Snakebite envenoming is a serious global public health problem, and international initiatives, under the coordination of the World Health Organization and its regional offices, are being developed to reduce the impact of this neglected tropical disease. The global availability of safe and effective antivenoms is one of the key aspects in this global strategy. This review discusses the role of public antivenom manufacturing laboratories for ensuring the supply of antivenoms. The difficulties faced by public laboratories are discussed, together with some tasks that need to be implemented for strengthening them. In addition, the concept of ‘redundancy’ in the supply of antivenoms is emphasized, as a way to cope with the risks associated with the provision of antivenoms by few manufacturers. In general, the public sector should play a leading role, in antivenom availability and other aspects as well, within the global struggle to reduce the mortality and morbidity caused by snakebite envenoming. Snakebite envenoming is a highly relevant public health problem on a global basis that kills and maims several hundred thousand people every year ,2. It haAs a further development, the 71st World Health Assembly, celebrated in Geneva in May 2018, adopted a resolution proposed by 22 countries from five continents, with the leadership of Costa Rica and Colombia, aimed at addressing the burden of snakebite envenoming on a global basis. This historical resolution urges member states to take immediate actions on several lines, with the aim of reducing the burden of this disease. These include: (a) Assessing the magnitude of the problem on a global basis; (b) improving antivenom availability, accessibility, and affordability; (c) promoting transfer of knowledge on this topic between member states; (d) integrating control of snakebite envenoming with efforts to control other diseases; (e) improving access to treatment and rehabilitation services to affected people; (f) providing training to health professionals in the diagnosis and treatment of envenomings; (g) supporting research activities on several aspects of snakebite envenoming; (h) promoting community awareness through culturally contextualized public campaigns; and (i) fostering of cooperation and collaboration between member states, the international community, and other relevant stakeholders. Likewise, this resolution established a number of requests to the Director General of the WHO on this health issue , strengthening the national regulatory agencies, and ensuring an appropriate characterization of the neutralizing efficacy and safety of antivenoms through preclinical and clinical research ,16. In tAccording to the WHO webpage on antivenoms , there a2 fragments as the active substance, by fractionating hyperimmune plasma with a combination of pepsin digestion and salting out procedures. Other products are made of whole IgG molecules, usually obtained by caprylic acid precipitation of non-immunoglobulin plasma proteins, and one manufacturer produces Fab antivenoms by digesting the immunoglobulins from ovine plasma with papain [The heterogeneity of this universe involves not only the volume of production and scope of distribution, but also differences in some technical aspects of antivenom design and production. Most manufacturers use horses for immunization, although one uses sheep , and anoh papain . Producth papain .Besides these variations in the design, and in the immunological and physico-chemical characteristics of antivenoms, there are marked differences in the situation of the infrastructure, laboratory equipment, qualification of technical and professional staff, implementation of GMPs, innovation, and in-process and final quality control of the products . Some maThe public health arena has witnessed significant shifts in the conceptualization of health in the last five decades. The concept of health as a ‘commodity’, within the context of a market-driven economy, has been fostered, together with trends in developing countries’ governments to reduce the public expenditure in health and other social services . NevertIn this global context, public antivenom manufacturing laboratories have faced significant challenges in the last decades. Public manufacturers of antivenoms were created in many countries during the past century and represent invaluable institutional assets, constituting scientific, technological, and public health patrimonies. In the Americas, the first public institution in charge of manufacturing antivenoms was Instituto Butantan, created in 1901 in São Paulo, Brazil . Then, sSeveral workshops of public antivenom manufacturing laboratories have been organized in Latin America during the last decade to discuss the situation of antivenom production in the region (see for example Ref. ), and exMany public laboratories in charge of antivenom manufacture lack innovation through research and development. Many have not modified the basic technological platform for plasma fractionation and for in-process and final quality control. An example is the improvement in the design of the most adequate combinations of venoms for immunization. Most of the combinations currently used were selected decades ago on the basis of rather empirical criteria. In the last decade there has been an enormous volume of knowledge generated on the biochemistry of snake venoms, including their proteomics, as well as on the cross-reactivity of antivenoms, by using neutralization tests and immunochemical methods, particularly antivenomics ,27,28. LThe immunization protocols require a thorough revision and innovation in aspects such as selection of venom doses to be injected, method of injection , use of novel adjuvants, schedule of venom injections as to avoid the immunosuppressive effects that some venoms exert over others, and a more detailed control of animal health status during immunization. Moreover, the protocols for animal bleeding can be improved through innovation in aspects such as the use of automated plasmapheresis equipment.There are plenty of possibilities to innovate in the technologies used for hyperimmune plasma fractionation in order to generate products of higher purity and better physico-chemical characteristics. Plasma processing groups should evaluate the steps in their fractionation protocols in order to optimize them. As an example, the introduction of caprylic acid fractionation instead of ammonium sulfate precipitation in the preparation of whole IgG antivenoms should be considered . LikewisThere has been a notorious lack of investment in infrastructure and equipment in many public antivenom-manufacturing laboratories. Owing to the growing financial limitations of public institutions and governments along the last decades, some of these laboratories have lagged behind in the need to update their infrastructure and to replace old equipment, with the consequent negative impact in antivenom production. Likewise, maintenance programs for equipment are limited. This has placed a number of laboratories at the brink of shutting down their operation. The solution to this situation demands creative political decisions in order to reinvigorate the financial support for these public laboratories by governments. There are notorious contrasts in the political will of governments of countries in the support of antivenom laboratories. In addition, institutions need to consider the development of public–private partnerships that may contribute to the upgrading of these laboratories. Likewise, international funding agencies in the field of public health should consider supporting public antivenom-manufacturing laboratories of long-standing tradition. The strengthening of public laboratories in various parts of the world is a safeguard for guaranteeing antivenom availability in the midst of ups and downs associated with a market economy.Public antivenom manufacturing laboratories are often understaffed, as a consequence of restrictive policies in governmental institutions. Moreover, there is a deficit in programs aimed at the permanent training and qualification of the existing personnel, which limits innovation. The possibilities for technical and professional staff to attend workshops, courses, and symposia are scant. This trend has to be reverted by establishing permanent training programs, adapted to the needs of the staff of manufacturing laboratories. Such training activities can be coordinated with local universities and other public and private institutions, and funding must be allocated for these activities. Likewise, seminars and group discussions of advances in the field and novel technological developments need to be organized, and an innovative environment should be stimulated within these laboratories. In Latin America, a group of public laboratories have integrated a regional network in which regular workshops have been organized. These activities have had a significant impact in the overall improvement of antivenom availability in the region . In WHO Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins [One aspect that requires urgent attention in these institutions is the implementation of GMPs at all levels in the chain of antivenom production. For this, professional and technical staff should receive training based on international guidelines, including the lobulins , and theThe tasks described could be achieved more successfully within a frame of international cooperation. To this end, the WHO and its regional offices have a leading role to play by establishing permanent programs for improvement of antivenom production and quality control, based on the diagnosis of the situation of these laboratories. These programs can involve regional workshops and seminars, as well as a variety of activities aimed at enhancing the capacity of manufacturers. At the same time, a dynamic networking activity should be fostered between manufacturing and quality control laboratories, regulatory agencies and research groups in universities and other institutions. For this, the use of information and communication technologies offers great possibilities. In Latin America, the network of public antivenom manufacturing laboratories has established an informal dynamics of inter-group consultations on specific aspects, which has become a useful mechanism for trouble shooting in antivenom production. Technology transfer projects and cooperation contribute to the upgrading of antivenom manufacture in public laboratories.The deficit in resources and personnel is often associated with weak managerial practices which hamper the productivity of these laboratories. Aspects such as estimation of production costs, purchasing and maintenance programs, administration of inventories, organization of the flow of activities, efficient allocation of staff in the production departments, distribution and marketing of antivenoms, and quality assurance programs need to be introduced, evaluated, and improved aiming at increasing the efficiency of antivenom manufacture. Likewise, preparation of strategic development plans and their follow up have to be considered. Overall, modern managerial and organizational procedures should be implemented in order to maximize the use of available resources. The appropriate selection of personnel in charge of managerial roles is of key relevance, as well as the differentiation of the profiles and suitability of people selected for managerial roles and those in charge of the more technical functions in antivenom manufacture.A crisis that took place in Brazil in the 1980s vividly illustrates the relevance of public institutions, including antivenom manufacturers, in ensuring the availability of antivenoms for health systems and the overall attention to snakebite envenoming. Antivenom production in Brazil started with the foundation of Instituto Butantan, in 1901, under the leadership of Vital Brazil Mineiro da Campanha. Then, in 1907 the Fundação Ezequiel Dias (FUNED) was created in Minas Gerais and, in 1919, Vital Brazil moved to Niteroi, State of Rio de Janeiro, to establish antivenom production at Instituto Vital Brazil. These three public manufactures developed over the next decades; however, at some point in the second half of the 20th century there was a reduction in public investment and innovation in this antivenom-manufacturing industry. By the 1970s, a multinational pharmaceutical company (Syntex do Brasil) was providing the majority of vaccines and antivenoms being used in Brazil. In 1973, the Brazilian government created the National Immunization Program, to take charge of the national immunization programs and the provision of antivenoms as well. This was followed in 1980 by the creation of the Instituto Nacional de Controle de Qualidade em Saúde . INCQS detected important flaws and deficiencies in the biological products, including antivenoms, and the production of immunobiologicals was halted. As a consequence, Syntex do Brasil decided to permanently stop the manufacture of antivenoms and vaccines, creating a serious national crisis in the supply of these products, since the public laboratories at that point had limitations and were unable to cope with the national demand ,32.In this context, the Brazilian federal government decided to create the National Self-Sufficiency Program in Immunobiologicals, with the goal of making this country self-sufficient in the provision of these essential vaccines and antivenoms, a wise political decision that has had long-term consequences for public health in Brazil. As a follow-up step, a committee for the study of envenomings and the production and testing of antivenoms was created. It was responsible for defining the most adequate combination of venoms to be used in the manufacture of antivenoms, the standardization of the potency tests for assessing antivenom efficacy, and the establishment of reference venoms for the most important snake species, to be used by manufacturers and quality control laboratories. Simultaneously, in 1985, a large investment by the federal government was implemented with the goal of making Brazil self-sufficient in antivenoms and several vaccines. This allowed the national public manufacturing laboratories to develop new infrastructure and significant technological improvements in their facilities. Behind this policy lay the belief that the country should be self-sufficient in the manufacture and distribution of life-saving antivenoms and vaccines through the work of public laboratories.In addition, a national surveillance system for documenting envenomings by bites and stings of animals was developed, together with a national policy of antivenom and vaccine distribution in charge of the National Program of Immunization. Since 1986, antivenom acquisition is centralized by the Brazilian Ministry of Health, and distribution is decentralized to the states and municipalities, which allows free-of-charge availability of antivenom treatment. The production of antivenoms at a national level is coordinated between the Ministry of Health and the four manufacturing laboratories . Likewise, an active research program in public universities and institutes was strengthened, including basic research in the biochemistry, toxicology, and immunology of animal venoms, as well as epidemiological and clinical studies on envenomings and their treatment. In other words, the country decided to control the problem of envenomings by animal bites and stings through a well concerted and supported public program which has consolidated over the decades, and has made this country self-sufficient in the provision of antivenoms and some vaccines, and a leader in toxinological research. For a detailed account on these developments, see Refs. ,32, and This brief historical account provides several lessons: (a) The dependence of a single manufacturer for the provision of an essential medicine, such as antivenom, puts the public health system of a country in a vulnerable position, as this Brazilian experience shows. (b) The public health authorities and, in general, governments should have a leading role for ensuring the availability and accessibility of antivenoms in public health systems. (c) The concept of ‘redundancy’ in the provision of antivenoms is very well illustrated in this historical example. Brazil has four public laboratories in charge of antivenom manufacture, with different scales and volumes of production, which ensure a steady national supply in close coordination with the Ministry of Health. The benefit of this redundancy is evident when, for technical reasons, one of these laboratories needs to temporarily stop production to carry out maintenance works or remodeling of infrastructure. In those circumstances, the other laboratories provide the necessary volume of antivenoms for the country’s needs. (d) The four laboratories have a close coordination in their activities under a frame of cooperation, hence contributing to the solution of problems that may arise in any of them. (e) This inter-laboratorial coordination with the Ministry of Health ensures that antivenoms manufactured by any laboratory have the same potency and quality control specifications, and all batches of antivenom are evaluated by the INCQS. In summary, the experience of Brazil represents a clear example of the impact of consistent public policies over decades for ensuring the national production and self-sufficient supply of antivenoms.It must be stressed that no single strategy in the field of antivenoms can be recommended for different countries and regions, since the local contexts greatly differ, and appropriate solutions have to be devised for each situation. For example, the concept of redundancy may apply to the combination of private and public, as well as national or international, manufacturing laboratories, and the variable scales of needs and production may demand different approaches, i.e., some countries do not have the conditions to develop their own antivenom-producing laboratories, hence having to rely on manufacturers from abroad. However, the basic idea of redundancy and the need for a strong commitment of public institutions and governments for ensuring antivenom availability remain as key components in the global efforts to reduce the impact of snakebite envenoming. Likewise, ministries of health should have national regulatory agencies with the capacity of evaluate the safety and efficacy of antivenoms produced in the country or imported. Overall, the public sector has to play a leading role in this field, as well as in other aspects of the control of snakebite envenoming.Bothrops asper, Crotalus simus, and Lachesis stenophrys [Bothrops jararaca, B. jararacussu, B. neuwiedi, B. alternatus, and B. moojeni [Bothrops atrox, B. barnetti, B. pictus, B. brazili, and Bothrocophias hyoprora [The concept of redundancy in the availability of antivenoms is well illustrated in the case of Latin America and the Caribbean. Several polyspecific and few monospecific antivenoms are manufactured in the region, with two laboratories (one public and one private) in Argentina, Colombia, and Mexico, four public laboratories in Brazil, and one public laboratory in Bolivia, Peru, Venezuela, and Costa Rica ,19. In aenophrys . On the  moojeni , whereashyoprora . Other chyoprora .Agkistrodon, Atropoides, Bothrops, Bothriechis, Cerrophidion, and Porthidium have demonstrated an extensive pattern of cross neutralization of several of these antivenoms [Bothrops asper, B. atrox, B. jararaca, B. neuwiedi (diporus), and B. neuwiedi (mattogrossensis), polyspecific antivenoms produced in Argentina, Brazil, Bolivia, Peru, Colombia, Costa Rica, and Mexico are effective in the neutralization of lethal, hemorrhagic, coagulant, and myotoxic effects of these venoms, albeit with different values of Median Effective Doses (ED50) [Lachesis in the immunizing mixtures are able to neutralize venoms of the four species of Lachesis [Crotalus sp venoms, two different patterns of venom composition have been described: type I venoms have a predominance of hemorrhagic metalloproteinases over the neurotoxic PLA2 dimer crotoxin, whereas type II venoms has a predominance of crotoxin and low amounts of metalloproteinases [Crotalus sp venoms in South America and Mexico, whereas antivenoms prepared by using type I venoms are effective in Central America and against non-neurotoxic venoms in North America [Despite the variations in the immunization mixtures, various preclinical studies on the neutralizing ability of antivenoms against a wide array of venoms from snake species of the genera tivenoms ,37,38,39s (ED50) ,40. LikeLachesis . Regarditeinases ,43. Thus America ,45,46.This body of evidence gives support to the use of several polyspecific antivenoms in different countries in Latin America. Hence, in the cases of countries that do not manufacture their own antivenoms , or those that may have deficits in their own supplies of antivenoms, several products from other countries can be used, thus constituting a scenario of regional self-sufficiency in antivenom supply. There is a need to further expand the studies on the preclinical efficacy of antivenoms in Latin America as to have a more complete view of the neutralizing spectrum of all antivenoms available in the region. This will help ministries of health and the Pan American Health Organization (PAHO) to know in detail which products could be used in which countries; this, in turn, could lead to regional purchasing schemes which ensure the regional availability of antivenoms. For example, polyspecific antivenoms from various manufacturers have been used in Central American countries, as well as in Colombia, the Guyanas, Paraguay, and Ecuador. This is an example of redundancy in the production and provision of antivenoms, an experience that could be replicated in other regions of the world.Micrurus antivenoms in the Americas, Atractaspis antivenoms in Africa and the Middle East, antivenoms against some ‘colubrid’ (sensu lato) venoms that can induce fatal accidents in Africa and Asia, and sea snake antivenoms in the Indo-Australian region. These and other ‘orphan’ antivenoms can be manufactured by public laboratories, under a non-for-profit scheme, and regional coordinated policies by the ministries of health and the regional offices of the WHO could be implemented in order to support their production and to organize distribution policies that ensure availability. Therefore, these antivenoms are relevant not only in the countries where they are manufactured and in those where related snake species are distributed, but they are also highly valuable in countries where exotic snakes are imported for private use, research, or exhibits, and antivenoms are required in the event of an envenoming.One niche where public antivenom manufacturers can play a key role in antivenom availability has to do with the manufacture of ‘orphan’ antivenoms, that is, antivenoms for the treatment of envenomings by species that inflict few, but potentially fatal, accidents; consequently, these antivenoms have a reduced market and low economic profitability. Examples are Micrurus antivenom by Instituto Clodomiro Picado, with the support of PAHO, during the 1970s [Micrurus antivenoms of wide neutralizing coverage, hopefully in the context of cooperative agreements between various laboratories. Likewise, antivenoms against the ‘colubrids’ Dispholidus typus and Rhabdophis tigrinus, and against sea snakes (Elapidae) are produced in South Africa, Japan, and Australia, respectively [An example was the development of a Pan-American he 1970s . Althougectively . Owing tAs stated in the Introduction, the global efforts to reduce the impact and suffering caused by snakebite envenomings demand a multi-component, multi-stakeholder strategy involving international and national public health authorities, the scientific and technological research community, antivenom manufacturers and quality control laboratories, national regulatory agencies, university schools in charge of medical and nursing education, local community organizations, non-governmental organizations (NGOs) and foundations that support health programs, health advocacy groups, and others, in order to achieve the goals included in the World Health Assembly’s resolution of May 2018 on snakebite envenomings and in the WHO strategic plan.A key component in this global agenda has to do with the improvement in the availability, accessibility, and affordability of antivenoms. For this, antivenom manufacture must be re-invigorated by initiatives aimed at augmenting provision of safe and effective products. An innovative approach is necessary in order to stimulate a steady growth in antivenom supply by (a) increasing the number of manufacturers worldwide through a policy of incentives; (b) elevating the volume of production by current and new manufacturers; (c) improving the quality of antivenoms by international cooperation networks and technology transfer schemes; (d) strengthening the national regulatory agencies to ensure that only appropriate antivenoms are introduced; (e) establishing financial programs for the consolidation of antivenom manufacturers; (f) introducing novel purchasing schemes that would favor a more stable market and create stimuli for manufacturers to increase their production; and (g) generating international cooperation platforms between antivenom manufacturing laboratories, research groups, health advocacy groups and foundations, and national and regional health authorities to improve antivenom availability and accessibility. Likewise, an increased availability of these products should be linked to interventions for improving their accessibility in remote rural regions where envenomings occur, and to train health personnel in the correct diagnosis and management of snakebite envenoming.To attain these objectives, and to follow the concept of redundancy in antivenom provision, an eclectic universe of manufacturers should be stimulated, including national, regional, and global producers with different scales of production and markets, involving public as well as private laboratories. Some antivenoms may be polyspecific and have a wide geographical range of efficacy, whereas others may have a more restricted regional scope, or be directed against the venom of a single snake species, depending on the particular needs of countries.Within this general landscape, public antivenom manufacturing laboratories have a relevant role to play. The invaluable expertise developed in these laboratories must be harnessed and upgraded, but the lack of political and economic support for many of them during the last decades threatens their productivity and even their existence. This trend should be reverted by ingenious and innovative programs supported by governments and international agencies. As discussed in this work, public laboratories constitute a safeguard for public health systems for the provision of antivenoms, as they are prone to resist the uncertainties of the market-driven antivenom manufacture and distribution.


Background: The Rwanda Human Resources for Health Program (HRH Program) is a 7-year (2012-2019) health professional training initiative led by the Government of Rwanda with the goals of training a large, diverse, and competent health workforce and strengthening the capacity of academic institutions in Rwanda.Methods: The data for this organizational case study was collected through official reports from the Rwanda Ministry of Health (MoH) and 22 participating US academic institutions, databases from the MoH and the College of Medicine and Health Sciences (CMHS) in Rwanda, and surveys completed by the co-authors.Results: In the first 5 years of the HRH Program, a consortium of US academic institutions has deployed an average of 99 visiting faculty per year to support 22 training programs, which are on track to graduate almost 4600 students by 2019. The HRH Program has also built capacity within the CMHS by promoting the recruitment of Rwandan faculty and the establishment of additional partnerships and collaborations with the US academic institutions.Conclusion: The milestones achieved by the HRH Program have been substantial although some challenges persist. These challenges include adequately supporting the visiting faculty; pairing them with Rwandan faculty (twinning); ensuring strong communication and coordination among stakeholders; addressing mismatches in priorities between donors and implementers; the execution of a sustainability strategy; and the decision by one of the donors not to renew funding beyond March 2017. Over the next 2 academic years, it is critical for the sustainability of the 22 training programs supported by the HRH Program that the health-related Schools at the CMHS significantly scale up recruitment of new Rwandan faculty. The HRH Program can serve as a model for other training initiatives implemented in countries affected by a severe shortage of health professionals. In the aftermath of 1994’s genocide, Rwanda was faced with the daunting challenge of rebuilding its devastated institutions and governance infrastructure, including the health system. Over the past 24 years, Rwanda has aggressively pursued excellence across all sectors  by incorporating a strong equity agenda into the national development plan, which was published in 2000 and is known as “Vision 2020.” This plan has paved the way for Rwanda’s subsequent development achievements, especially in health, which have included some of the steepest declines in premature mortality observed in recent history across countries and a dramatic increase in the uptake of maternal and child health interventions.2 The majority of practicing physicians, nurses, and midwives were lacking any kind of formal postgraduate degree while a shortage of faculty and limited infrastructure, equipment, and supplies in the country’s health graduate schools and teaching hospitals were preventing Rwanda from increasing the output and improving the quality of the existing training programs. It is to address the health workforce shortage and strengthen the capacity of its health graduate schools that the Government of Rwanda decided to launch the Human Resources for Health Program in Rwanda (HRH Program) in 2012.A core component of Vision 2020 is the establishment of a large, diverse, and competent health workforce. However, by 2011 Rwanda’s ratio of health professionals to general population of 0.72/1000 was still falling significantly short of the World Health Organization’s (WHO’s) recommended (at the time) target of 2.3/1000.3 The key features of the HRH Program are the product of broader changes and progress in the fields of global health and health workforce education over the past ten years.11 Many of these features are aligned with the United Nations’ Sustainable Development Goals, are shared with other US Government-funded health professional training initiatives in sub-Saharan Africa, and include: (a) alignment with responsiveness to local priorities; (b) country ownership; (c) strong stakeholder coordination; (d) funding flexibility; (e) competency-based training and pedagogic innovation; (f) institutional capacity strengthening; and (g) long-term sustainability.16 Similar features are also shared with the WHO’s Global Strategy for Human Resources for Health,17 the WHO’s Guidelines for Transformative Education for Health Professionals,18 and the 5-Year Action Plan for Health Employment and Inclusive Economic Growth by the Organization for Economic Co-Operation and Development, the International Labor Organization, and the WHO.19The HRH Program is an innovative and ambitious 7-year health professional training initiative led by the Government of Rwanda and funded by the US President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) and the Global Fund to Fight AIDS, Tuberculosis, and Malaria  with an initial budget of approximately US$150 million.a) increasing the number and competencies of Rwandan faculty; (b) strengthening the capacity of non-academic domains (such as management and administration or equipment and supplies) within the Ministry of Health (MoH), health-related schools, and teaching hospitals; and (c) pursuing additional academic partnerships and collaborations between Rwandan academic institutions and US academic institutions (a) present the activities conducted and milestones achieved by the program; (b) describe the challenges encountered during the program’s implementation; and (c) share good practices adopted and lessons learned by those implementing the program since 2012.The primary goal of the HRH Program is to train a large, diverse, and competent health workforce in Rwanda. The HRH Program also seeks to strengthen the capacity of academic institutions in Rwanda to sustain the training programs initiated and supported by the HRH Program by:  at the University of Rwanda and to the Nursing and Midwifery Schools in Rwamagana and Kabgayi. The CMHS was established in 2013 by bringing together different health-related schools under a single institutional umbrella and is comprised of 5 schools: the School of Medicine and Pharmacy , the School of Nursing and Midwifery (which has 4 separate campuses across the country), the School of Dentistry, the School of Public Health, and the School of Health Sciences  .The US academic institutions were selected by the MoH either because they had already been working effectively for years in Rwanda or because they had already expressed an interest in working in Rwanda and had established reputations as leaders in global health for their respective disciplines or clinical specialties. Because the HRH Program follows a tied-aid model, no academic institutions from countries other than the United States have joined the academic consortium since 2012.The visiting faculty are deployed to Rwanda for 2 to 12 months each year depending on departmental needs and specialty areas. Shorter deployments of 2 to 3 months generally correspond with sub-specialty areas while longer deployments of 6 to 12 months correspond with most clinical specialties and health-related disciplines. Upon graduation, the best performing Rwandan students are expected to be recruited as faculty by the CMHS and gradually replace the visiting faculty.The contributions of the US academic institutions are coordinated by the HRH Program management team within the MoH to maximize synergy and avoid gaps and overlaps in the resources and expertise provided to the CMHS . A steerWith support from The ELMA Foundation  the Clinton Health Access Initiative assisted the MoH in the first 2 years of the HRH Program with program design and the development of administrative, financial, and human resources policies and procedures. Since 2014, the MoH has had complete ownership of the HRH Program and is responsible for coordination and communication among stakeholders.3 The HRH Program was designed so that the MoH would utilize approximately 60% of the funds to cover salary, benefits, travel, and housing for visiting faculty through reimbursements to US academic institutions. The remaining funds are used to improve the equipment and supplies within the CMHS and the teaching hospitals and to support the HRH Program management team within the MoH. All of the US academic institutions agreed to charge an overhead rate of only 7% of their direct costs instead of the much higher rates usually charged for research grants to ensure that the majority of funds available are devoted to cover implementation costs in-country rather than to cover US-based administrative costs. While both the CDC and Global Fund began funding the HRH Program in 2012, the CDC (which covered approximately 70% of the costs) decided to cease funding after March 2017 because of a change in strategy which prioritized a more direct alignment between funding allocation and the pursuit of eradication of HIV/AIDS in Rwanda.Unlike other US bilateral and multilateral global health grants in low-income countries, funds for the HRH Program flow from the donors directly to the MoH rather than through an intermediary or directly to the US academic institutions .3 The HRhttps://www.journalslibrary.nihr.ac.uk/hsdr/hsdr04010#/table11.The authors decided to adopt an organizational case study design, which they believed would not be hindered by the limited amount of data collected in the years preceding this study and would be compatible with a post-hoc evaluation of the HRH Program. In conducting this study, the authors followed the guidelines and the checklist from the National Institute for Health Research for organizational case studies available at: a) Competency-Based Training and Pedagogic Innovations; (b) Changes in Governance and Administration of Training Programs; (c) Procurement of Equipment and Supplies; (d) Recruitment, Retention, and Career Development of Health Workforce in Rwanda; (e) Recruitment and Career Development of Rwandan Faculty; (f) Establishment of Additional Academic Partnerships and Collaborations. No ethics review approval was deemed to be necessary by the leaderships of the MoH and of the CMHS, based on their institutional requirements and policies, as the data collection and analysis for this manuscript fell under the category of “program evaluation.”The data for this organizational case study were collected through a variety of sources and methodologies including official reports from the MoH and the US academic institutions, databases from the HRH Program management team within the MoH, databases from the registrar’s office of the CMHS, and minutes from meetings and conference calls. Additionally, the authors were organized into working groups according to their discipline and clinical specialty and asked to complete a 63-item survey to capture descriptive data related primarily to the activities conducted and non-numerical milestones achieved by the HRH Program within the following programmatic domains: . For the Nursing and Midwifery Schools in Rwamagana and Kabgayi no student enrollment data was available at the time of the analysis. Therefore, the average number of graduates per year between 2013 and 2016 for the training programs offered by these institutions was used to infer the projected number of graduates for 2017, 2018, 2019. No correlation analysis was performed because of the difficulty of accounting for all additional variables linked to an individual milestone. Additionally, no analysis was performed to directly link the implementation of the HRH Program to more distal metrics of success such as improved health outcomes both within the teaching hospitals and across the health system.Since the launch of the HRH Program in 2012, 22 training programs (12 of which did not exist previously) have been supported across 4 health-related disciplines  . In the The majority of visiting faculty recruited and deployed to Rwanda have been graduates of North American academic institutions. In some instances (primarily for nursing and midwifery) the US academic institutions have also recruited and deployed visiting faculty from other sub-Saharan African countries, in order to ensure that the proper mix of technical knowledge and skills and understanding of local context and priorities would be available to stakeholders in Rwanda. Based on the analysis of 64 visiting faculty deployed by a sub-set of 7 academic institutions participating in the HRH Program , approximately 56% of visiting faculty were mid-career at the time of deployment (6-19 years since completion of training), 38% were junior (<5 years) and 22% senior (>20 years). Approximately 55% of the visiting faculty were deployed to Rwanda for six months or longer, and 52% returned to Rwanda at least one more year after their first year of deployment.The Schools at the CMHS have been able to increase the number of students enrolled across the 22 training programs initiated or supported by the HRH Program because of the increased number of faculty available through the US academic institutions. As a result, the HRH Program is on track to graduate an estimated total of 4598 students across these programs ; a signia) because of the need to devote the limited resources and expertise to the newly prioritized training programs; and (b) because new medical graduates opting to join the health workforce as general practitioners  were felt to already possess the proper knowledge and skills required to deliver basic medical, surgical, and obstetrical services.For the discipline of medicine, the training programs which were deprioritized  led to a total loss of 84 new physicians from the original target of 401 new physicians with specialty training, while the training programs which were newly prioritized (master’s degrees in neurosurgery and urology) added only 7 new physicians to the same original target . The MoHThe de-prioritization of the A1 (advanced diploma) to A0 (bachelor’s degree) nursing bridging program led to a loss of approximately 500 new nurses from the original target of 907 new nurses and midwives with bachelor’s degree. The MoH decided to de-prioritize the A1 to A0 nursing bridging program to devote additional resources and expertise to the 8 different tracks within the newly established master’s degree in nursing . In the case of the A2 (entry level) to A1 (advanced diploma) nursing and midwifery bridging program it was difficult for the School at the CMHS to sustain the high enrollment rates necessary to fully meet the ambitious original targets although the increase in training output remained substantial . StudentFor oral health, the higher number of projected graduates is explained by an effort by the School at the CMHS to meet new targets selected by the MoH for dental therapists and dental surgeons, which were higher than those originally selected for the HRH Program . For heaTo ensure their retention within the health workforce, and in exchange for government sponsorship during their training years, the MoH has enforced a mandatory 4- to 5-year contract of employment in the public sector for all new graduates. Additionally, visiting faculty have also supported the development and implementation of continuing professional development programs for practicing health professionals across the 4 health-related disciplines .Mandatory 4- or 5-year contracts for new graduates to work in public sectorContinuing professional development programs and sessions for practicing health professionalsPhysicians: cardiopulmonary resuscitation, child abuse, critical care, external and middle ear diseases, gastroenterology, hematology, emergencymedicine and acute care, infectious diseases, malnutrition, maxillofacial trauma, neonatology, non-communicable diseases, oral health, palliativecare, regional anesthesiaNurses and Midwives: advanced life support, basic life support, critical care, diabetes, evidence-based decision making, infection control,myocardial infarction, oral health, patient assessment and chart documentation, palliative care, viral hepatitisOral health professionals: evidence-based decision making, infection control, oral surgery, periodontology, prosthodonticsHealth administrators and implementers: executive leadership, global health deliveryBetween January 2012 and March 2017, 24 new Rwandan faculty and 31 tutorial assistants have been recruited by the Schools at the CMHS, 22 faculty have been recruited by the Schools of Nursing and Midwifery in Rwamagana and Kabgayi. As of March 2017, approximately 80 additional Rwandan faculty were expected to be recruited by the CMHS no later than by the end of the 2019-2020 academic year . The ratRecruitment of Rwandan faculty has required inter-sectoral partnership. The Schools at the CMHS, in the University of Rwanda, which reports to the Ministry of Education, have developed policies and procedures and secured funds to recruit new Rwandan faculty. Simultaneously, the MoH, which manages the HRH Program and developed the national strategy for health workforce development, has allowed the Schools at the CMHS to recruit some of these graduates as faculty rather than deploying them throughout the country.The HRH Program has strengthened the knowledge and skills of both Rwandan and visiting faculty by establishing a twinning program . Since 2012, Rwandan faculty have collaborated with visiting faculty on a variety of training, research, and health service delivery activities and have also benefited from continuing professional development programs developed and implemented with the support of the visiting faculty .100 Rwandan faculty and students have traveled to the United States to give lectures, participate in clinical clerkships, and pursue further training, while others have presented their work at national, regional, and international conferences. These activities have been funded by additional grants, not by the HRH Program, and highlight the importance of the additional academic partnerships and collaborations established since 2012. The US academic institutions have also benefited significantly from their participation in the HRH Program by providing opportunities to their own faculty and students to engage and pursue careers in global health and to learn and apply innovative approaches to pedagogy and health service delivery.16There are 19 US academic institutions participating in the HRH Program as of April 2017 (ranging from a minimum of 16 to a maximum of 24). Of the 5 academic institutions that have opted to leave the HRH Program since 2012, 2 did so because of changes in their departmental priorities, one because of the heavy administrative burden of managing their contribution to the program, and 2 because of ongoing challenges with the invoicing and reimbursement processes related to the program. The training, research, and health service delivery activities conducted by Rwandan and visiting faculty have led to more than 80 scientific publications .20-100 Ra) competency-based training and pedagogic innovation; (b) stronger management and administration of the training programs; and (c) improvements in equipment and supplies within the Schools at the CMHS and the teaching hospitals  across the health-related disciplines of medicine, nursing and midwifery, oral health, and health management and implementation. While increasing training output, the HRH Program has also sought to improve the quality of the training programs through:  the CMHS were often inconsistent and incomplete and extensive work went into reconciling differences and finding missing information . In retrospect, the resources and expertise available for monitoring and evaluation of the HRH Program were limited and did not enable the MoH and the other stakeholders to perform the needed systematic and in-depth evaluation of the HRH Program’s impact compared to the baseline. The prioritization in the budget (both by the MoH and the donors) of implementation costs, the simultaneous under-estimation of the costs associated with other critically important programmatic components , and the unprecedented scale and complexity of the HRH Program are the main reasons for the mismatch between needs and availability of resources and expertise. In the future, should health professional training initiatives similar to the HRH Program be implemented in other low-income countries, greater attention should be devoted to the establishment of a strong monitoring and evaluation platform. Additionally, all large-scale multi-year global health programs or interventions should include an implementation research component. Post-hoc evaluations conducted a few years after the launch of these programs or interventions, such as the one conducted for this study, are not designed to provide ongoing data-driven feedback to implementers, which is necessary to learn new lessons and improve the quality of implementation in real-time.Linking scale-up and improvement in the quality of training to improvements in the quality of health service delivery and in health outcomes  has been especially challenging. Additionally, the 63-item survey utilized to collect descriptive data did not include open-ended questions on perceived successes, opportunities, and challenges related to the HRH Program. As a result, the authors did not perform a thematic analysis  to identify recurrent themes in the responses provided by the co-authors or other participants in the HRH Program and consolidate them in an empirically validated list of lessons learned. The authors believe that the HRH Program would greatly benefit from a properly resourced external evaluation, which would look beyond the program’s activities and milestones presented in this article and focus instead on the program’s outcomes and more distal metrics of success . The same evaluation could also integrate a quantitative component with a comprehensive and detailed qualitative component through a mixed-methodology study design.Despite the study limitations, important good practices have been adopted and lessons have been learned by the authors  to guideRecruitment of visiting faculty was initially hindered by a limited pool of full-time senior and mid-career candidates, especially for the discipline of medicine, who were preferred by the Schools at the CMHS and by the students. However, if carefully selected and adequately mentored, junior visiting faculty can be equally effective while shorter durations of deployment for senior visiting faculty can be considered if continuity over multiple years is possible. Additionally, some visiting faculty initially struggled to transition to clinical practice in resource-limited settings and adapt to different professional habits and cultural norms. Serial revisions in the orientation training and the presence of a core group of returning visiting faculty have improved this transition but more needs to be done. For example, the HRH Program would benefit from the availability of more comprehensive and updated orientation materials that visiting faculty could review online prior to their deployment to Rwanda.88 Thus, leadership at the MoH and the CMHS recommended a revision of the twinning program in 2016 in which Rwandan and visiting faculty identify and conduct activities of shared academic interest and meet the objectives of the Schools at the CMHS and are then formally evaluated based on their ability to achieve these objectives. However, to this day, the revised twinning program has not been yet implemented broadly or uniformly across all Schools and Departments within the CMHS.Twinning between Rwandan faculty and visiting faculty has worked quite well at times. However, mismatched seniority levels, technical expertise, and academic interests between faculty twins, and difficulties protecting time for Rwandan faculty, as well as formal processes to evaluate and improve twinning, have been persistent challenges.Ensuring coordination and communication among many stakeholders has been difficult, especially in the early years of the HRH Program. It has taken several years to find the right balance between the role of the MoH, which manages the HRH Program and is the primary interlocutor with the US academic institutions, and the Schools at the CMHS, which are the primary recipients of the visiting faculty but whose line Ministry is the Ministry of Education. More importantly, both the Schools at the CMHS and the US academic institutions received insufficient funding for management and administration, which would have allowed them to improve communication and coordination and provide better mentorship and supervision to the visiting faculty. Additional funding would have enabled US based coordinators to travel to Rwanda to support the visiting faculty and establish closer ties with the academic leadership at the CMHS. Since 2012, coordination and communication has generally improved as meetings and conference calls with working groups for health disciplines and clinical specialties  are scheduled more frequently, although such improvement has been inconsistent, especially in the last 12 months, and challenges persist.Despite the positive impact of improvements in equipment and supplies within the Schools at the CMHS and the teaching hospitals, these have been insufficient to entirely address the existing gaps. Additionally, the Schools at the CMHS and the teaching hospitals have lacked the resources and expertise necessary to install and maintain the newly procured equipment which has led to delays and inconsistencies in its utilization. The MoH is now working to strengthen its supply-chain management, installation, and upkeep capacity.4 management of the funds has at times been challenging. Mismatches between fiscal years for the CDC, the Global Fund, the CMHS, and US academic institutions has made it difficult to process payments in a timely manner and track expenditures. Furthermore, funds have come with spending restrictions on critical items such as monitoring and evaluation, equipment, and supplies while renewal of donor commitment has occurred on a year-by-year basis and late within the previous academic year. These delays have hindered recruitment efforts from US academic institutions as numerous ideal candidates eventually have opted to seek other employment opportunities rather than wait until funds were secured.The flow of funds from donors to the MoH rather than directly to the US academic institutions has facilitated country ownership and alignment of the HRH Program to local priorities. Despite this novel funding model,Lastly, the decision by the CDC to cease funding for the HRH Program after March 2017 put a strain on the MoH, the CMHS, and its US partners and has led to approximately a 30% reduction in the number of full time equivalents for visiting faculty deployed to Rwanda for the 2017-2018 academic year compared to what had been originally planned. The number of visiting faculty to be deployed in the 2018-2019 academic year is yet to be finalized but will likely be similar. In the future, greater flexibility in funding expenditures and longer-term commitment from donors will be needed to ensure that initiatives such as the HRH Program achieve their full potential.As this organizational case study demonstrates, the resources and expertise available through the HRH Program have already strengthened the capacity of the Schools at the CMHS.However, the sustainability of these achievements will need to be pursued by all the stakeholders even more deliberately and aggressively. As a result, the academic leadership of the CMHS has finalized a sustainability strategy framework document with goals and objectives to strengthen the capacity of the Schools to sustain the training programs initiated or supported by the HRH Program. More detailed planning will now be needed to determine the precise amount of new Rwandan faculty to be recruited (and outline the process to recruit them), secure additional funds, and establish additional partnerships and collaborations with the US academic institutions that will continue after the HRH Program formally comes to an end.To ensure programmatic sustainability, the HRH Program was designed to gradually replace the visiting faculty with newly recruited Rwandan faculty, to be selected among the new graduates of the training programs initiated or supported by the program. While the transition between visiting faculty and Rwandan faculty has already begun, this effort will need to be scaled up substantially before the end of the HRH Program. Funding available through the Global Fund was utilized to maintain a core group of 56 visiting faculty in Rwanda for the 2017-2018 academic year and will be utilized to maintain a similar number of visiting faculty for at least one more academic year. Simultaneously, some of the responsibility for teaching junior students will also be delegated to adequately mentored and supervised senior students. Additionally, the MoH is considering extending funding for the HRH Program for 3 to 4 years beyond 2019 to ensure a more gradual transition between visiting faculty and Rwandan faculty.Once recruited, the new Rwandan faculty will need to be adequately supported by the Schools at the CMHS and by the visiting faculty, especially in the early stages of their career. The establishment of additional academic partnerships and collaborations with the US academic institutions and eventually the launch of additional training programs  will be critical to ensure that the newly recruited Rwandan faculty are able to further develop professionally and thrive academically.The Schools will also have to further strengthen their capacity across several non-academic domains, such as management and administration, finance, human resources, fund-raising and development. These domains are essential to a high-performing institution but are often overlooked by health professional training initiatives. In retrospect, even though the HRH Program sought to strengthen these non-academic domains, not enough resources and expertise where devoted to them. More importantly, when the HRH Program was first designed, not enough planning went into comprehensively and systematically determining the extent to which these domains needed to be strengthened and the timeline by which this would happen.Regarding the financial sustainability of the HRH Program, the cost of recruiting and deploying visiting faculty and procuring equipment and supplies within the Rwandan academic institutions accounted for the largest proportion of the overall budget. These costs were the highest in the earlier years of the HRH Program, when higher numbers of visiting faculty were needed in-country and the gaps in equipment and supplies were the greatest. The same costs have since decreased significantly now that Rwandan faculty have begun to replace visiting faculty and most of the planned improvements in equipment and supplies have been achieved.The primary costs that the MoH will need to sustain beyond the duration of the HRH Program will be those of the salaries for the increased numbers of Rwandan physicians, nurses, midwives, oral health professionals, and health managers that have joined or are expected to join the public sector. When the HRH Program was first designed, the determination was that the MoH would not need any external funding to cover these costs because of the projected increase in Rwanda’s gross domestic product (GDP) and in the percentage of government spending devoted to the health sector. This determination has not changed.The costs that the Rwandan academic institutions will need to sustain beyond the duration of the HRH Program will be primarily those of the salaries of the newly recruited Rwandan faculty but also the costs of subsidizing tuition fees for increasing numbers of students, further improving equipment and supplies, and further strengthening management and administration and other non-academic domains. While the Ministry of Education and the Schools at the CMHS have devoted additional funds to cover some of these costs, more funding will be necessary to achieve financial sustainability. Diversifying funding sources beyond the CDC and the Global Fund, strengthening the capacity of the CMHS to generate soft money through grants, and decentralizing fund-raising to individual schools and departments at the CMHS and their US partners will be critical. The schools at the CMHS and some of their US partners are already seeking additional funding opportunities, submitting proposals, and in some cases securing funds to sustain their work. However, these efforts will need to be scaled up substantially before the end of the HRH Program.3 Despite some persistent challenges, important lessons have been learned and good practices adopted by the MoH of Rwanda, the Schools at the CMHS, and a consortium of 19 US academic institutions participating in the HRH Program. The authors believe that the HRH Program can serve as a model for other initiatives that seek to address the shortage of qualified health professionals in low-income countries and strengthen the long-term capacity of local academic institutions. Liberia and Sierra Leone, where weak health systems were devastated by the Ebola epidemic,101 as well as other sub-Saharan African countries have expressed an interest in adopting a similar model. To realize their full potential and achieve sustainable impact, initiatives like the HRH Program require strong communication and coordination, adequate policies and procedures to recruit visiting faculty and support them once deployed, significant investment in the recruitment and career development of local faculty, adequate resources devoted to management and administration or infrastructure and equipment, and greater funding flexibility and long-term commitment from donors.The Rwanda HRH Program is an innovative and ambitious initiative that has already substantially scaled up and improved the quality of health professional training in Rwanda.The authors would like to acknowledge the hundreds of visiting faculty who participated in the HRH Program and the leaders and administrators of the MoH, the Schools at the CMHS, and the US academic institutions who rendered the implementation of the HRH Program possible. The authors would also like to acknowledge Laetitia Nyirazinyoye and Libby Abbott who conducted the majority of data collection and analysis for the Mid-Term Review of the HRH Program  and by representatives of the US academic institutions in the core working group for this article as the data collection and analysis for this manuscript fell under the category of “program evaluation.”Authors declare that they have no competing interests.This work was supported by The United States President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention funded the HRH Program from July 2012 until March 2017; The Global Fund to Fight AIDS, Tuberculosis and Malaria, has been funding the HRH Program since July 2012; The ELMA Foundation provided funding for early planning and management and administration assistance of the HRH Program between 2011 and 2013 and for the preparation of this article between January 2015 and December 2016; and The Abundance Foundation provided funding for the preparation of the article between April 2016 and the date of submission.CC and AgB conceptualized the manuscript, wrote the first draft, and led the development of the manuscript. JS, LVA, PC, RR, PEF, RoR, and SR provided feedback on first draft and supported initial development of the manuscript. EsN, JS, and LM provided data and feedback from the Rwanda Ministry of Health. CM, DKT, DoM, JK, PK, and SR provided data and feedback from the leadership of the College of Health Sciences, University of Rwanda. The following authors provided data and feedback on the manuscript related to their respective area of contribution to the Human Resources for Health Program: ACL, CDM, JEO, MD, RTM, and TT for Anesthesiology and Emergency Medicine; AG, CM, JB, and VM for Oral Health; BH-G, DKT, EK, JR, and ReW for Health Management and Implementation; AR, CC, JD, LVA, NT, PEP, ReR, TDW, and VD for Internal Medicine; BB, CAB, DC, DoM, LLM, MadM, MarM, MH, MR, RTK, TLH for Nursing and Midwifery; LB-M, RoW, SR, UM for Obstetrics and Gynecology; BR, DaM for Pathology; JCK, KW, LA, MC, MiK, NM, TR for Pediatrics; GR and SK for Psychiatry; LK and SS for Radiology; AlB, AmB, EmN, FN, JFC, MuK, RG, and RoR for Surgery; MM for 7 Harvard-affiliated institutions; and AS, IM, MeK, PO, and TN for support during HRH program design and initial implementation. AY and JM edited and provided feedback on the manuscript; collected, processed, analyzed data; and supported the development of the manuscript.1Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 2Office of the Vice-Chancellor, University of Rwanda, Kigali, Rwanda. 3Rwanda Human Resources for Health Program Team, Ministry of Health, Kigali, Rwanda. 4Office of the Dean, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 5Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston, MA, USA. 6Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA. 7Center for Health Equity, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. 8Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. 9Division of Global Health Equity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA. 10Office of the Principal, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 11Department of Surgery, Faculty of Clinical Medicine and Dentistry, Kampala International University - Western Campus, Ishaka, Uganda. 12School of Nursing and Midwifery, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 13Office of the Dean and Department of Oral and Maxillofacial Surgery, Oral Pathology and Oral Medicine, School of Dentistry, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 14School of Health Sciences, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 15Department of Anesthesiology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 16Department of Ear, Nose, and Throat, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 17Department of Internal Medicine, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 18School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia. 19Department of General Medicine, Calvary Mater Hospital, Newcastle, NSW, Australia. 20Department of Neurosurgery, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 21Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA. 22Department of Orthopedic Surgery, Rwanda Military Hospital, Kigali, Rwanda. 23Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 24Department of Pediatrics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 25Department of Mental Health, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 26Department of Radiology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 27Department of Surgery, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 28Yale School of Medicine, New Haven, CT, USA. 29Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York City, NY, USA. 30Department of Pediatrics, BronxCare Health System, Bronx, NY, USA. 31Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA. 32Division of Hospital Medicine, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, USA. 33Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 34Global Health Leadership Institute, Yale School of Public Health, New Haven, CT, USA. 35Department of Preventive and Community Dentistry, School of Dentistry, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda. 36University of Global Health Equity, Kigali, Rwanda. 37Clinton Health Access Initiative, Boston, MA, USA. 38Clinton Health Access Initiative, Kigali, Rwanda. 39Office of Global and Community Health, Harvard School of Dental Medicine, Boston, MA, USA. 40Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Boston, MA, USA. 41Department of General Pediatrics, Boston Children’s Hospital, Boston, MA, USA. 42Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA. 43Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA. 44Department of Pediatrics, Warren Alpert Medical School of Brown University, RI, USA. 45sidHARTe Program, Heilbrunn Department of Population and Family Health, Mailman School of Public Health, Columbia University, New York City, NY, USA. 46Department of Emergency Medicine, Columbia University College of Physicians and Surgeons, New York City, NY, USA. 47Department of Anesthesiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. 48Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. 49Department of Pediatrics, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. 50Department of Surgery, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. 51Duke Hubert-Yeargan Center for Global Health, Durham, NC, USA. 52Department of Medicine, Duke University School of Medicine, Durham, NC, USA. 53Duke Global Health Institute, Durham, NC, USA. 54Duke University Medical Center, Durham, NC, USA. 55Duke University School of Nursing, Durham, NC, USA. 56Department of Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, New York City, NY, USA. 57Obstetrics & Gynecology and Women’s Health, Montefiore Medical Center, New York City, NY, USA. 58Division of Nursing, Howard University College of Nursing and Allied Health Sciences, Washington, DC, USA. 59University of Connecticut School of Nursing, Storrs, CT, USA. 60New York University Rory Meyers College of Nursing, New York City, NY, USA. 61University of Illinois at Chicago College of Nursing, Chicago, IL, USA. 62Columbia University School of Nursing, New York City, NY, USA.63Department of Family & Community Health, University of Maryland School of Nursing, Baltimore, MD, USA. 64Global Education and Mentorship, Office of Global Health, University of Maryland School of Nursing, Baltimore, MD, USA. 65Department of Oncology & Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD, USA. 66Office of Global Health, University of Maryland School of Nursing, Baltimore, MD, USA. 67Partnerships, Professional Education, and Practice, University of Maryland School of Nursing, Baltimore, MD, USA. 68Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA, USA. 69Department of Anesthesiology Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA. 70Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA, USA. 71Center for Global Health, American Society for Clinical Pathology, Chicago, IL, USA. 72Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. 73Department of Psychiatry, Boston Children’s Hospital, Boston, MA, USA. 74Department of Radiology, Brigham and Women’s Hospital, Boston, MA, USA. 75Global Health and Research Programs, Biomedical Research Institute, Brigham and Women’s Hospital, Boston MA, USA. 76Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. 77Institute for Health Policy and Clinical Practice, Dartmouth College, Hanover, NH, USA. 78Office of the Vice-Chancellor, University of Global Health Equity, Kigali, Rwanda.Multi-year training initiatives based on partnerships between academic institutions in high- and low-income countries can help address theglobal shortage of health professionals.Expatriate local faculty will initially do most of the teaching but can gradually be replaced by new graduates from the training programssupported by such initiatives.Funding flexibility (without excessive restriction on how funds can be spent) and reliable funding availability over multiple years are critical toensuring the success of such initiatives.Sustainability can be achieved through institutional capacity strengthening, which encompasses investments in both academic  as well as non-academic  domains.The establishment of additional partnerships and collaborations between academic institutions in high- and low-income countries is alsocritical for sustainability.Health professional training initiatives like the Human Resources for Health Program (HRH Program) in Rwanda, funded by the US Governmentand the Global Fund for a total budget of approximately US$150 million over 7-years, can help address the global shortage of health professionals.In the first 5 years since the launch of the HRH Program in 2012, a consortium of US academic institutions has deployed an average of 99 facultyper year to support and/or launch 22 training programs, which are on track to train almost 4600 health professionals  by 2019. To ensure sustainability, new graduates from the training programs supported by theHRH Program have begun to gradually replace US faculty. The HRH Program has also served as a catalyst for additional academic partnershipsand collaborations between US and Rwanda academic institutions. These partnerships will also play a critical role in achieving sustainability bypromoting faculty career development and by diversifying funding for academic activities in Rwanda.


Molecules was developed in commemoration of the 100-year Anniversary of the discovery of Heparin. It would have been appropriate to have the lead article in this issue be by Professor Benito Casu, one of the lead pioneers who laid the foundation for the understanding of the heparin structure and function. Unfortunately, professor Casu unexpectedly and regrettably passed away on 11 November 2016. His legacy as a teacher, scientist, leader and a visionary who led a group of scientists at Ronzoni to advance the science of glycosaminoglycans will live for years to come. His diverse interest in this area is well represented in the manuscripts in this Special Issue.Heparin and related drugs have contributed in so many different ways to the drug discovery process, and have provided a platform to understand the pathophysiology of vascular and inflammatory diseases for nearly 100 years. Despite its discovery in 1917 by Jay McLean, then a medical student, the scientific and clinical progress in the understanding of heparin and related drugs has continued to expand. This Special Issue of friendly competition”, regardless of potential competitors, and used to cite a phrase of the Nobel Prize winner Rita Levi Montalcini: “Research is a tool of knowledge and not a matter of power and competition”.At the G. Ronzoni Institute in Milan , he contributed over the last sixty years to the advancement of the knowledge of polysaccharide chemistry and biochemistry, especially both heparin and glycosaminoglycan (GAG) derivatives, analogs and mimetics. Several of these resulted from translational networks fruitfully set up by Professor Casu, who had the merit of sharing intuitions and projects with scientists, academic institutions, and industry. He had a unique attitude towards “In 1951, he started his scientific career with brilliant research on starch and cyclodextrins at the G. Ronzoni Institute. In 1969, he was first introduced to heparin during a sabbatical year at McGill University, Montreal (Canada), joining the group of Professor Arthur Perlin. The pioneer NMR studies on the structure and conformational flexibility of heparin provided him an international notoriety ,3. For oStructural characterization studies of heparin pentasaccharide sequence binding to antithrombin, fundamental for anticoagulant activity .Bioactive biotechnological heparins obtained by chemo-enzymatic modification of a biosynthetic precursor of bacterial origin .An honorary doctorate of the Uppsala University (Sweden), awarded in 1998 for outstanding contribution to heparin and GAGs knowledge and development.More recently, as a result of an international collaboration among G. Ronzoni Institute, Alabama University, USA (Prof. Sanderson), and Technion University, Haifa (Israel), granted by NCI, USA, the identification of a new class of non-anticoagulant heparins endowed with antineoplastic activity through the inhibition of heparanase ,7, curreIn the framework of this preface, it is not possible to assess the content and richness of ideas, publications, reviews and patents of Prof. Casu. As a result of translational collaborations with academic institutions and/or industrial partners, the following highlights can be underscored:The traditional interdisciplinary and international network of the Ronzoni Institute, under the guidance of Professor Casu and his group, is well expressed by the contributions of this special issue covering some of the translational steps “from bench to bedside”.


In the original article, there was an error. We erroneously reported that peach fruits were delivered to the labs located at the Department of Applied Genetics and Cell Biology at the University of Natural Resources and Life Sciences, Vienna (Austria). Instead, peaches were brought to the Department of Agriculture, Food and Environment (DAFE), University of Pisa, Pisa , where UV-B irradiation and fruit infection were carried out.A correction has been made to Materials and Methods, Plant Material and UV-B Treatments, paragraph 1. Please find below the complete corrected sentence:Prunus persica cv. Royal Majestic, melting phenotype) were purchased from a local supermarket and brought to the laboratory of the Department of Agriculture, Food and Environment (DAFE), University of Pisa, Pisa .Organic peaches (The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Carlos Chagas was the first “modern” cardiologist in Brazil.Professor Nelson Botelho ReisPresident of the SBC: 1945-1975 managementCardiology as a medical specialty has been built from scientific knowledge derived frombasic and clinical areas and from the development of technological devices that enabledus to study and understand the cardiovascular system. Two technological disruptivecapacitors were: the stethoscope and the electrocardiogram, which allowed for theconstruction of two new “sciences”, the eletroctrocardiography and thephonomecanography. Certainly, the complexity of understanding the eletroctrocardiographyand its electroclinical correlation has made Cardiology to become a specialtyindependent from clinical medicine, in the early 20th century. In the post-war years,technical-scientific developments allowed Cardiology to be prepared to become a solidarea of action, and enabled the new search for therapeutic approaches, which contributedto the increased survival rates observed in basically all cardiopathies.1The foundation of the Brazilian Society of Cardiology (SBC), on August 14, 1943, was animportant mark in our country, which enabled to tie together doctors dedicated tocardiovascular teaching, research and care. Thus, since 2005, the cardiologists day hasbeen celebrated. The SBC and its brand logos have been transformed as it searches toconnect our tradition and the contemporaneity of our cardiology and its internationalinsertion and relevance .1The trajectory of this specialty traverses the emergence of the SBC, the propagation oftraining courses, the creation of the Arquivos Brasileiros de Cardiologia in 1948 andthe first specialists’ titles. Over the years, in association with the hospitalistpractice and the great technological development, Cardiology was divided into specificspecialty areas: emergency cardiology and cardiac intensivism, congenital cardiopathies,cardiac surgery, hemodynamics, echocardiography, electrophysiology, among others. Inorder to understand the future, it is necessary to look back into the past and realizethe huge steps of this specialty, which grows worldwide, aligned with thecontemporaneity of the challenges to prevent and treat cardiovascular diseases in a safemanner, based on guidelines and focusing on the patient.2 In themid-1500s, Andreas Vesalius published a wonderful atlas of anatomy in his "Fabricius".In this publication, he called the heart the "center of life". This publication correctsthe anatomical mistakes described by Galen and, for many historians, it is the mark ofmodern medicine. Modern cardiology has its beginnings with the publication of the bookDe Motus Cordis, written by the English physician and scientistWilliam Harvey, the father of Cardiology,3 which caused a “hurricane” in science and medicine when it asserted,based on studies in animals and humans, that the blood goes from the heart throughclosed spaces and returns through veins into the heart.Going back to remote times, we can rescue the registries of the first steps of thespecialty that we call protocardiology. Leonardo da Vinci’s observations, drawings andnotes of the heart, made in 1490, are deemed as pioneering in the history of Cardiology.As author of the first graphic representation of the coronary arteries, he alsoexplained the heart fluid dynamics and defined the formation of the aortic valve cuspand the sinus wall. It is possible to state that Da Vinci was a renaissancecardiologist.Arquivos Brasileiros deCardiologia, in 1986.4 Hereinforces that the clinical-anatomic method was the first method in clinical medicinethat evolved from a simple confirmation (“findings of necropsy”) or from theverification of the disease in an emerging scientific area, correlating the patient’sclinical picture. Important Italian ; French  and German (Virchow) physicians were fundamental to the construction of thisnew discipline. The Anatomopathology witnessed the emergence of Histology, which broughtto light the importance of examining cells and tissues, and of expanding the correlationand causal mechanisms of diseases. The physicians interested in the area of Cardiologypresented a growing and e robust method to explain the abnormal cardiovascular findingsand necropsy data.The evolution of the history of Cardiology in Brazil was brilliantly revised by professorNelson Botelho Reis and published in the Arquivos Brasileiros de Cardiologia also publishesits traditional anatomoclinical section, an important tool for the formation of youngcardiologists.In our country, the central influence of the cardiovascular anatomoclinical method wasimportant for the formation of cardiologists until the beginning of the 1980’s,initially influenced by Sylvio Carvalhal (São Paulo), Professor Luigi Bogliolo(Rio de Janeiro and Minas Gerais). Also, Professor Manoel Barreto Neto, whom I washonored to be a student of and from whom I received deep knowledge and the strength ofthe anatomoclinical method, along with the findings presented by Professor Raul CarlosPareto Junior. The In the second half of the 19th century, the third stage of Cardiology emerged: theexperimental medicine, the source of the brilliance of writers such as Claude Bernardand Carl Ludwig. The German and French schools made experimental medicine an independentarea and two researchers described the Frank-Starling Law, the first law of the heart.In the 19th century, scientific advances derived from new disciplines such asmicrobiology, immunology, histology and biochemistry. Other sciences were incorporatedinto the study of Cardiology, such as physics and electricity, which contributed to thediscovery of the x-ray and the chord galvanometer. In the future, these would constitutethe basis of cardiac radiology and electrocardiography. In the end of the 19th century,the combination of anatomoclinical data and the recording of stetho-acoustic findingsusing graphic methods (phonomecanographic) consolidated a new pathophysiologicalapproach, and a detailed description was made of a growing number of cardiovascularconditions.5It is possible to assert that the official study of Cardiology, as a science and medicalspecialty, started with the vital contribution of Dr. Carlos Chagas’ studies, whodiagnosed the chagasic cardiomyopathy in 1909, and was responsible for the firsttranslational studies and the publication of the first broad scientific study of acardiac disease in Brazil. In addition, he was responsible for introducing the firstelectrocardiogram, installed in the laboratory of Manguinhos, a valuable and unequivocalcontribution to Brazilian Cardiology.6 In the same period,the dissemination of the electrocardiograph made it possible to develop specificstudies, which resulted in a branch of clinical medicine that became an area of majorinterest for numerous physicians, who began to search for specialty programs in Braziland abroad. This movement, throughout the 1930s, led to the emergence of the medicalspecialty, thanks to the particular interest of this enthusiastic group for thisspecific study, which caused emerging resources to be redirected to the investigation ofcardiovascular diseases, through phonomechanography and electrocardiography. From thismoment, a great process of creation of annual specialty courses began, which initiallywere offered in São Paulo and Rio de Janeiro, even before the constitution of theChair and the formation of this Society, on August 14, 1943. The access to these greattransnational networks, and the whole American continent, benefited the investigation,the learning and trainings that took place until the end of World War II, and was theresult of the internationalization process of the SBC, which maintained the possibilityof interchange between Brazilian and North-American doctors and, consequently, of itsactions together with the American College of Cardiology.7Industry development and migration from rural to urban areas, with the creation ofmetropolitan areas, in the early 1920s, led to a huge change in the eating and workinghabits of the Brazilian population, with the spread of heart diseases among thesociety.Cardiology and cardiologists experienced deep changes in the beginning of the 20thcentury, due to the employment of the electrocardiogram as the cornerstone ofcardiovascular rationale. Another important change was the progressive loss of relevanceof the French school for Cardiology and the emergence of the North-American and Mexicanschools of Cardiology. The Mexican Institute of Cardiology, founded by Ignacio Chaves,in 1944, became a research and education pole in the area of electrocardiography and amodel center of cardiovascular education, attracting Brazilian young people for itsresidence in cardiology, as well as people from other nationalities. Between the 1940’sand 70’s, it would become a global reference center and contribute to important advancesfor the pathophysiology of congenital diseases, pulmonary hypertension, hemodynamics andelectrophysiology. The influence of the North-American school starts to consolidate inthe post-war period, when it incorporates economic resources to professionalize clinicalresearch and construction and new centers of cardiology, as well as into the developmentof cardiac catheterization and myocardial revascularization surgery. The Harvard groupled by Professor Eugene Braunwald consolidates in the discovery of new mechanisms ofdisease and in multicenter therapeutic studies.In the 1980’s and 90’s, noninvasive cardiovascular imaging, echocardiography, myocardialscintigraphy, computerized tomography and cardiac resonance were incorporated and becameincreasingly indispensable for diagnostic, prognostic and therapeutic evaluation.Parallel to this, we started to incorporate the principles of evidence-based medicineinto the process of clinical decision making in the therapeutic area. The BrazilianSociety of Cardiology establishes clinical guidelines to guide the cardiovascularpractice, incorporating and ranking the recommendations to confront severalcardiovascular diseases.8Since the hospitalist practice of our cardiologists, cardiac surgery has been present andof vital importance for the development of our specialty, as well as hemodynamics, bothbeing distinguished as the major departments in the first years of constitution of theSBC. Specialized sectors and equipment in hemodynamics and cardiac surgery, creation ofspecialized health care centers and units, such as the coronary unit and cardiacpostoperative unit, provide specific care, adding knowledge and value to the specialty.With the arrival of the 1980's, there was the dissemination of the use of coronaryangioplasty for the treatment of multiple vessel disease and acute myocardialinfarction, using reperfusion techniques and thrombolytic therapy. The advances ofinterventionist hemodynamics through the use of pharmacological stents, valvuloplastyand prosthesis implantation emerged around the world, and quickly arrived in Brazil,promoting a huge evolution step towards the formation of the specialist in Cardiology,as well as the need for the constitution of teams dedicated to each area.4Nowadays, the SBC consists of 13 active departments, where a total of 14,000 associatesare distributed in 26 regional clusters throughout Brazil, being the largest society inLatin America. Cardiology, in addition to having being the first specialty to establisha Chair at universities and teaching hospitals, was also responsible for the emergenceof accreditation procedures for specialist titles and, nowadays, has the support of8,429 doctors with a specialty degree in Cardiology.All this movement promoted the growing and the development of the SBC, leading to thecreation of the first five specialized Departments: Cardiovascular Surgery Department(1969), Pediatric Cardiovascular Department (1973), Cardiovascular and RespiratoryPhysiology Department (1974), Angiocardiography and Hemodynamic Department (1976) andHypertension Department (1981).lato sensu post-graduationcourses. In line with this demand for specialty courses, the SCB, alongside its regularpublications Arquivos Brasileiros de Cardiologia (Brazilian Archives ofCardiology), International Journal of Cardiovascular Science, the SBCJournal and its guidelines, provides DE (distance education) courses, abroad schedule of events and congresses with online access. In order to respond the needfor expanding translational research, the specialty counts with the possibility ofnetwork research, as in the case of stem-cell therapy, which involved several centers,the support to clinical trials and registries, in addition to epidemiologic studies onthe most prevalent cardiovascular conditions in our field. In the context ofstandardization of conduct and creation of protocols, the SBC dedicates extremedetermination for the development and publication of guidelines on approach andtreatment of the main diseases with high morbidity and mortality nowadays.In addition, several institutions offer In the late 20th century, Brazilian Cardiology constructed a solid legacy andinternational relevance, a trajectory from which renowned fellows were electedrepresentatives of this first century of our specialty .13This new decade emerges with a new design for Cardiology in a digital, connected,patient-focused environment, based on major pillars - artificial intelligence, big-data,robotics, biosensors, telemedicine, devices, sensors and genomics. Together they willsupport the Precision Cardiology paradigm. The need to incorporate into our mindset theidea of the cardiologist approaching the world of innovation and entrepreneurship is anew challenge in the formation of our new cardiologists with emphasis on the developmentof female leadership in cardiology. From the assistance point of view, our integrationwith the population health and family doctors will increase, as well as ourmultidisciplinary approaches, enabling the implementation of lines of care and themonitoring of clinical outcomes and focused on patient safety. This means to know anddominate the triad formed by cardiovascular biomedical knowledge, technology  and humanization. Knowledge moves forward quickly and unstoppable, in a globalmanner, supported and favored by numerous opportunities of knowledge exchange betweenpeers and institutions worldwide. The technology, which promotes the evolution ofDigital and Precision Medicine, favors the access to knowledge, the strengthening ofdiagnosis, the promotion of man-machine interaction and the possibility of personalizingtherapy to its molecular level. And, finally, the rescue of essence: the humanization ofsuch advanced and futuristic Cardiology. A new journey will be necessary into the dailypractice of doctor-patient interaction in order to promote empathy, patient empowermentand sensitivity to the doctor inserted in this new context for this newdecade.


The development of new biomaterials and regenerative medicine strategies appears as a major field of research in periodontology, oral surgery, and esthetic and implant dentistry (the POSEID disciplines) in the current era of tissue engineering and quest for tissue regeneration. Biomaterial research remains the core science of all these opportunities of regenerative treatments of the maxilla and improvement of oral rehabilitation .In our previous special issues in 2015 and 2016, we selected a series of articles with new data on a wide range of topics in biomaterials and regenerative research in periodontology, oral surgery, and esthetic and implant dentistry, and we highlighted how these interconnected fields of research are both transversal (multidisciplinary) and translational . In this 2018 special issue, we selected articles with the same insight and wished to illustrate the complexity of this research field.In our previous editorials in 2015 and 2016, we described particularly the strength, weakness, opportunities, and threats on these disciplines and how research in implantable materials, particularly dental implants (new implant design and surfaces) , is affeIn the 2016 editorial of this special issue, we described particularly some ethical and legal issues related to this field, especially concerning the lack of transparency and control in dental implants  or through the dramatic example of L-PRF (leukocyte- and platelet-rich fibrin) and related blood derivatives  . These mIn 2018, unfortunately, very little has evolved. As a strange matter of fact, the development of these new biomaterials and regenerative medicine strategies seems to have reached a plateau that no one seemed to expect so early, before any major breakthrough or revolution of the clinical paradigms. As we can observe in the current literature, research topics seem to be permanently turning around, and we see currently very little major developments.In this 2018 special issue on new biomaterials and regenerative medicine strategies in periodontology, oral surgery, and esthetic and implant dentistry, we continued our task to gather a meaningful corpus of relevant articles. More than before, a better control of the specialized literature is needed.