Introduction: To train pharmacists working in the public health system, the Brazilian Ministry of Health developed a specialization course called Pharmaceutical Service and Access to Medicine Management (PSAMM) between 2010 and 2016. The course was free of charge and used e-learning as its main approach. In the end, 2,500 pharmacists were trained. The purpose of this study was to identify and analyze the strengths, weaknesses, opportunities, and threats of an in-service and e-learning course for pharmacists working in a public health system.Materials and Methods: Three workshops involving 67 participants were conducted at the conclusion of the course to analyze the perspective of the PSAMM course's faculty  and students (pharmacists). Strengths, weaknesses, opportunities, and threats analysis and qualitative analysis methods were used.Results and Discussion: The strength dimension had the greatest number of items. The qualitative analysis resulted in six categories: the category “E-learning in continuing education” had the most cited items. Internal elements such as in-service hands-on activities directly related to the professionals' roles, course contents, faculty, and the methods to offer the course  were positively assessed. Nonetheless, external elements were considered critical for the course's outcomes such as investments in the infrastructure of pharmaceutical services, access to the internet, local managers' support for continuing education and innovation implementation, practice of interprofessional collaboration, and political stability. The continuing education course in the public health system was affected by internal elements such as its project and structure as well as external elements such as the sociopolitical scenario. Continuing education investment must be accompanied by infrastructure investment and coordination of services. The Unified Health System (SUS) provides access to health services for everyone in Brazil that are fully financed by public resources. The majority of the population relies on it . The rigDespite important normative framework on SUS management being available, there are still failures in the organization of pharmaceutical services in primary care. Governance of the access to medicines and management capacity are key factors to guarantee access to medicines and comprehensive therapeutic assistance. Many authors have argued that the professional skills of the currently available workforce do not correspond with the expected profile for work in SUS, particularly related to management and leadership skills –8.The Ministry of Health (MoH) identified the need for training pharmacists who are in charge of pharmaceutical policy and development of services –7 in theAfter course conclusion with the training of 2,500 pharmacists, the MoH requested the present study with the goal of investigating the general perceptions of stakeholders (participants fo the study), including students (pharmacists), of the development of the course and the use of e-learning for this purpose.Distance learning approaches are essential to qualify the pharmaceutical workforce in Brazil . GloballFurthermore, many authors argue the importance of evaluating the impact and effectiveness of CPD/CE actions on healthcare results –15. EvalThis course was free of charge. It was offered as a blended course, mainly through e-learning, with four face-to-face meetings. Besides financing PSAAM during the period of 2010–2016, the MoH was supporting other actions, such as infrastructure and workforce expansion, to develop pharmaceutical services in diverse municipalities  were from all regions of the country and linked to the regional course centers. The course had 132 peer tutors . A national central management committee organized regional centers operated the e-learning platform, and managed pedagogical and financial matters.The PSAMM program was prepared by 50 experts from 20 institutions from all over the country. The course material was produced in printed and online versions. The online version was designed for the Moodle platform, using audio and video resources. The PSAMM total workload was 375 h, distributed over three subject matters  and carrPSAMM's desired learning outcomes were to develop management competencies in pharmaceutical services, including social engagement, professional autonomy, and commitment to achieve the best results from the National Pharmaceutical Policy and the health system as a whole. It targeted pharmacists (government employees) from all over the country.The course content included theory and practices related to health policy and laws, strategic aspects of management and leadership, disseminating the principles of participatory planning, building alliances, encouraging collaboration, and involving key actors in the diagnosis of situations, as well as in the definition and execution of actions, thereby expanding the scope of pharmacists in the planning process of health services .The tutors were previously trained by the course's faculty and staff through workshops and online activities. Asynchronous activities such as texts, cartoons, video documentaries, forums, and questionnaire reports were evaluated by the tutors, based on criteria previously established by the faculty. Meetings were held between tutors and the faculty to assist in correcting activities and clarifying students' questions. Synchronous activities such as chats were available to facilitate interaction between students and tutors.Every student needed to develop an in-service training activity called the Operative Plan. It was founded on Carlos Matus' principles of Strategic Situational Planning. Such principles are based on clearly defining representative institutional aims, explaining the problems, targeting the causes of the problems, analyzing the technical-operational management capacity, mobilizing resources, and collaborating with partners . The aimDescriptive qualitative methods followed by an online survey were adopted for this study. A sample size of 67 stakeholders were selected to represent the different regional centers from various regions of the country. The sample included course's staff (tutors); course faculty ; health manager's representatives, and students (pharmacists) enrolled in PSAMM. Three independent workshops to collect data were conducted 2 years after the end of the course, in order to allow adequate time for participants to report their own perspective on the impact of PSAMM.Held in the Southern Region of Brazil (50 participants), was targeted at politicians and managers, course staff, and course faculty representatives. All the staff and course faculty were invited and 42 participated. The MoH, the states' and municipal governments' councils, and pharmaceutical professional bodies were invited. They nominated their representatives and 8 stakeholders participated .We organized four groups in the workshop 1, described in Conducted in the Southeast (9 participants) and Northeast (8 participants) regions of the country, were target at PSAMM pharmacists who completed the course. These pharmacists received an invitation through e-mail and phone calls, without exclusion criteria. Those who were available and agreed to participate were included. During Workshops 2 and 3, participants discussed all four topics. Each workshop lasted 4 h.The strengths, weaknesses, opportunities, and threats (SWOT) analysis approach was used for data collection. It is a strategic management tool applied to policy diagnosis and planning as well as decision-making processes –23. It iTo guide the procedures in the workshops held, four topics were defined in the SWOT analysis: curriculum, course organization, communication flows, and learning tools, described in An online survey was then developed, and a link sent to all participants. The survey required respondents to share their level of agreement on relevance and importance of each item. For the relevance analysis, a 5-point Likert scale was employed . For the importance analysis, a 3-point Likert scale was used (very important/important/unimportant). Items that scored more than 80% for both agreement and importance were subject to further analysis by the participants.In the results session, similar items from different workshops were grouped to facilitate the discussion. When necessary, the results were rearranged amongst the dimensions to ensure compliance with the methodology . ParticiTable 5) and the transcription of the discussions that took place during the sessions through thematic analysis. The analysis focused on identifying patterned meanings and organizing analytical categories to further discuss the results.The tapes of each session were transcribed into a Word® document. Three trained researchers with experience in qualitative methods independently analyzed the SWOT results . All participants were asked to provide written consent. The information was anonymized, and no personal identifiers were used during data analysis or publication.The profiles of the participants in Workshops 1, 2, and 3 are described in via the online survey, the items that had more than 80% were included in the results . There were 29 items after the selection on the dimensions of strength, weakness, opportunity, and threat. After the agreement on relevance and importance analyses of the listed items Six categories were identified in the qualitative analysis: management training, e-learning in continued education, the course's infrastructure, issues related to public health services' working conditions, interprofessional collaboration in practice, and the political and social context in Brazil. The results of Workshops 1, 2, and 3 are presented in The main strengths identified are related to the didactic and structural organization of the course and the training focused on management. The pharmacists who took the course highlighted the richness and quality of the didactic material developed for and used in the course. These students also pointed out the support system for studies as an important factor for their success in completing the training. Students considered the hands-on activities important to the development of skills that were immediately applied to their daily practice.Most of the weaknesses were identified by non-students  and were related to their concerns about having little previous experience in the application of distance education. On the other hand, the pharmacists, who were the students in the course, highlighted some difficulties in the development of the course's practical activities; students asked for conditions to carry the activities out in the health services. Such conditions were not always present.Factors related to the political and social scenarios dominated the opportunities identified by all participants. The period during which the course was developed was marked by investments in public health and education policies, including the hiring of pharmacists and the offering of CE. Participants stressed the importance of such investments to provide opportunities for improving access to medicines and pharmaceutical services in the country.Issues related to work conditions in the public health services were prevalent among the identified threats, highlighting the necessary relationship between CE and the generation of material and managerial conditions for the development of health services. Participants, students and non-students, thought that the political and social scenario was also noteworthy. The time frame during which this study was carried out was marked by political changes, budgetary restrictions, and divestments in public policies. Participants perceived these conditions as threats to the continuity of CE programs like this course.The study enabled us to analyze the CE program in its internal characteristics and in relation to the external scenario in which the course was offered.Political and social scenario in Brazil; Issues related to public health services' working conditions; E-learning in continuing education.In Brazil, pharmacists have been staffing public health services for many years. However, their inclusion in primary care health teams is relatively recent. The data indicate a 75% increase of pharmacists in the primary care workforce from 2008 to 2013 , which wParticipants also emphasized that the political and economic scenario is a threat. Investment in public services has been declining, owing to the current political situation, including the 2016 political coup. The political crisis promoted a major change in public policies, with the adoption of austerity measures resulting in a reduction of investments throughout the public sector . In a coThe PSAMM was offered during a historical period that was described by all workshop participants as a favorable political scenario for the expansion and enhancement of health policy. Federal public funding for access to medicines and pharmaceutical services increased from around R$2 billion in 2003 to ~R$15 billion in 2015 . During Public funding is important and necessary for effective CPD/CE strategy. It was fundamental to allow the implementation of this project, when the health system itself had identified the need for management training and provided it to its professionals through UNA-SUS. Political and social stability are key issues to maintain and support public investments such as health professionals' training. However, professional training should not be an isolated activity, but an investment within a developmental service project and must be accompanied by investments in infrastructure and workforce teams. As the participants indicated, good local working conditions are fundamental to provide opportunity to foster advanced practices and achieve better results.The existence of new forms of digital communication and information technologies for the training of professionals in the SUS, such as UNA-SUS, was understood as an opportunity. However, disparities in the quality of the internet in Brazilian regions were pointed out as a threat, as it causes accessibility problems to the course. Some research has indicated that in 2014 only 54.9% of private households in Brazil had internet access . LocalitThe distinguishing feature of the course in addressing the management of pharmaceutical and approaching management as a cross-content matter rather than an isolated content was considered a strength by participants. Management training is a recognized skill, as corroborated by the literature –36, giveIn all workshops, participants identified the Operative Plan as an important strength. It provided the development of skills related to management, including leadership, autonomy, proactivity, communication, and team-work.It also enabled pharmacists to interact with other health professionals, health care facility directors, and also with the patients. Besides the development of management skills, the Operative Plan was underlined as an adequate strategy to promoting such interactions and was supported in the health care facility and professional engagement contexts. However, one of the threats quoted was the poor experience of interprofessional collaboration in health services. Some health centers' managers and staff were not open to new ideas about service organization and management, and did not support the Operative Plan development. It can limit opportunities for developing new practices arising from the exercise of the Operative Plan.In the literature, despite the recognized impact of interprofessional work on health care , many diThe Operative Plan performed a didactic task and also an actual intervention in health services. It was an important method to bridge the gap between the contents studied and their application in the service. It encouraged interprofessional collaboration in the pharmaceutical system management to promote better access to medicines and their rational use. Our findings indicate the development of management skills as a result from the combination of the ongoing pedagogical processes and the circumstances of the practice scenario. The results demonstrate that theories must be studied along with practical activities in actual services. The local manager should be an articulator and facilitator of CE processes to enable the positive impact of such investments in training programs.Brazil's geographical, cultural, and social diversity can be noticed in its pharmaceutical system management, as highlighted by the participants. Accommodating this complexity of professional and service organization at municipal, state, and federal levels has posed the challenge of designing this educational strategy when planning PSAMM.The organization as a blended program with e-learning as the main approach was an adequate strategy and considered a strength, however the number of four face-to-face meetings was mentioned as a weakness. Participants considered face-to-face meetings to be highly valuable, and they would have liked to have had more meetings. The PSAMM has succeeded in achieving the goal of training professionals from all the regions of the country, despite the vast geographical distances. This was possible due to the modality of learning chosen for the program. Many municipalities are located in remote and less privileged geographic regions in terms of CE offers. Nonetheless, face-to-face meetings have an important role in professional training—motivating participation and encouraging networking. Authors stress that blended programs with a mix of synchronous, asynchronous, co-located, and remote learning opportunities, are most likely to balance face-to-face learning benefits with e-learning flexibility , as corrInternet accessibility constraints require flexibility in the course's organization to deal with any administrative or pedagogical problems and help students to complete activities and evaluations. During the course, technical issues faced by students led the central committee to post-pone scheduled activities and only asynchronous activities were mandatory. Other strategies adopted by the PSAMM program were the supply of teaching materials on flash drives and the provision of computers with internet access for students by the regional centers. It is also necessary to identify different levels of digital skills among students  and offeThe tutors' engagement was also fundamental in supporting students with low digital skills. They helped students deal with the restrictions and manage course activities. In Workshop 1, participants recognized tutors' technical qualifications in pharmaceutical services, but indicated insufficient pedagogical training for mentoring learning processes. Training tutors for distance learning activities is a well-recognized need and ought to be an important investment in developing e-learning programs. In this study, only non-alumni participants reported this concern. In Workshop 1, the little previous experience in distance education was a theme that emerged as a possible weakness. However, for the students (Workshops 2 and 3), little previous experience in e-learning of both tutors and faculty were not observed as weaknesses.However, limited experience of Course Completion Work supervisors in public health service management was highlighted as a weakness in all three workshops. According to university rules, Course Completion Work supervisors should have at least, a master's degree. This issue limits the faculty to professionals with greater academic experience and, to some extent, those with little in-service experience in management. The shortage of faculty with expertise in health system management can be considered an important limitation to offer education in this area However, the expanded offer of leadership and management training for health professionals can strengthen the health system  and hopeResearch  suggestsThe PSAMM's issues were contextualized and analyzed within the real-life circumstances of the local and national contexts, as presented in the analyses on labor and learning conditions. The importance of developing management skills, interprofessional collaboration, and the political and social challenges of implementing a course of such magnitude in a context of profound disparities emerged.Authors indicated that the implementation of e-learning activities can help to overcome the problems in professional training . E-learnThe perspectives from the diverse people involved in PSAMM through this SWOT analysis have indicated the key elements to CE development for professionals engaged in public health services. Some important lessons can be learned from this study. The success of CE projects for health professionals, particularly in public health systems, is affected not only by the course's internal elements such as the contents, as well as the organization and didactic methods, but also by external elements from the healthcare institutions, the health professionals work conditions and accessibility to technological resources, and the political and economic scenario. The planning of CE programs must consider all these issues. The characteristics of the health professionals, the health system's infrastructure, and the technology to which professionals have access are also key elements to consider.Based on the results presented here, it is recommended that investments in CE are accompanied by: investments in improvements in infrastructure and coordination of health services; improvement of working conditions for professionals; investments in technologies for distance education; intensification of the interactivity between the health system and educational institutions; incentives for interprofessional collaboration. All these efforts need to be oriented toward a scenario of political and administrative stability, providing motivation and confidence for health professionals for their development and dedication to the health system.Some limitations of the study should be noted. The limited time available in the workshops may have constrained the discussions. The students' workshops were performed in only two of the five geographic regions, but those are the two most populous regions of the country which concentrate most of the pharmacists who attended the course. The findings of this study might not lend themselves to generalization over other social, political, and economic conditions. Nonetheless, the internal and external factors that affected the course can advise policy makers, CE providers, and healthcare managers to prevent important constraints in the development of CE for health professionals in diverse scenarios.This analysis of a CE strategy for health professionals intended to contribute to drive future investments in continuing education for public health systems, being able to guide projects in other countries.The original contributions generated in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethics Committee on Research with Human Beings—Federal University of Santa Catarina. The patients/participants provided their written informed consent to participate in this study.All authors have contributed equally to this work.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.


The genitourinary tract was recently identified as a potential site of complications related to the congenital Zika syndrome (CZS). We provide the first report of a series of cryptorchidism cases in 3-year-old children with Zika-related microcephaly who underwent consultations between October 2018 and April 2019 as part of the follow-up of the children cohort of the Microcephaly Epidemic Research Group, Pernambuco, Brazil. Of the 22 males examined, eight (36.4%) presented with cryptorchidism. Among 14 undescended testis cases, 11 (78.6%) could be palpated in the inguinal region. Seven of the eight children had severe microcephaly. Conventional risk factors for cryptorchidism were relatively infrequent in these children. We hypothesize that cryptorchidism is an additional manifestation of CZS present in children with severe microcephaly. As in our cases, for most of the children, the testes were located in the inguinal region, and the possible mechanisms for cryptorchidism were gubernaculum disturbance or cremasteric abnormality. Although neurologic impairments, including morphological alterations – most notably, microcephaly – and radiologic anomalies, including brain calcifications, are among the most common features, it is increasingly recognized that CZS can be associated with abnormalities across a range of organ systems.4 Although there is a known association between cryptorchidism and cerebral palsy, the link with ZIKV is limited to a single postmortem report of cryptorchidism in a neonate with microcephaly and other severe defects who died within 20 hours of birth.6Here, we provide the first report of cryptorchidism cases in children with Zika-related microcephaly. Cryptorchidism is one of the most common congenital malformations of males occurring in about 1% of the boys at the end of the first year of life and is associated with testicular cancer, infertility, and hypogonadism.All parents/caregivers signed an informed consent form. This study was approved by the Ethical Committee (CAAE: 94544518.2.0000.5192).http:/www.cpqam.fiocruz.br/merg/). The criterion to refer to the pediatric urologist was exclusively the diagnosis of Zika-related microcephaly. The MERG is following approximately 200 children with microcephaly  identified mainly during the microcephaly epidemic in the state of Pernambuco with clinical and/or radiological and/or laboratorial evidence of Zika exposure.8 During these evaluations, 22 microcephalic males  were evaluated using the 2018 pediatric guidelines of the European Association of Urology.9 According to these guidelines, true cryptorchidism is defined as testis that cannot be brought to the scrotum during physical examination.This case series includes all 3-year-old male patients with Zika-related microcephaly who underwent consultations by a pediatric urologist between October 2018 and April 2019 as part of the follow-up of the children cohort of the Microcephaly Epidemic Research Group (MERG), Pernambuco, Brazil  or obtained by telephone interview with the mothers . One mother was not available for telephone interview.Data on potential risk factors for cryptorchidismOf the 22 males with Zika-related microcephaly examined, eight (36.4%) presented with true cryptorchidism. Seven boys with retractile testis were not included. The other seven did not present cryptorchidism. The age at diagnosis of cryptorchidism ranged from 8 days to 46 months. Of the eight children, five had microcephaly at birth, one classified as moderate microcephaly (≤ −2 SD) and four as severe (≤ −3 SD). The other three children were diagnosed with severe microcephaly at the first evaluation. Of these eight children, one or both testis had failed to descend to the scrotum, were unable to be mobilized and maintained in their anatomical position, and/or were absent/undetectable on clinical examination. Of the cryptorchidism cases, six were bilateral, one was on the right, and one on the left . Six of Among the five children with cryptorchidism and available gestational age at birth information, only one was born less than 37 weeks. Four of seven with complete data on delivery mode were born vaginally with cephalic presentation. In the three children born by caesarean section, the mothers had not been informed by the obstetrics team of the reason for this option. With respect to the birth weight, two weighed less than 2,500 g at delivery, and the birth weight was unreported in one case. None of the children were reported to be born from pregnancies resulting from assisted reproduction. Of the families with available data, no mothers and only one father reported smoking during pregnancy. One child with cryptorchidism was reported to be a twin. In terms of the children’s race/ethnicity, six mothers classified their children as being of mixed ethnicity, and one identified her child as black. None of the families interviewed had a history of cryptorchidism.11 Genitofemoral nerve issues, which ultimately affect gubernacular function, may also be associated with mechanisms of cryptorchidism. The finding of cryptorchidism with three impalpable gonadal units in two boys still requires surgical exploration to confirm the true nature of their involvement, which may be related to agenesis, congenital atrophy (vanishing testis), or ectopic testis. None of the children presented with genital anatomical abnormalities, suggesting that the cases in question are not related to specific urological syndromes. Non-syndromic cryptorchidism in humans is multifactorial and mediated by an intricate neurohormonal imbalance.12 The children in this series presented with severe microcephaly associated with significant impairment of the central nervous system, similar to that which occurs with cerebral palsy. Although an association between cerebral palsy and cryptorchidism has been described, the underlying mechanisms remain unclear.13 One possible mechanism for the findings could be alterations to the cremaster muscle, which has been especially suggested in cases of ascended testis. In these cases, the cremasteric reflex, influenced by neurological impairment, could be responsible for late ascension of gonads, but gubernacular abnormal insertion has been suggested as a cause too.14One child was diagnosed as early as 8 days indicating a congenital cryptorchidism. Later diagnosis in the other children may have occurred either because of missed diagnosis or may represent cases of late ascended testis. Most of the testicular units in this series of cases were palpable in the inguinal region, and, therefore, had successfully concluded the phase of intra-abdominal descent. This finding suggests a lower probability of interference in the early stages of embryonic testicular development, which occurs between the fourth and 12th week of gestation or in the production and/or action of insulin-like 3 protein, responsible for the intra-abdominal descent phase. As in our cases, for most of the children, the testes were located in the inguinal region, a possible explanation is that the mechanism that produced cryptorchidism was a gubernaculum disturbance because it is responsible, under androgenic action, for transferring the testicles to the scrotum through the peritoneal–vaginal conduit until the 35th week of gestation.10 do not seem to explain the presence of cryptorchidism. We observed just two cases of low birth weight and one case of prematurity. All vaginal deliveries were of cephalic presentation. Among the cases delivered by caesarean section, it was not possible to obtain the data that led the medical team to opt for the caesarean section, and it is possible that a non-cephalic presentation could have been the reason for such a recommendation. We also note that despite public policies to encourage transvaginal birth, the caesarean rate in Brazil is high, so it is plausible that the delivery mode was not medically indicated. In the present series, no pregnancy had resulted from assisted reproduction. Only one case of paternal smoking was reported in the children. Only one case of twinning was reported. Regarding ethnicity, six children were identified by their mothers as being of mixed ethnicity and one as black, so any ethnicity-related patterns were not discernible. We also not had a reported case of family history of cryptorchidism.In our case series, traditional risk factorsAlthough this investigation had limitations because of the small sample size and the absence of surgical exploration, this study is of public health significance in that it provides the first description of cryptorchidism in a series of children with CZS. It is not likely that the very high rate (30%) of cryptorchidism found is due to selection bias. Even if all children with microcephaly were not evaluated by a pediatric urologist, referral to this specialist was not based on any clinical finding; therefore, we will not expect that the frequency of cryptorchidism will be different in those not yet examined. In addition, eight of 91  is still a high frequency.Although conventional risk factors for cryptorchidism were relatively infrequent in these children, all were affected by severe impairment of the central nervous system. Therefore, we hypothesize that cryptorchidism is an additional manifestation of CZS present in children with severe microcephaly. We suggest that the observed cases may be associated with gubernacular and cremasteric abnormalities, although surgical exploration will be essential for a better understanding of possible mechanisms. Because of the greater risk of future complications such as functional impairment of the gonads, as well as cancer, male children with Zika-related microcephaly should also undergo routine urogenital assessment. Further studies should be performed to better characterize this new clinical feature associated with CZS and to clarify the mechanisms leading to cryptorchidism in these children.


China’s Serious Disease Insurance Scheme (SDIS) was set up to relieve the financial burdens on serious disease patients. It is a crucial part of the national basic medical insurance scheme, which is regarded as one of the largest government-funded social security programs in the world. The most significant institutional innovation of the SDIS is that the approach of a public–private partnership (PPP) is applied in an attempt to facilitate the efficiency of its implementation. The objective of this paper is to evaluate the implementation of the SDIS in China through PPPs, and to identify the problems to be tackled if the Chinese government intends to make such a plan work better for the majority of urban and rural residents. With the effective support from local officials and practitioners, the authors of this paper collected copies of SDIS contracts of multiple cities in Guangdong, one of the most developed provinces of China. Guided by a research framework drawn from the PPP literature, details of contract enforcement were also examined. The authors discovered that the role of local states is rather dominant; they have manipulated contract drafting and implementation. Additionally, current mechanisms for profit sharing, risk sharing, and information exchange have placed insurance companies in a rather disadvantageous situation. To achieve the sustainable development of the SDIS, the authors suggest that a further reform on implementation of a PPP must be pushed forward. In the West, reforms on health systems are continuously conducted to enhance efficiency and improve resource allocation. In 1991, market mechanisms were introduced to the National Health Service (NHS) of the UK in pursuit of a better use of public funding. However, the effects were rather limited, as some essential conditions that are required for a market to operate were missing . In the In recent years, the development of the Serious Disease Insurance Scheme (SDIS) via the approach of a public–private partnership (PPP) has become a primary part of China’s social and economic policy. It was praised by the domestic media that one of the substantial achievements of China’s development was the establishment of a government-funded medical insurance scheme. According to the Ministry of Human Resources and Social Security (MHRSS), universal coverage of basic medical insurance has been provided to all rural and urban residents since 2016 . The healthcare safety net consists of the Urban Employee Essential Medical Scheme (UEEMS) and the Urban and Rural Resident Basic Medical Insurance Scheme (URRBMIS). The former is provided to urban workers who are hired by various types of organizations such as enterprises, governmental sectors, and non-governmental organizations. The latter combined the previous “Urban Resident Basic Medical Insurance” and “New Rural Cooperative Medical Scheme”, which, respectively, served the nonworking urban residents and peasants. Previously, only basic medical services were covered by UEEMS and URRBMIS. In 2016, Keqiang Li, Premier of the State Council, declared that a “serious disease insurance scheme” would also be included into the basic medical insurance when he was delivering a government work report at the annual parliamentary session. As a result of the upgrade, China’s basic medical insurance has become the largest public insurance program in the world, as it covers more than 1.3 billion of the country’s population and has substantially increased the expenditure by incorporating the SDIS. As an extension of the basic medical insurance, the SDIS was established to prevent more people from “falling back to poverty due to serious diseases (yin bing zhi pin)”. In practice, the SDIS purchases insurance services from commercial insurance companies with a portion of basic medical insurance surplus. Once a qualified insuree is diagnosed with a listed serious disease, he or she can apply for reimbursement for a certain proportion of the medical expenses. According to the Premier, by the end of 2017, 17 million people had settled claims successfully under the SDIS, and such a number was set to rise to 20 million by the end of 2018 [In China’s social security system, two major forms of PPP are widely applied. The first form is that the government sells franchises to private insurance companies, allowing them to sell basic compulsory insurance to the citizens. The second form is to outsource the whole package of a certain kind of insurance, while the government plays such roles as funder, rule-maker, or supervisor . HoweverThe purpose of this paper is to evaluate the implementation of the SDIS in China through a PPP, and to identify the problems to be tackled if the Chinese government intends to make such a plan work better for the majority of urban and rural residents. It is still unclear whether the government and the insurance companies are working closely enough and whether the SDIS has made achievements as expected by the country’s leadership. Among all provinces, Guangdong is the earliest one to have completed setting up its own SDIS. According to our case studies, more than 70 million people had joined the scheme by the end of 2014, and SDISs are conducted via a PPP in 18 prefectures, accounting for more than 85% of the cities in the province. Based on the fieldwork supported by the provincial and local officials, the authors of this paper successfully collected all of the current SDIS contracts in Guangdong, which were signed between insurance companies and local governments. Findings of this paper are based on the reviews of the contract details and their enforcement.The rest of this paper is divided into five parts. In the following section, we briefly review the literature on the PPP theory and generate an applicable analytical framework for this paper. The third section provides an overview of SDIS implementation in China and Guangdong Province; the research methods are also introduced. The fourth section provides empirical evidence to evaluate the implementation of the SDIS. The fifth part discusses the results presented, and the last part concludes the paper.The accurate definition of a PPP remains controversial. Scholars summarize that participants of a PPP include governmental departments, citizens and volunteers, private firms, and non-profit organizations (NPOs) ,9. HowevThe necessity and incentive of PPPs is another hot topic to be discussed. It is advocated by scholars that private firms and NPOs, which normally have stronger economic and social motivations, could be much more efficient than governmental departments . The mecPPPs were not frequently discussed in the field of healthcare until the late 1990s. Scholars tend to pay attention to the effectiveness, benefits, public interests, efficiency, and partnership of PPPs . Among aIn terms of the application of PPPs in China, scholars mainly focus on the relationship between state and social organizations. Ideally, researchers deem that the government should be a smart buyer and a sophisticated supervisor in the purchase of public goods . HoweverCurrent literature has pointed out that PPPs are a promising way to enhance the efficiency and quality in providing healthcare services. However, several gaps are waiting to be filled. First of all, previous research has overlooked the importance of good relationships between the government and non-public sectors in the field of healthcare. Scholars confirm that the government is too strong to maintain good partnerships with social organizations in China, while only a few of them pay attention to the healthcare PPP projects. Second, only a limited number of studies concentrate on the application of PPPs in healthcare insurance. Financing is one of the crucial parts in healthcare services, yet there is an insufficient number of studies that can elaborate on how the approach of PPPs performs in building the insurance system. Third, existing studies have provided plenty of cases in developed countries, while empirical details of developing countries are rare. There is a pressing need to identify the effectiveness of PPPs in healthcare services in China, the largest developing country of the world.To fill the aforementioned gaps, this paper discusses the implementation of the SDIS in Guangdong by reviewing the specific contracts signed by the prefecture-level governments, alongside their subsequent enforcement. Since our analysis mainly depends on the copies of contracts and interviews with local officials, insurance company staff, and scholars, the relational aspect of partnership is emphasized. According to previous studies, the characteristics of PPPs include cooperation; durable relationships; development of mutual products/services; sharing of risks, costs, and benefits; and mutual value addition—most of which are closely related to the relational aspect . The resThis study is mainly based on the implementation of the SDIS in Guangdong Province. Under the documents and guidelines prepared at the national level, provincial and prefecture-level governments began to explore the idea of adopting PPPs while setting up the SDIS. By mid-2014, 260 prefecture-level cities of 26 provinces had built up their own SDISs, covering up to 470 million people in the country .Among all of the provinces, Guangdong was the first province to launch the SDIS in China. In 2009, Zhanjiang became the first city that provided serious disease insurance to the citizens jointly by the local government and commercial insurance companies. In a short period of time, attention from researchers and the leadership was drawn to the innovative experiment of Zhanjiang. By the end of 2012, four other cities in Guangdong, including Shantou, Zhaoqing, Qingyuan, and Yunfu were designated as pilot cities, applying the PPP approach to the operation of basic medical insurance schemes. One year later, SDISs were established in these places, while another 16 prefectures also promulgated planning documents for SDISs. According to the data collected from our fieldwork, 18 prefecture-level cities out of 21 in Guangdong decided to use the PPP approach to set up SDISs. In 2014 alone, more than 70 million of those insured had joined the scheme and 407,000 people had settled their claims. In spite of the rapid development, our data show that there were deficits in 12 cities’ SDISs in 2014, accounting for two-thirds of the total number of prefectures. Does this imply that PPPs are not a suitable approach for SDISs? Using detailed evidence, In this paper, the implementation of the SDIS was examined using the analytical framework comprised of contract status, profit-sharing mechanism, risk-sharing mechanism, and information exchange mechanism. One of the greatest difficulties of research on PPPs is data collection at the local level. Previously, contracts signed between the government and contractors were usually confidential. It was almost impossible to collect a true copy to support academic arguments. Having benefited from the policy of information disclosure, official documents like bid invitations and clauses of the PPP contracts are gradually becoming open to the general public. Although some information may only be available online for a very short period, it still greatly enhances the accessibility of SDIS data. For instance, the city of Zhaoqing located in western Guangdong issued an SDIS bid invitation in early 2019 via the online platform built by the Ministry of Finance. The invitation specified details such as budget, needs, and bidder qualifications. Similar websites of other cities or provinces can also be found easily online. Not only in prefecture-level cities, but also some county-level cities invite SDIS bidders through the same platform. Another advantage of data collection, particularly in this study, is the authors’ close relationships with officials and representatives from both the governments and enterprises, which makes in-depth interviews with them rather convenient to be conducted. In total, the authors interviewed 24 stakeholders, including 16 officials from Guangdong provincial government and nine prefecture-level cities, five senior staff from four major insurance companies, and three researchers in this field. These three researchers are, respectively, from the Institute of Social Security affiliated to the Ministry of Human Resources and Social Security, and the top universities in Guangdong Province and Zhejiang Province. They made suggestions as to how this study could be conducted and provided valuable insights into SDIS from both national and local perspectives. Several informants of this research were also recommended by them.Specifically, this research was carried out as follows. First, we searched for and downloaded bid invitations and contract templates from Guangdong Public Resources Trading Center and local Human Resources and Social Security Bureaus (HRSSBs). Contracts and documents from 18 cities were collected. A preliminary judgement of contract status was formed at this stage. After the thorough review of documents was finished, we invited stakeholders of SDISs to have in-depth interviews and verified our findings. Semi-structural interviews and participant observation were the main techniques used. The authors were also invited to participate in a number of meetings and to provide suggestions as third-party experts. The major meetings are including two seminars on SDIS organized by the Human Resources and Social Security Department of Guangdong Province, negotiation meetings between local governments and insurance companies in two prefecture-level cities and two symposiums organized by Guangdong Social Insurance Association. As the authors are not affiliated to, or funded by the above governmental departments or organizations, we are capable of giving advice on how to promote and improve the implementation of SDIS from a neutral point of view. The documents and notes collected were reorganized and sorted out manually or by software . The selected key findings and arguments are presented in the following sections. To protect the interviewees’ identities, all of their personal information was removed. The names of the related cities were replaced by codes  to make sure that the sensitive information is untraceable.In a healthy relationship, the statuses of HRSSBs and insurance companies should be equal, based on the fair clauses in the contracts. Yet the real story was not told as expected. Our fieldwork indicates that the HRSSBs tend to have full control in the processes of contract preparation and execution.In terms of contract drafting, the cities’ HRSSBs are the dominant actors. All of the rules and details are decided by the local officials. In practice, the government does not care much about the professional qualifications of insurance companies. Instead, they only pay attention to how low their quotations can be. As long as the price is low enough, a bidder will possibly win the competition. In one of our interviews, an associate department head of a HRSSB said:“Current bid invitations of SDIS and contracts are all prepared by the local government sectors. Details including management cost, profit rate and even staff headcount are prescribed rigidly. In some cities, communication between government and insurance companies may be better than others, but it does not make any substantial differences.”(Interview Number: BJ02092401)The length of the contract is another critical factor. According to other scholars, contract length reflects the degree of trust between the partners ,44. An SSigning short-term contracts is rather harmful to PPPs. For insurance companies, deficit becomes almost unavoidable. To cut the loss, they can only invest limited resources and manpower into SDISs, jeopardizing the interests of the common insured. For the governmental departments, frequent changes of partner also significantly increase managerial cost and uncertainty.In addition to the contract drafting and contract length, execution of contracts also restricts the operation of the insurance companies. Savas advocates that enough flexibility should be left to the contractors in order to encourage them to innovate . InsteadA rational profit-sharing mechanism is the key component to the building of sustainable partnerships between the public and private sectors . Documen“The existing deal in our city is rather harsh. The management fee of the insurance company is six million yuan per year. I am sure that they cannot break even. According to the contract, they should assign 200 staff to handle SDIS. The maximum profit rate they can reach is 4%, which is definitely less than six million. As a result, they come to me every day and tell me how difficult they feel.”(Interview Number: RS02091101)The breakdown of management cost is also controversial. The China Insurance Regulatory Commission merely stipulates that manpower cost and promotion cost can be covered by the funding for SDISs; temporary costs, including software maintenance cost, staff training cost, and consultation cost, cannot be taken into account. In some cities, these kinds of costs can account for up to 90% of the total management cost. A department head of a large state-owned insurance company stated to us:“We have hired a large number of staff specifically for SDIS. The burden of our human resource department has been increased substantially. The building of information system for SDIS also costs a fortune. To be fair, I propose that all these expenses should be taken into account as formal management cost approved by the government.”(Interview Number: SYBX01102001)Even though an SDIS is not a profit-seeking project, it is rather necessary to review the rationale of the current calculation method of cost-bearing and profit-sharing. In the cases of Guangdong, deficits are commonly seen in most of the SDISs. To motivate the insurance companies, a more competitive rate of profit should be put forward.The major risk of implementing SDISs is the potential deficit. At the provincial level, only a broad guideline is provided by the Implementation Scheme of Serious Disease Insurance of Guangdong (Guangdong dabing baoxian shishi fangan). It stipulates that deficits brought by state policies (zhengcexing kuisun) should be handled according to the contract, while other kinds of deficits (feizhengcexing kuisun) should be undertaken by the insurance companies. At present, there are four types of risk-sharing or deficit-sharing mechanisms in Guangdong. As The existing flawed deficit-sharing mechanism fails to provide sufficient protection to the insurance companies. Referring to our fieldwork, deficits of SDISs were recorded in 10 cities of Guangdong in 2014. The total loss was 133.95 million yuan. Only 20.53 million yuan (15.3%) of the total loss was covered by the local governments. Seven cities did not pay any money for the loss. The rest of the deficits  were undertaken by the insurance companies. Technically, even loss covered by the government is undertaken by the basic medical insurance, which is actually supported by the insured themselves. In this manner, the local government takes no responsibility at all, whereas the allocation of deficits of SDISs indicates that insurance companies take too much.Information exchange is crucial to the success of PPPs ,42. The First, the local HRSSBs refuse to provide the historical data of medical insurance programs. Actuarial analysis relies heavily on accurate information of the past. It is a technique based on the assessment of “big data”. Without the help from local officials, insurance companies can merely estimate and figure out a rather rough number of premiums, which could significantly deviate from reality.Second, information sharing is against the current legal arrangements. According to the current version of Social Security Law, public sectors are prohibited from leaking personal information of the insured (Article 81). As a result, it is impossible to set up an information exchange mechanism between local HRSSBs and insurance companies. The associate head of C City’s HRSSB stated:“Social insurance information system contains a vast amount of personal information of all the insured. Protecting it is one of the most important jobs of both national and local governments. Unless the higher level orders us to do so, we will never sharing any of personal information with insurance companies.”(Interview Number: RS02091102)Third, insurance companies have no right to inspect the operational details of SIDSs. In most of the projects, SDISs are associated with the basic medical insurance. Therefore, inspection of the operation of SDISs can only conducted by HRSSD officials. Staff from insurance companies are forbidden to join. A department head of A City explained:“The insurance company wanted to inspect our data of basic medical insurance. We turned them down for two reasons. First, we believe that they should contact the hospital instead of us to acquire data. Second, according to the signed contracts, it is already a mutual agreement that SDIS should settle the claims once a case is qualified. We are the ‘accountants’ and they are the ‘cashiers’. They should follow our orders and trust our decision. We will not share out basic medical insurance data with them.”(Interview Number: RS02091103)According to the evidence above, SDISs are an extension of basic medical insurance and are set up with the PPP approach to financially protect Chinese insurees from serious diseases. The growing number of settled claims in recent years indicates that SDISs are rather successful on the demand side. However, our study argues that the performance of the supply side is far from satisfactory due to the unfavorable relationship between the local state and insurance companies. We established and applied an analytical framework to evaluate SDIS implementation in Guangdong and discovered that the status of the local state and insurance companies is not equal under the PPP. The latter can only take orders from the state and they must follow every detailed rule. They also bear most of the risks while they can only share a small part of the profit. In terms of information exchange, insurance companies cannot gain enough data for basic operation. In the relational aspect of PPPs, we argue that the major constraint of SDIS implementation at the current stage is the predominance of the local government and the lack of trust. It appears that a de facto “master–servant” type of relationship between the local government and the insurance companies has formed. Having revisited some of the key officials and insurance company staff, we identified two major explanations, which will be elaborated in the following subsections.The local governments have extremely strong motivation to prevent insurance companies from becoming involved in the core business of SDISs. Scholars argues that social security system reform is a process to find an optimal combination of the state and the market . In 2009In this case, what is the opinion of local HRSSBs? In cities where HRSSBs are understaffed, insurance companies are quite welcome by the officials. The SDIS of Z City is a vivid example. One of their officers said to us:“In 2009, due to the combination of UEEMS and URRBMIS, the population managed by us had increased from 580,000 to 5.46 million. At that time, we were underfinanced and understaffed. People’s Insurance Company of China (PICC) contacted us and proposed that they could set up SDIS. As the result of negotiations, we agreed that 15% of basic medical insurance premium of Z City would be used to purchase serious disease insurance from PICC. With their help, we can handle a larger amount of work without increasing the headcount of our staff.”(Interview Number: RS02091604)However, HRSSBs and insurance companies do not get along well in many other cities. According to the findings from previous studies, bureaucracies inherently tend to maximize their budget . They haFrom the perspective of many HRSSB officials, whether the approach of PPPs should be introduced remains rather controversial. Opponents deem that insurance companies merely want to take a share of the profit generated by SDISs. Referring to a high-level official, local HRSSBs are absolutely capable of handling SDISs by themselves without using additional facilities or hiring more staff . In othe“Whether to invite insurance companies to SDIS is a case-by-case topic. If the local HRSSB is too small to handle it, using PPP is understandable. But the case is different in our city. When we invited PICC in 2014, we actually had a large team of staff who can deal with all kinds of SDIS matter. We agreed to use PPP only because it was the policy actively promoted by the central and provincial governments.”(Interview Number: RS02072805)Commercial insurance companies are enthusiastic to take part in SDISs because they have set their sights on long-term goals. They decide to pay more attention to acquiring larger future development space rather than short-term interests. With this principle, insurance companies do not refuse to operate defective SDIS projects. From their point of view, being involved in government-funded projects offers them the chance to get in touch with more potential clients and explore more business opportunities, just as a project manager said:“We believe that SDIS is definitely not the only insurance program that conducted by PPP approach. We can learn from Premier Li’s report that market mechanisms will be introduced to much more social security projects. For companies like us, operating SDIS is a process of building trust with government officials and fellow citizens. When the insured want to purchase other insurance programs or the local governments plan to launch another social insurance project, we are likely to be selected and become their partners again.”(Interview Number: SYBX01102003)Another reason for the companies’ enthusiasm is the accessibility to valuable data. Compared with developed countries, the Chinese insurance industry lacks reliable data and experience. This situation has severely limited the development of nearly all insurance companies. SDISs provide an option to change the status quo. By sorting out the information of the insured, insurers can design and develop more suitable plans for their Chinese clients. For the larger companies such as PICC and Pingan, operating SDISs can also optimize their decisions on selecting the location of branches, and on allocation of staff. An officer from E City had seen it through and said to us:“The main objective of our partners from insurance companies is to access to our data. In the near future, they may seek for more chances to set foot in the detailed management of basic medical insurance. To achieve this goal, they are willing to undertake current losses. In the long run, they will absolutely benefit from it.”(Interview Number: RS02072806)In summary, although the central government actively promotes SDISs conducted through the PPP approach, many of the local states merely react passively. The principles of PPPs have been severely twisted in multiple cases. Local HRSSBs only regard insurance companies as a tool to relieve their financial burden, while they have made great efforts to keep the companies away from the center of their turf-power, funding, and information. According to our examination on the implementation of SDISs in Guangdong, the de facto “master-servant” relationship between local HRSSBs and local insurance companies has caused four aspects of damage. For the local HRSSBs, the morale of officials is generally low, as they should maintain the control over SDISs and always take precautions against the insurance companies. For the insurers, the effectiveness of participating in SDISs is always questionable. The pursuit of profit is at variance with deficits generated by SDISs. At some point, it could be rather difficult for the insurers to decide whether they should continue to invest in SDISs, regardless of the growing cost. In addition to impairing the “master” and the “servant”, collateral damages are also suffered by hospitals and patients. In the past, only the local Health Commissions  and HRSSBs were responsible for regulating the operation of hospitals. Currently, the insurance companies are encouraged by the central government to engage in controlling medical expenses. Even though insurance companies have no genuine authority at this stage, taking orders from one more regulator is the last thing that hospitals are willing to do in the future. As the insured of SDISs, patients are supposed to be the major beneficiaries, especially the poor. Nevertheless, since the insurance companies have not yet acquired sufficient clearances to access to the data they need, the process of settling claims via an SDIS could be long and tedious. If the aforementioned unfavorable circumstances do not improve as soon as possible, PPPs based on SDISs are likely to break down at some point in the future.Relying on the national expansion of basic medical insurance, serious diseases insurance has nominally covered every Chinese citizen. The number of claims settled by SDISs has been growing every year since its large-scale implementation. As the pilot province of most of the reforms, Guangdong was the first place to launch an SDIS and applied PPPs as the major operational approach. The purposes of using PPPs in SDISs include enhancing efficiency, encouraging institutional innovation, and improving the state-society relationship. This idea is similar to the one advocated by the “Reinventing Government” movement in the US, which believes that the government should “steer, not row, the boat” ,52.The findings of this paper are against the above vision. The authors thoroughly reviewed the accessible SDIS contracts of 18 cities in Guangdong. The details of contract enforcement were also investigated through interviews with local officials, insurance company staff, and scholars. We realized that the relationship between the local government and the insurance companies is of a de facto “mater–servant” type rather than an equal “public-private” partnership. Such a summary is based on four findings. First, local governments have manipulated contract drafting and enforcement; thus, the status of insurance companies becomes rather subordinate. Second, insurers are merely allowed to pursue meager profit; it is impossible to yield a considerable amount of income from SDISs. Third, insurers undertake nearly all of the risks. Following the provincial guidelines and contracts, it is always the insurance companies that are responsible for covering the majority of the losses incurred by SDISs. Last but not least, information exchange is blocked by the local state. Therefore, insurance companies have no choice but to operate SDISs blindly without sufficient data. Substantial evidence indicates that the twisted public–private partnership has jeopardized the further development of SDISs. To improve government-funded medical insurance services, a more fair and equal status between China’s local state and insurance companies is awaiting to be built.The findings of this paper confirm the importance of the relational aspect in PPP operation. As the literature suggests, we also found that the performance of SDISs heavily depends on the quality of the contract, interaction, managerial activities, and trust between both parties ,35. The We also admit that this study has some limitations. Since our analytical framework is mainly based on the relational aspect of PPPs, proper adjustments are needed when it is applied to cases other than SDISs. Moreover, although we took most of the cities in Guangdong Province into account, concentrating on a handful cases may not be able to reveal the whole picture of SDISs in China. Comparisons offered by future studies would definitely improve the findings of this paper.


Background: One Health is a comprehensive and multisectoral approach to assess and examine the health of animals, humans and the environment. However, while the One Health approach gains increasing momentum, its practical application meets hindrances. This paper investigates the environmental pillar of the One Health approach, using two case studies to highlight the integration of environmental considerations. The first case study pertains to the Danish monitoring and surveillance programme for antimicrobial resistance, DANMAP. The second case illustrates the occurrence of aflatoxin M1 (AFM1) in milk in dairy-producing ruminants in Italian regions. Method: A scientific literature search was conducted in PubMed and Web of Science to locate articles informing the two cases. Grey literature was gathered to describe the cases as well as their contexts. Results: 19 articles and 10 reports were reviewed and informed the two cases. The cases show how the environmental component influences the apparent impacts for human and animal health. The DANMAP highlights the two approaches One Health and farm to fork. The literature provides information on the comprehensiveness of the DANMAP, but highlights some shortcomings in terms of environmental considerations. The AFM1 case, the milk metabolite of the carcinogenic mycotoxin aflatoxin B1, shows that dairy products are heavily impacted by changes of the climate as well as by economic drivers. Conclusions: The two cases show that environmental conditions directly influence the onset and diffusion of hazardous factors. Climate change, treatment of soils, water and standards in slaughterhouses as well as farms can have a great impact on the health of animals, humans and the environment. Hence, it is important to include environmental considerations, for example, via engaging environmental experts and sharing data. Further case studies will help to better define the roles of environment in One Health scenarios. One Health is a concept that has gained popularity during the last years, especially since the Tripartite engagement of the World Health Organization (WHO), the Food and Agriculture Organization (FAO) and the World Organization for Animal Health (OiE) in 2010 [“An approach to address a health threat at the human-animal-environment interface based on collaboration, communication, and coordination across all relevant sectors and disciplines, with the ultimate goal of achieving optimal health outcomes for both people and animals; a One Health approach is applicable at the subnational, national, regional, and global level.”Infectious zoonotic diseases are a main One Health issue, as these diseases transmit from animals to humans and vice versa. The environment, where humans interact with farm animals, pets or wild animals, plays an important role for disease transmission. The ecosystem and how it is shaped by human activities like agriculture, is an important determinant for the risk assessment of zoonoses transmitted by wildlife . ClimateAntimicrobial resistance (AMR) is another topic that points out the connectedness of animals, humans and the environment. It is a global concern as it threatens the ability to treat infections in humans, animals and plants. AMR occurs when microbes such as bacteria, fungi, viruses or parasites change so that conventional treatments fail. Factors that increase the selective pressure toward resistant pathogenic strains are misuse and overuse of antimicrobial drugs in humans and livestock; inadequately tested antimicrobial pesticides for plants; inadequately enforced agricultural regulations; as well as insufficient awareness. AMR can spread between humans and animals and circulate through the environment; for example, via food products . The preThe increasing threat of zoonoses and AMR highlight the importance of a One Health approach able to cope with complex, multifaceted problems. While the One Health approach evolved especially since the Tripartite engagement of the WHO, FAO and OiE in 2010, similar approaches like farm to fork have been introduced, too . In partHowever, while the One Health approach gains increasing momentum because of its multifaceted aspects and due to the Covid-19 pandemic, its practical application meets hindrances . One HeaIn the evolving One Health field, there are gaps, open questions and challenges about meaningful integration and institutionalisation of the approach . ZoonoseWhen reviewing One Health activities, veterinary as well as medical themes prevail and the environment is often neglected . Neverth(I)Environmental changes modulating risk factors for healthIn the following and displayed in A good example for environmental changes is provided by climate change. Events driven by climate changes may increase the availability of toxicants for food-producing organisms: erosion of soils from flooding, heavy rainfall, thawing of frozen soil and forest fires release mercury from “trapping” environments into the ecosystem . Factors(II)Anthropogenic activities as a source of One Health risk factors through the environmentAnthropogenic activities are main drivers that shape the environment ,33. EnviAs highlighted above, it appears that the environmental pillar of One Health is evident, yet, case studies are needed to assess and exploit the environmental component in a One Health-based risk analysis.This study presents two cases to portray the importance of environmental considerations in the One Health interface. The abovementioned scenarios are used as an orientation under which the cases are arranged. The two cases describe the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) and the environment-driven impact of the mycotoxin aflatoxin M1 on dairy farming in Italy.Two cases were identified to exemplify One Health approaches with environmental considerations. The first case describes the DANMAP. A scientific and grey literature review was conducted to locate relevant articles and documents to describe the case. For this purpose, the database Web of Science was searched. The literature search included relevant articles in English from 1995, the year in which DANMAP was implemented, until January 2021. Keywords used for the search for the DANMAP case included the terms “DANMAP”, “AMR”, “Antimicrobial resistance”, “from farm to fork”, “One Health”. Included were English articles that mentioned DANMAP or articles containing themes pertaining to antimicrobial resistance in Denmark. Disregarded were articles that presented research on specific pathogens or scientific methods.https://www.danmap.org/ (accessed on 27 January 2021)). The reports are mainly in English, but the report from 1997 written in Danish was also included. Additional sources were either found through references in the reports or internet searches.The grey literature search gathered DANMAP reports and additional information on the Danish and European antimicrobial resistance approach. The grey literature was located through a web search via Google. DANMAP reports were found on the website created for the programme . From this search, two subsets were extracted, using as search terms “climate” and “Italy”. The search included English articles published from the early 2000s, when the first aflatoxin case in Italy occurred, until January 2021.Datasets from an EFSA opinion on aflatoxins and by the Italian Food Safety National Committee were also used ,40. GreyThe literature search revealed scientific articles and reports that aided the analysis of the two case studies. The search identified 294 articles, of which 28 articles were included into the analysis; see Denmark implemented the AMR monitoring programme DANMAP to tackle the challenges of AMR in 1995, and it was the first country to do so . The proEscherichia coli from fruit and vegetables was also found for eight antibiotics. No further specifications of actions or implications were mentioned in the report. While in the 1996 and 1997 reports, fruit and vegetable sampling was mentioned, it was not mentioned in the DANMAP reports after 1997.The DANMAP has since produced scientific knowledge on AMR and it focuses on the collaboration between the human, food and veterinary sectors, but also includes other stakeholders like farmers, slaughterhouses and pharmacies . Since tFor most of the years from 1997, the DANMAP reports have mentioned the approach from farm to fork and it was integrated into the AMR surveillance activities ,48. The Since 2010, the One Health approach has been incorporated in the reports and emphasised as a fundamental principle when monitoring and researching AMR . AlthougSeveral aflatoxin “crises” have occurred in northern Italy, the first and most severe in 2003 and the last happened from 2015 to 2017. These events were characterised by highly increased levels of Aflatoxin B1 (AFB1) in corn used for feed, and of Aflatoxin M1 (AFM1) in milk and dairy products. This happened in relation with environmental conditions featuring high temperatures, drought and enhanced insect damage of the crop ,52,53.Aflatoxins rank prominently among mycotoxins because of their genotoxic potential. AFB1 can cause hepatocellular carcinomas in humans, a type of liver cancer, with a higher risk for people infected with the hepatitis B or hepatitis C virus. EFSA considers that current levels of exposure to aflatoxins in foods may represent a health concern, in particular for younger age groups. In Europe, the food categories “liquid milk” and “fermented milk products” have been identified as the main contributors to overall AFM1 exposure throughout all age groups, infants being most exposed. Legal limits of foods and feeds and official monitoring programs are in place to prevent the risks for human and animal health due to aflatoxins. In the European Union, the legal limit for AFM1 in dairy products is 0.05 microgram per kilogram . AflatoxAFB1 affects mainly grains and nuts, which are also the main sources of human exposure. However, the contamination of crops, such as corn used as animal feed, lead to the intake and digestion by farm animals. Dairy-producing ruminants transform AFB1 into AFM1, which is also a public health hazard, because it is genotoxic and carcinogen in vivo, even though it is less potent than AFB1 with respect to liver carcinogenicity. The toxic metabolite resulting from feed contamination is found in dairy products of ruminants like cattle, sheep, goats and buffaloes ,51. DairThe area with the highest milk production is the Po Valley in northern Italy, and it is among the foremost agriculture intensive areas in Europe. The different environmental farming conditions of low- and high-yield dairy cows have an impact on AFM1 contamination. In low-yield cows, the carry-over of AFM1 to milk is in the 0.1–0.5% range of the AFB1 intake, but it is 1% to up to 6% in high-yield cows ,58,59. TThe latest data provided by the National Reference Centre for the quality of bovine milk showed that the climatic trend in late spring and early summer is the critical factor influencing the extent of AFB1 contamination in cereal and corn crops . This trIn southern Italy, the climate affects aflatoxin occurrence as well, although concentrations in milk are generally low in this area due to lower humidity, less intensive farming and lower milk yield per animal. However, AFM1 contamination was significantly higher in cold season, particularly in autumn, than in the warmer season of spring. In this scenario, the non-compliance with the legal limit was just 0.1% .The crisis of 2003 has prompted the Italian Ministry of Health to issue a contingency plan for the prevention and risk management of aflatoxins contamination in the dairy chain and in the production of corn for human and animal consumption in extreme climatic condition . BesidesThe two case studies illustrate how the environment interacts with the health of humans and animals, making up an essential pillar of One Health. Indeed, environment-related factors can play multiple roles that need proper characterisation to manage the complexity inherent to One Health issues. In the following, the two cases will be categorised under the established scenarios  to highlThe Italian aflatoxin case illustrates well how toxic pollutants fit into the One Health context, bringing together human health, animal health and their products as well as the environment . AflatoxThe AFM1 case study highlights some noticeable implications. A number of economic drivers orient a large part of the dairy production of the Po Valley toward high-quality products like the made-in-Italy cheeses Parmigiano and Grana. These meet high demand from national and international markets, but require high-yield cows and high costs to maintain the technologically developed intensive farming . This ecThis case study exemplifies the far-reaching impact of the environment in which feed is grown, from a One Health perspective. Although the current data indicate a low or very low carcinogenic risk from AFM1 in Italian dairy products, changes in the climate, as well as potential health hazards, justify continuous monitoring, crisis preparedness and regular updates of the exposure assessment . In partAnthropogenic activities have led to new challenges for the environment . Hence, The involvement of researchers from different disciplines and the cooperation among veterinary, food, human and environmental laboratories in terms of data sharing and common technological platforms are proficient ways to integrate the environment sector into AMR surveillance ,48. AddiFor instance, plant agriculture frequently uses antibiotics to enhance crop yields. This means that fruits and vegetables can be a source for AMR ,63. PestHowever, more data are needed to conduct a meaningful risk assessment that comprehensively considers these environmental factors and weighs their possible contributions. Continuous monitoring and assessments must be maintained to prevent AMR and toxic by-products entering the ecosystem. Readopting sampling and screening measures within DANMAP for fruits and vegetables can aid in determining the current role of AMR and pesticides.Further, monitoring manure used on soils is essential to screen AMR and infectious agents to prevent the spread into the food chain ,67. In cIn the case of DANMAP, the farm-to-fork approach and the One Health strategy are integrated into the programme. The reoccurring emphasis of the One Health approach can strengthen the inclusion of all disciplines. Nevertheless, it is important to consider that this does not necessary entail that all disciplines must be represented equally in each scenario. Transmission routes for AMR-carrying microbes occur more often through contacts between animals, their products and humans rather than through the environment ,70. HencThe two case studies show that the assessment of environmental risk factors is relevant to One Health surveillance. The accumulation of toxins from fungi, pesticides, manure or other sources in the environment can have downstream effects on human and animal health. Food as well as feed safety and surveillance are important to detect foodborne diseases and harmful accumulated chemicals. A structured analysis based on the identification of points of particular attention can support surveillance activities. Under this respect, Lombardo et al. have proposed a scheme for the analysis of environment-related factors in the animal farming scenarios with a One Health view. The proposed system considers the area  and farm characteristics  . In addiThe surveillance of terrestrial and aquatic ecosystems are of increasing interest and relevance in the One Health approach, as knowledge of the ecology of organisms can help to model and predict recurrent threats. Examples include, but are not limited to, blooms of toxic algae and outbreaks of infections spilling out from wildlife like bats, to humans ,73. In tThe environment can encompass water or soil, but it can also cover less obvious areas such as slaughterhouses or other areas where food is produced and processed, as it was exemplified by the DANMAP and the AFM1 cases. Through these different environments, humans and animals are in some ways always connected, which highlights the importance of finding ways to integrate environmental perspectives via engaging experts, employing techniques to assess environment-related factors and sharing data. The One Health approach provides an essential tool to link various disciplines, and to investigate the specifics and added values of each field. Not missing out on the environmental pillar will benefit the One Health approach through opportunities for environmental research that aid to better understand links between humans, animals and the ecosystem. Additionally, the Covid-19 pandemic points out that the health impact of an infection can be significantly modulated by a number of environmental factors ,29,30,31One Health is an approach to assess and manage complex public health issues that are cross-cutting and require the cross-fertilisation and integration of different expertise ,2. ThereInternational engagements like the Tripartite or European approaches must continue to refer to One Health, while also emphasising the importance of the environment pillar of the One Health approach.In the AFM1 case study, environmental components are represented mainly by climate patterns and by the more or less intensive dairy farming scenarios in different Italian areas. These determinants are directly influencing the extent of contamination of feed by AFB1 and of milk by AFM1, and thus are directly linked to the AFM1-associated risk to human health ,53,55,56In the AMR case study, the environment is not the main area of focus of the DANMAP, but nonetheless important, as anthropogenic activities contribute to the flow of bacteria-carrying AMR from sources like hospitals and farms. Potential overuse and misuse of AMR contribute to the occurrence of AMR in the environment, in particular soil and water, which are reservoirs for animals and humans ,63,67.One Health is a developing, multifaceted web of feedbacks and interactions among its components. The goal is not to drown in complexity, but to manage complexity. Further work is needed to better define the roles of environment in One Health scenarios. The characterisation of environmental factors is paramount to model the risks for animal and human health. One Health should be implemented as an institutional tool in public health, especially fit for evidence-based priority setting and to support decision-making ,20. More


Drosophila has been a useful model organism for the interpretation of different phenotypes during development as well as the understanding of the dynamics of this complex. Interestingly, phenotypes similar to those observed in humans caused by mutations in the TFIIH subunits are present in mutant flies, allowing the study of TFIIH in different developmental processes. Furthermore, studies performed in Drosophila of mutations in different subunits of TFIIH that have not been linked to any human diseases, probably because they are more deleterious, have revealed its roles in differentiation and cell death. In this review, different achievements made through studies in the fly to understand the functions of TFIIH during development and its relationship with human diseases are analysed and discussed.Human mutations in the transcription and nucleotide excision repair (NER) factor TFIIH are linked with three human syndromes: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). In particular, different mutations in the XPB, XPD and p8 subunits of TFIIH may cause one or a combination of these syndromes, and some of these mutations are also related to cancer. The participation of TFIIH in NER and transcription makes it difficult to interpret the different manifestations observed in patients, particularly since some of these phenotypes may be related to problems during development. TFIIH is present in all eukaryotic cells, and its functions in transcription and DNA repair are conserved. Therefore,  The transcription of genes that encode messenger RNAs, (mRNAs), long non-coding RNAs (lncRNAs) and micro-RNA (miRNA) precursors in eukaryotic cells is conducted by the RNA polymerase II (RNPII) enzyme . HoweverTripterygium wilfordii plant used in traditional Chinese medicine, targets the XPB subunit by covalently binding the ATPase domain and therefore inhibits its translocase and helicase activities [Interestingly, drugs that target some of the enzymatic functions of TFIIH have been found or developed. For instance, the drug triptolide, a diterpene tripoxide produced by the tivities ,12. Furttivities ,14,15,16In addition to all the important roles of TFIIH in transcription, DNA repair and cell-cycle control in eukaryotic organisms, TFIIH is also relevant to human health, since mutations in some of its subunits are related to three complex human syndromes. Mutations in the XPB, XPD and p8 subunits are linked to the generation of xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). Mutations in XPB and XPD may generate XP syndrome; patients with XP syndrome are highly sensitive to UV irradiation and prone to develop skin cancer ,19,20,21Drosophila has been useful to not only understand how defects in TFIIH that affect transcription and DNA repair impact the development of the organism but also study the effect of mutations in other TFIIH subunits that have not been related to human diseases, probably because they have a more deleterious effect on mammal development. In the following sections, we will analyse and discuss the contribution of Drosophila to understanding how alterations in the functions of TFIIH affect tissues at different developmental stages and adult tissues.Due to the different functions in which TFIIH is involved, it has been challenging to associate the different manifestations of human syndromes related to TFIIH with particular molecular processes. The molecular nature of the mutations linked to each of these syndromes in the corresponding TFIIH subunit has been identified in many human patients ,26. In tDrosophila to study homozygous organisms carrying lethal alleles has been possible, allowing the analysis of the defects at different stages of development. This has been the case for the use of different mutant alleles of the TFIIH subunits. The first characterization of a mutant allele of a TFIIH subunit gene was the haywire (hay) gene, which encodes the Drosophila XPB subunit. This allele, named nchay, was identified in a genetic screen for genes that interact with testis-specific tubulin and generate male sterility [hay phenotype in the testis was suppressed were isolated and identified as point mutations of the same hay gene [nc2hay allele and all the revertants were highly sensitive to UV irradiation, as heterozygous mutants, and haync2 behaved as an antimorphic mutation, while all revertants were hypomorphic and homozygous lethal [hay alleles was semilethal, allowing adult organisms to be obtained [hay gene under a mutant hay heterozygous background enhanced these phenotypes [hay mutant alleles and a conditional cdk7 mutant for these phenotypes, which was the first demonstration of a functional interaction between two TFIIH subunits in a complete animal. Both the cuticle and bristle phenotypes were shown to correlate with a reduction in the transcript levels of genes involved in cuticle formation and, together with the genetic interaction between hay and cdk7 mutants, strongly suggested that these phenotypes are linked to transcriptional defects [hay mutants [The use of terility . In addihay gene . The hays lethal ,34. Howe mutants ,34, demoDrosophila has also allowed the study of mutations in TFIIH subunits that have not been related to human diseases, probably because their effects are more deleterious and these subunits have a structural and regulatory role in TFIIH. One such example is the p52 subunit. The marionette (mrn) gene encodes the p52 homologue in Drosophila, and initial studies using a combination of alleles showed phenotypes similar to those observed in hay mutants, particularly cuticle and bristle defects [Drosophila contributed not only to finding cellular defects generated during development when TFIIH is not functional but also to understanding the mechanistic role of this subunit in the functions of TFIIH. defects . In addi defects . Additio defects . These eThe implementation of the UAS-GAL4 system in Drosophila allows an easy study of gene functions. Using this system, it was possible to direct specific interfering RNAs against TFIIH subunits in particular cell types. Using this system against the p52 and p34 subunits in the wing imaginal disc, a reduction in the size and number of the cells that generated smaller wings compared with wild-type wings was shown . IntriguThe p8 TFIIH subunit is enigmatic. When TFIIH was purified from human cells and yeast, all components of the complex were visualized by SDS-polyacrylamide gel electrophoresis, and 9 subunits were identified; however, p8 was not visualized because despite its presence in the gels, as p8 is a 72 amino acid protein, it was not stained. In addition, rare cases of TTD in which neither XPB nor XPD was mutated were identified. A mysterious gene was still missing and named TTDA . It was Drosophila and in all arthropods, p8 is encoded as a bicistronic transcript with a subunit of the SWIR complex [Drosophila. Homozygous flies for this allele are viable; however, males are sterile and present a minute-like phenotype, similar to p52 mutants [Drosophila has allowed a better understanding of the effects of the TFIIH complex during development linked to the different manifestations observed in humans afflicted with XP, CS and TTD.In  complex . Thus, t mutants ,40. Inte mutants  and seemDrosophila, the necessity of Cdk7 for CAK activity was demonstrated in vivo, since temperature-sensitive mutants were defective in activation of the cdc2/Cyc A and cdc2/Cyc B complexes and therefore exhibited defects in cell division [Drosophila that dominant negative mutants of cdk7 delayed the onset of transcription in the early embryo but did not affect the fast and synchronized nuclear cycles at the syncytial blastoderm [As mentioned before, the CAK subcomplex of the TFIIH complex independently participates in cell cycle control. For some time, the direct role of Cdk7 as a Cdk-activating kinase (CAK) was elusive. In division . Howeverastoderm .Drosophila embryos generated a decrease in the T-loop phosphorylation in other Cdk proteins as well as mitotic defects; in contrast, a reduction in XPD levels caused an increase in CAK activity and cell proliferation [In addition, the dual role of the CAK subcomplex in cell-cycle control and RNPII transcription has been the subject of investigations on how the CAK subcomplex is regulated. Initially, it was suggested the XPD subunit of the core subcomplex of TFIIH controls the cell cycle function of Cdk7 . This hyferation .Drosophila XPD was shown to interact with MMS19, Galla1 and Galla2, which are homologues of MIP18, and the product of crumbs [Drosophila could be rescued by overexpressing the CAK subcomplex or reducing the levels of XPD [hay (XPB) in Drosophila cause defects in mitosis and chromosomal segregation in early embryos that are identical to the phenotypes observed in XPD mutants that were attributed to deregulation of the CAK subcomplex [Further studies on the possible regulatory role of XPD in CAK activity showed that the complete absence of XPD in early embryos caused defects in the formation of the mitotic spindle as well as changes in the distribution of the CAK subcomplex in different subcellular compartments . Intriguf crumbs . Mutatios of XPD . Additios of XPD . These ls of XPD . Within s of XPD . XPD alsbcomplex . In addibcomplex . FurtherDrosophila, then, is an interesting model in which to study the association between cancer and TFIIH. All the mutants flies in which core subunits of the TFIIH complex were mutated were shown to be sensitive to UV irradiation with different penetrance. Intriguingly, the XPD mutations that generated the highest degree of UV sensitivity in Drosophila were not correlated with XPD mutants in humans that generate a higher predisposition to cancer [The fact that mutations in TFIIH subunits generate mitotic defects and chromosome instability links TFIIH with cancer. In addition, patients with XP have an increased predisposition to skin cancer. o cancer . On the o cancer . These rDrosophila, it was demonstrated that the TFIIH complex plays a direct role in regulating the fly homologue of human MYC. MYC in humans is a proto-oncogene that is overexpressed in a large number of different types of tumours, and part of its role in oncogenesis is to over-activate a large number of genes [Drosophila, Hlp acts as a tumour suppressor; furthermore, mutations in this gene generate cellular overproliferation due to XPB-dependent overexpression of fly myc [In addition, in of genes . One of of genes . Part ofof genes . Half pr fly myc ,53.T. wilfordii, a plant used in traditional Chinese medicine with antiproliferative properties, targets the XPB subunit of the TFIIH complex [Drosophila. Therefore, the loss of apico-basal polarity by a reduction in the levels of disc large 1 (dlg1), which is involved in basolateral junctions [ras mutant allele was used as a model in which severe carcinomas in the wing disc were generated (wingless (wg) was dysregulated, but in the discs from similar larvae fed TPL, the expression pattern of wg was partially recovered , one of the more intriguing stages in animal development, is the moment when gene expression is activated for the first time . During  the egg . After n the egg . To acti the egg  More rec the egg .In addition to RNPII and TBP dynamics and the functions of components of the PIC, only studies of TFIIH complex subunits have been performed in the early fly embryo. The first studies on the TFIIH complex suggested that most of the core subcomplex components of the TFIIH complex were cytoplasmic and that these components were localized in the nuclei before the first wave of transcription . HoweverDrosophila are important for understanding the role of TFIIH during development and to relate the TFIIH complex with the functions that are affected in cancer and human syndromes since mammalian models are more complicated and expensive.These studies in Drosophila is a suitable model to analyse the effect of genetic alterations related to human diseases. In the particular case of TFIIH-related syndromes, it has been possible to study defects in the fly produced by mutations in different subunits at a level that cannot be attained in mammal models. In addition, interpretation of the complex genotype–phenotype relationship has been less complicated in Drosophila, particularly in phenotypes that are generated during the development of the organism, such as the increase in apoptosis in the nervous system and catastrophic mitosis in the early embryo and larval tissues. In addition, phenotypes in Drosophila similar to some of the manifestations of TTD or CS in patients, such as a thin cuticle, brittle bristles and the minute phenotype, were clearly shown to be caused by problems in transcription. Furthermore, in Drosophila, it has been possible to study mutations in other TFIIH complex subunits that appear to be highly deleterious in mammals. However, there are still several aspects of this complex that can be studied in Drosophila to complement work performed in other models and humans. For instance, it is necessary to analyse mutations in other core TFIIH subunits, such as p34 and p44, and compare the related phenotypes with the reported phenotypes following XPB, XPD, p52 and p8 mutation. Additionally, it would be very informative to determine the genetic interactions of the TFIIH complex with other PIC components and to analyse double mutants in CAK subunits with mutations in the TFIIH core. The TFIIH complex also interacts directly with several transcriptional activators in human cells, the homologues of which in Drosophila have been analysed by genetic interaction studies, and their analysis during development will be highly informative for understanding the function of several transcription activators during development. Finally, the performance of chemical genetic experiments by introducing substances that inhibit the enzymatic activities of the TFIIH complex in embryos will allow the role of these specific activities in different developmental processes to be determined.