaccine development. It highlights focus areas for public-private partnership and regulatory harmonization that can be directly applied to current vaccine development efforts for SARS-CoV-2, while drawing attention to the need for parallel consideration of issues beyond development that are equally important to achieve global preparedness and response goals. Zaire ebolavirus started in West Africa and was declared a Public Health Emergency of International Concern in August of that year. By the time the outbreak ended in 2016, more than 11,000 people had died and more than 28,000 people were infected primarily in three countries, Guinea, Liberia, and Sierra Leone1.First discovered in the Democratic Republic of the Congo in 1976, the highly lethal Ebola virus has infected people in a number of African countries leading to sporadic outbreaks of Ebola virus disease over the past 40 years. While most of the outbreaks have been limited in geographic scope and number of cases, two of the outbreaks over the last 6 years have been large, resulting in major loss of life and socioeconomic disruption in the region. In early 2014, an outbreak of Ebola virus disease caused by 2. These vaccine candidates were not taken into clinical development prior to the West African outbreak for several reasons, which included the inability to demonstrate clinical efficacy in the absence of an ongoing outbreak and lack of interest by the public health and vaccine development community to invest in the lengthy and costly process of vaccine development without a clear demand for an Ebola vaccine2. The West African outbreak changed this perspective and numerous vaccines entered clinical development during the outbreak resulting in the generation of safety and immunogenicity data for many of these novel vaccine candidates and the demonstration of efficacy for one vaccine3.In the decade prior to the West African outbreak, research efforts for biodefense purposes resulted in the identification of some promising Ebola vaccine candidates that protected monkeys from a lethal challenge of wild-type Ebola virusZaire ebolavirus. Extraordinary efforts were made to advance this vaccine candidate through Phase 1, 2, and 3 clinical trials and the data generated in the context of the West African Ebola outbreak has supported its licensure by the US Food and Drug Administration (FDA), conditional authorization by the European Medicines Agency (EMA) and several African countries, along with prequalification by the WHO. The period of 5 years from the start of Phase 1 trials in Oct 2014 to the approval of this vaccine in Nov 2019, was much faster than the typical 10–15 year timeline for vaccine development and approval4. A timeline of the key activities in the development of this Ebola vaccine is summarized in Fig. ERVEBO® is a live, attenuated, recombinant vesicular stomatitis virus (rVSV)-based, chimeric-vector vaccine, where the VSV envelope G protein was deleted and replaced by inserting only the envelope glycoprotein of This Ebola vaccine was initially designed as a biodefense vaccine by scientists at the Public Health Agency of Canada (PHAC). Preclinical studies performed by PHAC and their collaborators demonstrated that a single-dose of the vaccine candidate was highly efficacious in animal models. In preparation for potential clinical studies or emergency use, PHAC partnered with IDT Biologika to prepare GMP supplies. Beginning in the autumn of 2014, a diverse set of public-private partners mobilized to collaborate on the evaluation and development of the vaccine candidate. The global collaboration spanned a broad range of organizations, including national governments ; various agencies ; field response and non-governmental service organizations (such as Medecins Sans Frontieres); global public health entities ; Universities  and private sector companies .Each of these entities had a specific role in the broad partnership, including conducting preclinical studies, manufacturing Good Manufacturing Practices (GMP) trial materials, conducting clinical trials, and funding portions of the research and development. MSD has a well-established history in manufacturing and clinical development of vaccines, with experience in taking novel vaccines through the regulatory process to approval and providing global access. However, MSD did not have prior experience with Ebola virus nor clinical development expertise in the African countries in which the Ebola outbreak was taking place. Therefore, MSD relied on the expertise of organizations that were already involved in the public health response efforts to implement and complete nearly all the clinical trials. Important lessons from this effort are that leveraging the expertise of different organizations can help to accelerate product development and that broad public-private partnerships require strong leadership and coordination to facilitate cooperation of diverse partners with different expertise and missions.5. Therefore, clear and transparent communication with community leaders and the community at large, ethical review committees, local ministries of health, and other government agencies is critical to ensure that the purpose of the research is well understood and aligned with accepted local and international norms. Failure to do so can result in delays or roadblocks to research on potentially life-saving products.Furthermore, concerns over evaluation of any investigational product are present in less developed parts of the world and these concerns may be further exacerbated during an outbreakUltimately the responsibility to convert the data generated by all the collaborators into a coherent regulatory submission to support licensure of a product lies with the Marketing Authorization Holder. Recognition and proactive planning for that eventuality can help to accelerate the regulatory submission to support product approval. Examples of these types of activities include the following.MSD’s role in advancing the product to licensure included integrating all the data generated by partners to support the marketing authorization applications. Nine of 13 nonclinical studies, 1 of 2 clinical assay validations, and 11 of 12 clinical trials were performed by partners. MSD needed to obtain all the datasets and reports from these partners to include in the license applications. Data from clinical trials that were performed by partners needed to be migrated into a central database that could be used for data integration, analysis, report-writing, and submission by MSD to regulatory agencies. A lesson learned during this process is to account for the time needed to convert different formats and languages used to collect the data into standard formats required by regulatory agencies, such as use of the Medical Dictionary for Regulatory Activities (MedDRA) and Study Data Tabulation Model (SDTM).With the clinical trials all being designed and implemented in the context of the outbreak, it was not possible to harmonize the study designs. While this is not an issue a priori for the conduct of the trials, it introduced challenges when assembling the data to support licensure. For example, it was not possible to conduct extensive integration of the safety data for the product because the data collected and methods used were different for each trial. A key lesson learned during this process is that standardization of clinical trial protocols and data collection is preferred, and that to the extent possible late stage clinical trial designs should be defined prior to outbreaks. Another challenge specifically related to conducting trials in response to emerging diseases is that there is a need to build clinical development capacities, laboratory and adverse event reporting infrastructure in outbreak-prone regions. This was a challenge taken on by individual trial sponsors in the affected countries and required significant and sustained support by the trial sponsors and their local partners. Establishing mechanisms to maintain the capabilities established during outbreak response to provide experienced clinical trial sites for future research is another key lesson learned. Examples of this in action include the ongoing partnership between the US and Liberia and the Partnership for Research on Ebola VACcination (PREVAC) consortium established in the wake of the West Africa outbreak.A key immunogenicity endpoint assay was developed and validated through a collaborative effort by private and public sector partners. The intent was to provide an assay available to all vaccine developers, which might ultimately allow comparison of different vaccine candidates. While the collaborative effort was successful, balancing the input of numerous partners took time. Consequently, clinical assay validation took two years to complete, resulting in a back-log of samples from clinical trials that needed to be processed. A lesson learned is that whenever possible clinical immunogenicity sample collection should be standardized and assays should be validated prior to the start of late stage clinical trials. This requires knowledge of the target pathogen well in advance of clinical trials, which is a challenge for SARS-CoV-2.6. A lesson learned is that the deployment of an investigational product requires careful consideration and thorough planning.With the rapid collection of efficacy data in support of the vaccine, it was recognized that there was the possibility that new Ebola outbreak(s) could occur ahead of the licensure and availability of licensed doses and that a mechanism was needed to support access to the investigational product. For this scenario, it was necessary to manufacture doses to support outbreak response and establish regulatory frameworks needed to support vaccine deployment . The WHO, MSF, and other groups took the lead in implementing expanded access protocols in African countries, working closely with national governments and ministries of health. Through this effort, more than 300,000 people were vaccinated during the 2018–2020 Ebola outbreak in the Democratic Republic of the CongoThe manufacturing process had to be rapidly scaled-up to handle the needs for emergency use and expanded access programs, in addition to establishing a final manufacturing facility. The approach taken by MSD was to take the initial manufacturing process that was developed at a contract manufacturing organization, scale it up in a clinical manufacturing facility, and transfer it to a commercial manufacturing facility. Technology transfer and the establishment of a new manufacturing facility has many steps and requires significant time to execute . There is limited understanding outside of vaccine manufacturers and regulators on the rigorous requirements leading to approval of a vaccine manufacturing facility. This broad lack of understanding can lead to misperceptions of “delays” when in fact timelines are driven by the elements required for licensure. For example, although clinical data were available in 2017–2018, the vaccine could not be approved until the commercial manufacturing site was established due to expectations from regulatory agencies that the manufacturing process needs to be validated at the final manufacturing site. A lesson learned is that education is needed on how vaccines are manufactured and the time needed to establish and gain approval for a new manufacturing facility. This is particularly relevant for the COVID-19 outbreak where all aspects of vaccine development are being accelerated at an extraordinary pace with the goal of being able to produce unprecedented quantities of vaccine to address global needs.Manufacturing site selection for vaccines is a complex decision, which is further complicated when seeking to move fast with incomplete information. The company needed to manage multiple factors, such as existing space, technical capability, infrastructure, and capacity. Site selection also needed to account for the regulations in the country in which the manufacturing site is located and the permits and licenses necessary to support the efforts. The country’s employment environment and labor laws can also impact the ability to hire qualified staff quickly where these factors need to be considered early. A lesson learned is that aggressive timelines are enticing for public health partners, but also require “right-first-time” execution to qualify the facility and manufacturing process, for which the probability of success for a new vaccine is likely medium to low. All parties involved must work to balance the desire to be ambitious  with execution realities and stakeholder expectations. Parallel work and extensive collaboration between manufacturers will be needed in order to successfully bring a SARS-CoV-2 vaccine to the world.From the start of the West African Ebola outbreak, the US FDA, EMA, and Health Canada worked closely with each other and with the National Regulatory Authorities of the impacted West African countries, sharing information about candidate vaccines that were being tested and reviewing the clinical protocols, available data, and benefit-risk profiles. Frequent conversations with manufacturers helped the agencies expedite the start of clinical trials simultaneously in different countries. A lesson learned is that existing preclinical data and availability of clinical supplies afforded the opportunity to start Phase 1 trials rapidly during the West African Ebola outbreak.7. Efficacy data from this trial, together with safety data from 12 trials and immunogenicity data with validated assays, were accepted for registration by regulatory agencies. A lesson learned is that the regulatory pathway to licensure for pandemic vaccines need to be clearly defined. Novel trial designs might need to be implemented in order to maximize the possibility of evaluating efficacy during a waning outbreak, and alternative endpoints, such as using immune responses as a surrogate for efficacy, could be used to gain accelerated approval or conditional marketing authorization.Placebo-controlled, randomized, double-blind studies are typically used to demonstrate the efficacy and safety for new vaccines. However, in the midst of the Ebola outbreak, some countries considered it unethical to administer placebo to at-risk individuals. Different study designs were implemented for the Phase 2/3 trials and a cluster-randomized trial conducted by the World Health Organization in Guinea was the only trial that demonstrated efficacyBased primarily on interim clinical efficacy data, the manufacturer applied for and was granted access to expedited regulatory pathways, such as Priority Medicines (PRIME) status from EMA and Breakthrough Therapy Designation (BTD) from FDA, which helped to obtain alignment on data requirements for product approval using frequent meetings. Under BTD, the FDA accepted rolling submissions of portions of the Biologics License Application (BLA), which resulted in approval in December 2019, three months before FDA’s target approval date. The FDA determined that a program specific advisory committee meeting was not needed. Similar frequent discussions with EMA under PRIME status, enabled the company to gain alignment on key aspects of the development program quickly.8. This allowed the company to make simultaneous submissions to EMA, WHO-PQT, and regulatory authorities in 14 African countries, with EMA acting as the reference agency. Following submission, the WHO-PQT and members from AVAREF, which represented the 14 African countries, were invited to participate in teleconferences between MSD and EMA and in the inspection of the manufacturing facility. After a positive opinion from EMA in October 2019, the European Commission granted a conditional Marketing Authorization on November 11th. Within 36 h, the WHO granted prequalification. One month later, African countries started to approve ERVEBO®, starting with Burundi and the Democratic Republic of the Congo. A lesson learned is that strong collaboration and willingness to share information with everyone involved resulted in registration nearly-simultaneously in the countries that needed the Ebola vaccine. For SARS-CoV-2 vaccines, regulatory agencies should prepare for the simultaneous approval of candidates in multiple countries. WHO’s leadership will be needed to facilitate innovative review processes and collaborative mechanisms to expedite approvals.WHO is a recognized global public health leader with regional offices in many countries, and established connections with the African Vaccines Regulatory Forum (AVAREF). In order to accelerate vaccine access to African countries, the World Health Organization’s Prequalification Team (WHO-PQT) in collaboration with the EMA and AVAREF developed an innovative facilitated process (roadmap) for decision making on the acceptability of the vaccine for registrationSince this Ebola vaccine was a recombinant virus, some countries required a detailed environmental risk assessment prior to the start of clinical trials and as part of the marketing authorization application. In some countries, the vaccine was considered a Bio-Safety Level 2 organism, requiring special handling and permits for the manufacturing and testing sites. These permits took a significant amount of time to obtain, which prevented rapid transfers of material. Samples and technology, which even included parts of the marketing authorization application, required licenses for export because this vaccine is made from the genetic sequence of two viruses that are considered “dual-use” agents and subject to trade controls. A lesson learned is that these regulations led to delays and additional costs incurred in starting clinical trials, manufacturing, testing, and shipments. For manufacturers of SARS-CoV-2 vaccines, countries should consider waiving these requirements, or waiving the fees and expediting these processes.After approval, companies face challenges with product distribution due to the need to follow country-specific product labeling regulations covering package inserts, cartons, and artwork in addition to serialization requirements. This causes a supply chain issue for a vaccine product intended to be placed in a stockpile and diverted quickly to any country. A lesson learned is that these heterogenous requirements counter the goal of flexibility, speed, and cost-efficiency relevant to emergency preparedness, and there is an urgent need for harmonized solutions. Electronic labeling and Quick Response (QR) codes could be a possible solution, but in most countries, legislation does not currently exist to support this option. There is an urgent need to find a solution to this problem for pandemic vaccines.In addition to considering lessons related to vaccine development for epidemic preparedness, it is equally important to consider the unique challenges and opportunities related to sustainable manufacturing, supply, access, and delivery of these vaccines at the scale and speed needed to achieve preparedness and response goals. Such challenges include right-sizing manufacturing capacity and production while having to accommodate lead-times, managing uncertain demand-and-supply dynamics, ensuring equitable allocation and access, and achieving operational and economic sustainability for all partners. Producing and supplying any vaccine is inherently complex. It is exponentially more complex when there are high levels of uncertainty and unpredictability across nearly every dimension of the program: unpredictable disease, unpredictable and relatively low demand, unpredictable stakeholders and customers, unpredictable timing of need, and unpredictable geographies in which needs might arise. Policy, program, and system innovation—in parallel to research and development innovation—needs to be addressed to realize the full promise of innovative, new vaccines in advancing global public health preparedness.Emergency preparedness and response vaccines, such as ERVEBO®, are critical tools in the arsenal against pathogens that can cause pandemics. Public-private partnerships are a powerful and effective approach to develop these vaccines. Setting clear roles, expectations, and accountability enables each partner to bring their respective strengths to the effort. Shared purpose, trust, flexibility, and cooperation are critical to ensure success.9, the variability and complexity in regulatory processes and requirements interfere with the speed, flexibility, and efficiency needed to prepare for and respond to public health emergencies. There is an urgent need for global regulatory harmonization and standardization in the approach to the development of vaccines for emergency preparedness. Regulatory agencies need to work together to remove roadblocks and put solutions in place to allow the rapid global development of vaccines for SARS-CoV-2 and other emerging pathogens.As highlighted in this report and in another recent article