As climate change, food crises, sustainable development, and ecological conservation gain traction, the revival of traditional fishing villages has become an important governmental policy for Taiwan. To reduce cognitive bias, the choice experiment method was applied to construct an attribute function in fishing village tourism coupled with virtual reality headsets. Conditional logit and random parameter logit models were employed to estimate tourism utility functions. Moreover, a latent class model was employed to determine whether hetxerogeneous preferences regarding fishing village travel existed. The sampling sites were distributed across the Dongshi area. In total, 612 tourists and 170 local residents were interviewed. After incomplete questionnaires were removed, 816 valid questionnaires remained, representing 95.83% of the total questionnaires. Older residents and residents with shorter histories of education were inclined to increase land development and utilization by reducing natural landscapes; tourists preferred preserving landscapes and preventing land development. Residents with more education believed that local landscape imagery was essential. Tourists who were more educated, with high incomes, and those who were older believed that a selling platform incorporating local industries and products within the villages would be attractive for other tourists. Taiwan is a typical island country with 224 fishing ports. Fishing villages clustered around the ports as corresponding industries have flourished. However, due to depleting fishery resources, the pollution of the marine ecological environment, and the enforcement of the United Nations Convention on the Law of the Sea, the fishery economy witnessed a decline. The prosperity of these villages has also contracted because of the dearth of employment opportunities, thus further engendering the emigration of young residents and leaving behind a largely aging population in the fishing communities. The rural and remote nature of these villages, coupled with dated public facilities and constructions, only further exacerbates the problem. To increase their value, agricultural and fishing villages across the globe actively explore solutions for the socioeconomic problems that they encounter. These villages propose these solutions to induce industrial transformation and enhancement, to strike a balance between the development and preservation of resources, and to ensure the sustainable development of agricultural and fishing villages ,2,3,4. KThe authorities introduced new plans, such as “Building Rich and Beautiful Agricultural and Fishing Villages,” “New Style in Agricultural Villages,” and “Agricultural Villages Revival 2.0,” with the hope of accelerating agricultural and fishery transformation by combining local industries and culture in a bid to solve the existing problems. With special environmental attributes, such as natural landscapes, precious wildlife, and unique settlement cultures ,6, touriThe tourism industry contributed 8.8 trillion USD, i.e., nearly 10.40% of the global gross domestic product (GDP), in 2018, and it has created 319 million jobs across the world , from 20Overseas fishing villages proactively promote transformation and upgrade at the same time. Misali Island in the United Republic of Tanzania established a marine protected area and developed ecotourism to preserve ocean resources and engage in sustainable development . FurtherWith reference to the aforementioned literature, we understand that whether local or overseas, fishing villages encounter various difficulties and changes in relation to the environment. To ensure continued developments, villages use their unique features to engender transformations and upgrades, promote leisure traveling, and design numerous fishery-related activities, thereby adding value to the villages. Jiménez de Madariaga and García del Hoyo suggested that the development of tourism in fishing villages could redefine fishery culture and usher in multiple new approaches into the economy ; nonetheDongshi fishing village, the target research area, suffered from problems such as emigration, aging population, labor shortages, decline in fishery economy and productivity, and long-term ecological damage. Owing to guidance from and planning of the government, the Dongshi fishing village has gradually revived and transformed itself in recent years. By selling valuable fishery products and holding related cultural celebrations, Dongshi has earned a reputation in supplying fish specialties and fetches economic revenue for its surroundings. Experiences on the sea , land–water interface zones , special cultural activities on land , and experiences related to ecology  has together made the village a new tourist hotspot. However, this transformation eventually affects the natural environment. Cars and motorcycles produce air and noise pollution, while human activities on the sea damage the habitats of animals and plants. The growing number of tourists negatively affects the local quality of life due to the leftover rubbish, polluted water, and ensuing security problems. Sustainability is threatened because natural resources are prone to being exhausted, thus leaving nothing for sightseeing. Owing to the vulnerability of the ecological environment in agricultural and fishing villages, especially due to limited transport, land, and economy, development in such locations could lead to positive or negative effects on the local environment and economy ,21. MuraSustainable tourism usually develops after precise planning and cautious consideration of revenue and environmental impact in areas housing highly sensitive environments. Consequently, evaluating sustainable tourism through an economic analysis entails managing units with respect to decisions in the planning of the usage or continuous functioning of local ecological resources ,19. In tCEM can assess use value and non-use value simultaneously as well as define a hypothetical market through questionnaire surveys to investigate public preferences in landscape preservation and natural development, which, in turn, reflects the value of environmental goods or services. As CEM can evaluate multiple attributes and levels, different combinations of alternative plans can be raised according to the important characteristics of non-market goods or services. Respondents can identify appropriate alternative plans in accordance with their preferences and avoid bias in assessment through choice sets in different scenarios . Given tIn empirical modeling, conditional logit (CL) models can estimate tourists’ average preferences on multi-attributes of ecotourism and estimate the marginal willingness to pay (MWTP) of ecotourism attribute degree ,44. To eVirtual reality (VR) is a high-technology, simulated system manufactured through computer assistance. A sense of space is created through computing, while substances in reality and digital data are turned into a simulated three-dimensional environment, which can be seen or even touched. Users can choose between various input and output equipment, be submerged into a three-dimensional space, and become direct participants in the virtual scene. Interactive, immersive, and real-time features create a vast difference between VR and traditional 3D animation. VR is now extensively applied in research encompassing virtual tours ,50, shopExtant research examining the economic value of non-market resources primarily focuses on forests, coastal areas, national parks, and naturally protected areas. Few studies examine the value of fishery tourism; no research has ever applied VR to the topic. This study combined CEM and VR as a cross-disciplinary approach to broaden the depth of research on sustainable tourism in fishing villages. The construction of this methodology is based on representativeness and research originality and fills a gap in the research efforts on sustainable fishery tourism development that are lacking. Studies on and contributions to the abovementioned problems will serve as references, thus benefiting researchers who aim to evaluate models for sustainable fishery tourism development and those who practice management and administration policies in fishery tourism.The Dongshi fishing village is located in western Taiwan, facing the Taiwan Strait. The village has an area of approximately 820,000 square kilometers  that they meet, and the options would maximize utility as shown in Equation (1):ni is the utility of attribute n for person i, Vni is the observable utility function, and εni is an error that cannot be observed.CEM is a typical random utility model (RUM) for examining MWTP, given various attributes and levels . Therefoni is the utility coefficient of observable variable Xni and respondents’ characteristic Sn and represents the respondent’s preference, while εni is the error.This study expects to examine different preferences and the MWTP of respondents from diverse socioeconomic backgrounds, given various attributes and levels; therefore, an RPL model and an LCM were employed for analysis. The overall utility in the LCM is as follows:k are represented by b1,…,bk, probability is represented by Sk, while β=bk. Therefore, the option probability is as follows:The estimation method of the LCM assumes that ƒ(β) distribution is separated, while β is the differentiate value of a finite set. It is assumed that under β, possible values of option j remain the same, the marginal change in WTP of the kth attribute can be given by Equation (4):In the above equation, By referring to related survey reports and studies and interviewing professionals and scholars from different disciplines, this study set “land use planning,” “cultural experience,” “local imagery landscape and architecture,” “product and industry promotion,” and “willingness to pay/leisure attractiveness” as the five attributes. Travel attributes and the view of the fishing village were completely shown using VR to reduce cognitive differences due to words or a single photo, which might have an impact on research results. In an evaluation of efficiency, different measurements are applied to different groups of respondents. The investigation focus for the locals is set as the “willingness to pay,” which concerns maintenance and construction with a foundation’s support. For the tourists, the focus is on “leisure attractiveness,” that is, to weigh their preferences regarding various attributes by assessing how much additional time they would spend on sightseeing, following the inclusion of new features. Carlsson et al. observed that the maintenance of the natural landscape would significantly and positively affect tourism . RiddingDemarco suggested that a cultural experience would deepen tourists’ understanding of local culture and history . ChaminuThis explains how producers project compelling site meanings and how tourists decode these meanings through the lens of an imagined community. Oh et al. argue that tourists primarily seek and consume engaging experiences accompanied by the goods and/or service components of the destinations . Thus, bFerretti and Gandino studied the efficiency of reviving and using abandoned rural buildings at world heritage sites and found that most respondents preferred to turn abandoned buildings into bicycle shops followed by traditional product shops . GrebituAgimass et al. determined the leisure attractiveness of forests to tourists based on the distance of forests from the respondents . Further2 × 32 × 5) combinations to 18 alternative combinations through orthogonal design, and one current solution. After you include the current scenario in each group’s selection set, each scenario contains two scenarios with random alternatives and one current scenario. Each questionnaire contains five selection sets drawn from it, with 34 versions. The combination of the design process and the above selection sets improves the statistical efficiency of the selection set design.Orthogonal design is often used as a tool for scaling down experimental programs and can achieve statistical accuracy in the case of scaling down. The study reduced 180  Tourist behavior: this section was primarily designed to understand the traveling behavior of tourists, including the frequency of travel, types of activities, travel time, and satisfaction regarding the activities, in order to decipher a basic picture of tourists’ situations and how they graded different conditions of tourism attributes.(2) Fishing village attribute preference: this section involved applying CEM to examine respondents’ preferences in fishery tourism, including “natural landscape protection,” “fishery cultural experience,” “local imagery landscape and architecture,” “revival of industrial environment,” and “leisure distance.”(3) Basic information of tourists: this section aimed to identify the socioeconomic background of respondents, including their gender, age, education level, occupation, residence location, and average monthly individual income.Local residents and tourists were interviewed in early January 2019 using an initial questionnaire. This questionnaire was subsequently modified based on the conservation and management status, expert opinion and advice, and the initial results. Interviews using the final questionnaire were conducted from April to August 2019. Respondents were randomly selected and received an individual on-site interview. Respondents could experience the targeted destinations through VR and fully understood the research attributes in concrete expressions. This prevented information asymmetry confusion due to differences in understanding and cognition. The sampling sites were distributed across the Dongshi area. The respondents were divided into two groups: local residents and tourists. In total, 612 tourists and 170 local residents were interviewed. After incomplete questionnaires were removed, 816 valid questionnaires remained, representing 95.83% of the total questionnaires. .Of all the respondents, 401 respondents (51.30%) were female. Most respondents were in the age group of 31–40 years, with 288 (36.80%) in this group, while 178 respondents (22.80%) were aged 41–50 years. In terms of education, 476 (60.90%) respondents had a bachelor’s degree, and 183 (23.40%) had a master’s degree. Finally, 453 (57.90%) respondents had an average monthly individual income of 25,001–50,000 NTD, while 216 (27.60%) earned under 25,000 NTD.This study adopted CL and RPL models to estimate fishing village travel utility functions . The CL The creation of three kinds of cultural experiences would increase attractiveness to visitors to the highest degree (254 min), followed by natural landscape preservation (184 min), the creation of two kinds of cultural experiences (181 min), product and industry promotion (54 min), and local landscape and architecture imagery (24 min). Overdevelopment of land would decrease the willingness to travel. From the perspective of tourists, the attractiveness of tourism attributes such as cultural experiences, natural landscape preservation, and product and industry promotion was much higher than that of local landscape and architecture imagery, which means that the attractiveness of local landscape and architecture imagery is weak.Local residents’ WTP was the highest (304 NTD) for the creation of three kinds of cultural experiences, followed by the creation of two kinds of cultural experiences (239 NTD), product and industry promotion (130 NTD), local imagery landscape and architecture (111 NTD), natural landscape preservation (103 NTD), and land development and utilization (72 NTD). From the perspective of local residents, preferences are higher for increasing cultural experiences, product and industry promotion, and creation of local imagery landscape and architecture. Notably, land development and utilization and natural landscape preservation both bore positive results, reflecting a division of opinion in land use within the residents.Respondents had different preferences regarding tourism development resources because of their identities and standpoints. Through an examination and comparison via a cross-analysis on their socioeconomic backgrounds, The cross-analysis on tourists’ socioeconomic backgrounds and attribute preferences indicated the following. (1) The two attributes, natural landscape preservation and lowering development and utilization of land, were highly attractive to more educated and younger respondents. (2) Increasing cultural experiences was highly attractive to married respondents under the age of 50 with bachelor’s degrees. (3) Local landscape and architecture imagery was more attractive to older respondents. (4) The incorporation of local products and industries into the fishing village could effectively attract individuals who are more educated and with a higher income over the age of 50.The cross-analysis on local residents’ socioeconomic backgrounds and attribute preferences showed the following. (1) More educated and younger residents were willing to reduce land development and preserve natural landscapes. (2) Less educated and older residents believed natural landscapes should be reduced while increasing development and utilization of land. (3) More educated residents believed that the local landscape and architecture imagery were essential. (4) Residents from different age groups had divided opinions on incorporating local products and industries into the fishing village.Through the LCM, this study further analyzed tourism environment preferences of different tourist categories. From Sustainable tourism is usually regarded as a solution to the environmental impact of tourism, which emphasizes the appeal of environmental conservation , and envFrom the abovementioned results, tourists and residents evidently had different cognitions concerning several tourism environment attributes. Factors for the tourists’ environmental preferences included the following: (1) concerning the development and preservation of natural resources, tourists preferred reducing land development and utilization and supported preserving landscapes; (2) more cultural experiences would attract more visitors; (3) although the creation of local landscape and architecture imagery was still moderately attractive to tourists, their attractiveness was lower than other attributes; and (4) product and industry promotion led to evident positive results, suggesting that when a destination provides more local products, the willingness of tourists to visit increases. The environmental preferences influencing the factors of local residents included the following: (1) concerning the development and preservation of natural resources, some local residents believed in more development and utilization of land, while others supported enhancing landscape preservation; (2) residents agreed to increase cultural experiences to draw in more visitors; (3) residents generally believed that the creation of local landscape and architecture imagery attracts more visitors; and (4) product and industry promotion brought clear positive results, indicating that residents believed that tourist destinations should open more spaces to sell and display local agricultural and fishery products.The above analysis shows that tourists and local residents have great differences in their environmental preferences. Tourists hope to reduce land development and utilization and supported preserving landscapes, whereas residents hope to reinforce the development and utilization of land. The results of this analysis are same as those of Chen and Chen (2019) , which iSecond, some residents believed that deficiencies exist in the current fishing villages tourism environment, which should be overcome by increasing land development and using hardware facilities to expand tourism capacity. They believed that local landscape and architecture imagery can attract visitors but were divided on incorporating local products and industries into the fishing village. However, the factors that further attracted tourists included experiencing the village life, the maintenance of the natural rural landscape, and the incorporation and promotion of local products and industries in the fishing village. Local landscape and architecture imagery was the least attractive attribute to tourists. Previous studies have indicated that a cultural experience would deepen tourists’ understanding of local culture and history , and by In this study, only five environmental resource attributes are illustrated because of the limitation in expression via panoramic images. However, there are many more environmental resource attributes that can be discussed with regard to fishing villages, such as the maintenance of the leisure environment, car park spaces, the design of shaded walking trails, and guided tours. Through a related evaluation of environment attributes, we can learn more about tourists’ actual traveling preferences, and the results can act as references for the government and concerned parties when planning and implementing policies. Furthermore, concerning the socioeconomic status of respondents, the survey only focused on gender, age, education level, occupation, income, and residence location. Future research may include more survey items, such as status of travel companions, the number of travel companions, the age of the companions, and the major aim of travel , to further examine if there are more aspects that affect respondents’ preferences regarding environmental resources.This study performed an extended application of CEM using VR panoramic images and audio to deliver attributes evaluated and to avoid cognitive differences caused by traditional expressions via pictures and words. The preferences of local residents and tourists on travel attributes were also further examined. Perspectives on land resources , cultural experiences , history and humanities , and industry  were included in the evaluation model. The results demonstrated that tourists and local residents had different preferences regarding the allocation of fishing villages tourism resources. Sociodemographic and economic characteristics such as age, education, and income were also found to significantly influence tourists and local residents’ perceptions towards the environmental impacts of fishery tourism. Cognitive differences exist between tourists and local residents on various topics, including land development and utilization, local landscape and architecture imagery, as well as the incorporation of local industries and product development into villages. Less educated and older residents are inclined to increase land development and utilization by reducing natural landscapes, while tourists preferred preserving landscapes and preventing land developments. More educated residents believed that local landscape imagery was essential, but its attraction to tourists was the lowest of all the attributes. The opinions of local residents were divided on incorporating local industries and product development into villages, while tourists who were more educated, older and higher earners believed that a selling platform combining local industries and products within the villages would be attractive for tourists with similar backgrounds as them. In conclusion, to ensure the sustainable development of a tourism destination, we must incorporate stakeholders’ ideas as well as consider tourists’ needs and preferences in tourism environments together with the present situation of leisure resources, environmental characteristics, and the management of the destination.In the future, planners of fishing village development should consider the opinions of tourists and local residents. Additionally, when there are plans to adjust the allocation of tourism environment resources, it is important to avoid a result that is merely beneficial to a minority of residents. Thus, local residents should be invited to discuss the adjustments. In such discussions, planners should explain the reasons for the reallocation of environmental resources and the benefits of the adjustments to resolve disagreements with residents and reduce any impediments in implementing policies.


Nine years elapsed between Gavi’s investment decision to support typhoid conjugate vaccines (TCVs) in 2008 and Gavi support becoming available for countries to introduce TCV. The protracted path toward Gavi support for TCV highlights the challenges of vaccine development for lower-income countries and the importance of Gavi engagement as early as possible in product development processes to support the alignment of manufacturing, global policy, and program implementation. Early engagement would provide inputs to inform strategic vaccine investment decisions that transition more efficiently toward country implementation. Several countries have been approved for Gavi support to introduce TCV in 2019–2020. The paucity of generalizable typhoid epidemiological data in early introducing countries has reinforced the need for continued evidence generation regarding typhoid epidemiology and TCV impact. This has led to the development of guidance and tools to support country decision making for TCV introduction based on enhanced understanding of local typhoid burden and risk. In 2000, Gavi, the Vaccine Alliance (Gavi) was created to increase access to and affordability of new and underused vaccines for people living in low-income countries through an innovative public–private partnership model comprised of governments, the private sector, United Nations agencies, and civil society. Countries are eligible to receive Gavi support based on gross national income (GNI) per capita. As GNI per capita increases, countries increasingly finance immunization program costs before transitioning from Gavi support. Between 2000 and 2018, Gavi’s support has enabled > 760 million children to be reached and prevented 13 million future deaths through increased access to immunization services [Since Gavi’s inception, the portfolio of vaccines it supports to meet public health needs in low-income countries has steadily grown. In 2008, Gavi adopted a process to periodically update its vaccine investments. Gavi’s Vaccine Investment Strategy (VIS) uses standardized, evidence-based criteria to comparatively assess potential vaccine investments to inform prioritization of Gavi’s resources . The scoWhile Gavi’s initial investment decision to support typhoid vaccines was made in 2008, due to product development challenges and setbacks related to TCV, 9 years elapsed between Gavi’s initial investment decision and Gavi support becoming available for countries to introduce TCV. The protracted timelines for a commercially available, World Health Organization (WHO)–prequalified TCV and accompanying Gavi support for eligible countries to introduce the vaccine highlights some of the key factors related to effectively linking product development with Gavi investment decision making and implementation planning.Salmonella enterica serovar Typhi (S. Typhi) Ty21a strain oral vaccine administered in 3–4 doses, and Vi capsular polysaccharide (Vi-PS) injectable vaccine administered in a single dose. The Gavi Board, comprised of governments, the private sector, United Nations agencies, and civil society and responsible for Gavi’s strategic direction, policy, and investment decisions, indicated a preference to support TCV once licensed, due to its anticipated administration to infants, more robust immunologic response, and an extended duration of protection compared to Vi-PS and Ty21a. The Gavi Board chose not to make a financial commitment to TCV at that time and requested exploration of potential support for the Vi-PS vaccine for a limited duration while the regulatory requirements were completed for the lead TCV candidate. The vaccine procurement–related costs estimated for TCV were approximately US$175 million for the 2009–2015 period, assuming introduction in 14 Gavi-supported countries. The Gavi Board’s decision to prioritize TCV for inclusion in the portfolio was an important moment in Gavi vaccine investment decision making, marking the first time the Gavi Board committed to support a vaccine still under development, largely due to the inherent risks and challenges involved with vaccine development.Gavi assessed a potential investment in typhoid vaccines in 2008. At that time, there were an estimated 16–33 million cases of typhoid fever annually, causing 216 000–600 000 deaths per year, predominantly infants and school-aged children . In 2008In 2011, the Gavi Board’s Programme and Policy Committee (PPC) was asked to approve implementation strategies for typhoid vaccines following its prioritization in the 2008 VIS. The lead TCV candidate experienced product development setbacks and the most advanced pipeline candidate was not expected to become available until at least 2016. As such, the PPC reviewed a strategy focused on the temporary use of Vi-PS through targeted one-time, wide age-range catch-up campaigns in high-burden countries until TCV became available. Ultimately, Gavi’s PPC reaffirmed a preference for TCV, thereby retaining the Board’s 2008 VIS decision due to the existence of alternative treatment options and the potential need to readminister Vi-PS because of its limited duration of protection. The product development setbacks encountered with the lead TCV candidate caused a protracted lead time between Gavi’s original investment decision and country introduction.Between 2011 and 2017, the Bill & Melinda Gates Foundation supported efforts to accelerate the availability of TCV. This included support for multicenter hospital-based surveillance studies to improve the understanding of the regional and global burden of typhoid fever, development of updated global policy for typhoid vaccines, as well as investments to spur the development of pipeline TCV candidates. Bharat Biotech International’s Typbar-TCV was licensed in India and further evaluated through a controlled human infection model study that demonstrated 87.1% efficacy against typhoid fever in immunologically naive patients , 7.S. Typhi and support informed country-level decision making regarding TCV introduction. WHO announced the prequalification of Typbar-TCV in January 2018, marking the first time it had prequalified a TCV. Eligible countries were able to apply for Gavi support for TCV introduction, beginning in May 2018.In 2017, following the WHO Strategic Advisory Group of Experts on Immunization (SAGE) recommendation, Gavi updated the original analysis that informed the Gavi Board’s 2008 VIS decision to support TCV. The updated analysis found Gavi’s TCV investment would avert 0.3 deaths per 1000 fully vaccinated persons and cost US$6580 per future death averted (with a range of US$3320–US$10 420), which were comparable with existing vaccines in Gavi’s portfolio [S. Typhi, through inclusion into routine immunization schedules coupled with catch-up immunization up to 15 years of age at the time of introduction, based on local epidemiology of typhoid fever, including antimicrobial resistance patterns and programmatic considerations of routine immunization programs [The support provided by Gavi to eligible countries for TCV is aligned with the 2018 SAGE recommendations and WHO position paper, which recommends prioritized introduction of TCV in countries with the highest burden of typhoid disease or a high burden of antimicrobial-resistant programs . DependiS. Typhi outbreaks, as well as assessments of water, sanitation, and hygiene (WASH) as an indicator of potential typhoid fever risk and country-specific estimates of modeled typhoid burden. Liberia’s introduction decision was not informed by reliable, age-specific typhoid burden data based on blood culture confirmation. Instead, Liberia’s TCV introduction decision was informed by country-specific estimates of modeled typhoid burden; evidence of nontraumatic ileal perforations; and indicators of potential typhoid fever risk, including WASH and comparison with neighboring countries with similar typhoid risk factor profiles where estimates of typhoid fever incidence based on evidence of blood culture confirmation existed. Several other countries are currently in the advanced stages of decision making regarding TCV introduction, which may result in additional applications for Gavi support to be submitted in 2020.Since the Gavi Board’s decision in 2017 to open a funding window to support TCV, 3 countries—Pakistan, Liberia, and Zimbabwe—have been approved to receive Gavi support to introduce TCV into their respective routine immunization systems. Pakistan became the first country to introduce TCV with support from Gavi. In November 2019, Pakistan conducted a catch-up immunization campaign and reached > 9 million children aged 9 months–15 years with TCV in high-risk urban areas of Sindh province. Pakistan’s TCV introduction into routine Expanded Programme on Immunization began in December 2019. Due to both epidemiological and vaccine supply considerations, Pakistan’s TCV introduction is being conducted in phases and the catch-up immunization is being targeted at urban areas. Liberia and Zimbabwe plan to introduce TCV in 2020. Each of the countries which have applied for Gavi support used different data to justify their vaccine introduction and vaccination strategy decisions. Pakistan and Zimbabwe’s introduction decisions were based on evidence of blood culture–confirmed typhoid either through research-oriented prospective hospital-based typhoid surveillance or passive surveillance, evidence of extensively drug-resistant or multidrug-resistant strains of Countries interested in potentially introducing TCV are advised to conduct a thorough assessment of domestic typhoid disease burden and risk factors to inform vaccine introduction and delivery strategies that are context specific and programmatically and financially feasible. Gavi’s current application guidelines for TCV include instructions for countries to collate, assess, and interpret past, current, and likely future typhoid risk, including laboratory-confirmed disease and risk factors for typhoid. This information must be submitted as part of country applications to inform the rationale for requesting Gavi support and a country’s selected vaccination strategy. Support from the Gavi Secretariat and Alliance partners is available to support country evaluation of evidence and application development. Country applications for TCV are reviewed by Gavi’s Independent Review Committee, in line with other Gavi supported vaccines. Applications are reviewed to determine the sufficiency of evidence justifying selected vaccination strategies as well as linkages to coverage and equity objectives, including strategies to reach populations at highest risk for typhoid.The Gavi Board’s commitment to support TCV though not yet commercially available was unprecedented, marking the first time the Gavi Board committed to support a vaccine still under development. At the time of the Gavi Board’s original TCV investment decision, significant product development and epidemiological uncertainties existed that influenced the structure of the Board’s decision and its delayed financial commitment until a pipeline TCV candidate neared commercial availability. Gavi has historically relied on other stakeholders to ensure a coherent pathway from product development to introduction, which necessitated much of the Bill & Melinda Gates Foundation’s effort to bring TCV to market . EnhanceInformed by the TCV experience, the Alliance has also evolved the ways in which vaccine policy making and implementation are designed and operationalized. For example, in the 2018 VIS, a learning agenda was developed for prioritized potential vaccine investments to address key knowledge gaps, including improved understanding of disease burden and optimal delivery strategies, that would help inform the design of future Gavi vaccine programs and country vaccine decision making. The internal structure of the Gavi Secretariat was also modified to establish closer links between market shaping, policy, and implementation to enhance Gavi decision making and program design.Despite improvements in understanding of the burden of typhoid fever in low-income contexts, many countries still lack surveillance data incorporating confirmation of cases through blood culture, currently recommended by WHO for diagnosis of typhoid fever, due to capacity and financial limitations, as well as the technical challenges of typhoid blood culture testing . TherefoS. Typhi, resulting in potentially underestimation of typhoid fever incidence, the simpler Widal test that was a staple of typhoid testing in many countries has been shown more recently to be nonspecific, resulting in overestimation of typhoid fever incidence, a problem shared by currently available typhoid rapid diagnostic tests [S. Typhi is heterogenous spatially and temporally, limiting the generalizability and utility of those data in supporting the development of cost-effective vaccination strategies in settings with variable incidence outside of the areas covered by those sentinel sites. This heterogeneity in part influenced WHO’s recommendation for TCV, which indicates that countries need to select a context-appropriate vaccination strategy for TCV introduction based on factors including analysis of typhoid disease burden, risk factors for transmission, and availability of quality surveillance data, as well as operational feasibility considerations. However, from the initial implementation of Gavi’s TCV program to enable appropriate uptake of TCV, countries have demonstrated that additional guidance, tools, and support are required to make informed TCV introduction decisions using data that are readily available.Although blood culture has low sensitivity for ic tests . Additioic tests . The relIt is also important to recognize that Gavi support for TCV is occurring in a different context than historical support for other new vaccines for infants. First, as noted above, TCV does not have a WHO recommendation for universal use; as such, countries require more resources and data to inform decision making for introduction and implementation planning. Additionally, as many countries begin to transition from Gavi support and as Gavi’s portfolio of vaccine support continues to expand, the complexity of decision making for new vaccine introductions is increasing and, in many contexts, local burden of typhoid fever must be demonstrated to justify the introduction of TCV over other vaccines for which more robust data may be available. Finally, there remains a need to better understand performance of TCV in a range of settings, populations, and delivery strategies to inform decision makers at global, regional, and country levels. The global typhoid community is still in the early stages of understanding TCV’s impact on typhoid fever incidence, the vaccine’s duration of protection, and how it should be optimally used, including in response to outbreaks of typhoid fever. This contrasts with the Gavi experience with other vaccines, which had been in use for years in high-income countries before being introduced in countries eligible for Gavi support. Addressing these uncertainties will bolster global guidance and recommendations for TCV but also inform country-level decision making for TCV introduction.In light of the diagnostic challenges related to typhoid fever and our evolving understanding of typhoid fever epidemiology, further investigation of typhoid transmission dynamics, including the role of chronic carriers and the transmissibility of drug-resistant strains, is also required to support intervention strategies and optimal use of TCV in different endemicity settings. Given the challenges and limitations of laboratory-confirmed typhoid burden data, there is a critical need to establish pragmatic ways to assess typhoid burden using existing surveillance and proxy data as well as new prospective methods including serosurveys and environmental surveillance to inform TCV introduction and delivery decisions. There is also need for better understanding of the outbreak potential of typhoid and optimal response strategies, which may include TCV, to effectively halt transmission. These issues, along with other barriers that exist for country-level TCV introduction decisions, require further understanding to enable appropriate deployment of TCV in endemic and outbreak settings.The challenges and uncertainties that remain to be addressed to optimize Gavi’s support for TCV and ensure uptake of context-appropriate TCV vaccination strategies have also highlighted the critical role Gavi has following its investment decisions for continued learning and evaluation. It is imperative that, moving forward, investments are made in advance of Gavi program implementation to improve the understanding of key data gaps and generate critical insights that address key uncertainties to inform policy, program design, and country decision making.The availability of TCV has ushered in a new era of typhoid control, and Gavi remains committed to supporting TCV introduction and is eager to continue collaborating with the global typhoid community to address the challenges that remain in our understanding of typhoid as a disease and the optimal use of TCV to combat it.


We present a retrospective analysis of trends in human immunodeficiency virus (HIV) small molecule drug development over the last thirty-five years based on data captured by ChemDB, a United States (US) National Institutes of Health (NIH) database of chemical and biological HIV testing data. These data are analyzed alongside NIH funding levels, US Food and Drug Administration (FDA) drug approvals, and new target identifications to explore the influences of these factors on anti-HIV drug discovery research. The NIH’s ChemDB database collects chemical and biological testing data describing published and patented pre-clinical compounds in development as potential HIV therapeutics. These data were used as a proxy for estimating overall levels of HIV therapeutics research activities in order to assess research trends. Data extracted from ChemDB were compared with records of drug approvals from the FDA, NIH funding levels, and drug target discoveries to elucidate the influences that these factors have on levels of HIV therapeutics research activities. Despite the increasingly wide suite of HIV therapeutic options that have accumulated during decades of research, interest in HIV therapeutics research activities remains strong. While decreases in research activity levels have followed cuts in research funding, FDA-approved HIV therapeutics have continued to accumulate. The comparisons presented here indicate that HIV drug research activity levels have historically been more responsive to changes in funding levels and the identification of new drug targets, than they have been to drug approvals. Continued interest in HIV therapeutics research may reflect that fact that of the 55 drugs approved for HIV treatment as of 2018, only seven inhibitory targets are represented. Moreover, drug resistance presents substantial clinical challenges. Sustained research interest despite drug approvals and fluctuations in available funding likely reflects the clinical need for safer, more palatable and more efficacious therapeutics; robust attention to both novel therapeutics and inhibitory targets is necessary given the speed of development of drug-resistant HIV strains. Only with such continued interest will we reduce the burden of acquired immunodeficiency syndrome (AIDS) disease and control the AIDS epidemic. Thirty-five years have passed since the identification of human immunodeficiency virus (HIV) as the etiological agent of acquired immunodeficiency syndrome (AIDS) ,2. Over With the advent of effective antiretroviral treatment regimens including highly active antiretroviral therapy (HAART) , lifespachemdb.niaid.nih.gov) maintained by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). ChemDB contains information extracted from the scientific literature and patents on the structure and activity of pre-clinical compounds with potential therapeutic activity against HIV. In addition to their utility for a variety of drug discovery purposes, from virtual screening and structure-activity relationship (SAR) studies to building drug discovery models based on machine learning [As many challenges face antiretroviral therapeutics development, an examination of historical influences and indicators that helps us better understand past developmental trends and milestones is warranted. We undertook a focused study of influences on the direction and pace of the HIV drug development field, analyzing the relationships between the quantities of therapeutic targets identified and potential HIV therapeutics tested in pre-clinical studies, levels of funding for such research, and the achieving of HIV drug approvals by the FDA. For this analysis, we leveraged the ChemDB HIV, Opportunistic Infection and Tuberculosis Therapeutics Database  Since the database is continually updated with information extracted from published literature and patents, including the structure and activity of compounds that have been tested against HIV, HIV enzymes or opportunistic pathogens, it was considered to be a comprehensive data source. See the Past years’ budget information for HIV/AIDS-related research activities throughout the NIH was obtained from NIH budgetary and reporting archives  the total number of putative HIV-inhibitory compounds described; (2) the number of unique viral or host cellular components investigated as targets for HIV inhibition; (3) the number of publications (or patents) describing a compound(s) with putative activity against HIV; and (4) the total number of target references for HIV inhibition within the publications (or patents). Comprehensive research activity data were gathered from ChemDB and here serve as proxies for activities throughout the therapeutics development field.On the whole, the four research activity metrics examined followed similar trends : activitAfter 2005, all four research activity metrics decreased, reflecting decreases in funding. In 2017, the last full year for which data were available, the research activity metrics lay at 53–80% of their respective maxima; meanwhile, therapeutics funding was at 67% of its maximum. Also notable is the 2014 spike in compounds and target references, the result of a one-year spike in the average number of compounds described per publication – 30 – when no other year’s publications averaged more than 21 , and posFirst-in-class HIV drug approvals by the FDA through 2018 are indicated in Antiviral drugs may inhibit HIV replication via interactions with viral targets or with cellular host targets. According to the data within ChemDB, most described potential targets for inhibition of HIV replication are host cellular components, at 176 of 204 total targets (86%), with the remainder being viral components. Conversely, of the nearly 100,000 anti-HIV compounds registered in ChemDB between 1984 and the first half of 2018, 89% were investigated for inhibitory activity via interactions with viral targets, and only 11% via interactions with host targets. Of the 204 targets identified for potential therapeutic intervention, only 10  have commanded enough sustained research interest such that the sum of all potential inhibitory compounds described for each meets or exceeds 1% of the total compounds entered into ChemDB. These 10 targets are listed in To develop a comprehensible view of target-specific research activities, ChemDB-based proxy metrics were examined in five-year intervals for the 35-year history of the field for the top 10 targets. The overall proportion of potential inhibitory compounds aimed at each target for the entire 35-year history of the field shows that the focus of HIV therapeutic research activities has shifted over time, moving from RT inhibitors in the 1980s to the inclusion of protease inhibitors in the mid- to late-1990s, and then of integrase inhibitors post-2000 . Thus, wNot surprisingly, the proportion of approved drugs for each target mirrors its overall rank in research activity, with 53% (29/55) of approved drugs targeting RT (including 6 RT-only combination therapeutics), 24% (13/55) targeting protease, ~7% targeting integrase (4/55), and the balance targeting fusion, entry, or other processes, and the growing number of multi-class drugs . HoweverInspection of In this study, the 35 years of data within the ChemDB HIV, Opportunistic Infection and Tuberculosis Therapeutics Database served as proxies for annual levels of HIV therapeutics “research activities.” Overall, the proxy metrics indicate that interest in developing therapeutics for HIV has remained robust since the advent of the epidemic in the early 1980s, yet varied in response to the availability of research funding .ChemDB data underscore the difficulties of the therapeutics development process, with the vast majority of investigated compounds failing to progress; while ChemDB houses over 100,000 compounds that were tested for inhibition of HIV, only 55 therapeutic options have progressed to FDA approval (as of 2018). In fact, the percentage of novel compounds published relative to the total number of compounds described, on an annual basis, averaged 82% over the 35-year history of the field median, . That isFor the top therapeutic targets of RT, protease, and integrase, there appears to be a link between levels of target-specific research and drug approvals . By the The approval of even several dozen drugs to date does has not negatively influenced the expanding research interests of the field in terms of identifying new targets for inhibition p>0.7, . For exaThe fact that therapeutics research funding continues to represent a substantial proportion of the NIH HIV/AIDS budget after 35 years of research, 100,000 potential inhibitory compounds, and 55 FDA-approved drugs indicates that investment in therapeutics research remains a significant priority for patients, healthcare providers, and policymakers. Funding was seen to be the factor with greatest influence on therapeutics research activity levels, although only for RT/AZT did a druggable target move from first identification to FDA-approved drug target quickly. Although the sample size is small and the reasons may be myriad, we noted that the first-in-class drug approvals that occurred after the peak of NIH HIV therapeutics funding (2003) averaged development times that were twice as long (21 years) than those that occurred before/at peak funding (<10 years). Looking toward the future, robust research interest levels are likely to continue to bear fruit at a steady, albeit slow pace, so long as adequate funding is maintained. Over time, these fruits will benefit patients in the form of improved HIV treatment regimens in terms of safety, tolerability, and efficacy. Whether the harvest will happen in a timeframe that supports the UNAIDS 90-90-90 goals and eradication of AIDS by 2030  remains This analysis of HIV therapeutics research activities was limited in scope to those activities for which the data contained within ChemDB could be used as a proxy, and is therefore focused on preclinical data only, with an emphasis on small molecule drug discovery. Analysis of influencing factors considered only NIH funding sources and only drugs approved by the FDA. These choices were made to best leverage a comprehensive set of data to investigate defined, tractable questions. Future analyses in this area might use a broader, international lens to assess the influencing factors of funding and drug approvals, and might be expanded to include clinical research and a focus on drug development rather than drug discovery activities.Jackson2020_supp


They were analyzed and categorized into 12 dimensions of safety culture, and differences in response rate or scores were identified compared to the mean of the dimensions. The heterogeneous of safety culture's situation among Southeast Asian countries, both in practice and in research, can be explained since patient safety policy and its application are not prioritized as much as they are in developed countries in the priority compared to the developed countries. However, Vietnam, Cambodia, Myanmar, and Laos are the priority countries for South Korea's official healthcare development assistance in the Southeast Asia region. Vietnam, for instance, is an economically transitioning country; therefore, consolidated patient safety improvement by inducing patient safety culture in the provincial and central health system as well as strengthening project formulation to contribute to health policy formation are needed for sustainable development of the partner countries' health systems. It is recommended that more evidence-based proactive project planning and implementation be conducted to integrate patient safety culture into the health systems of developing countries, toward health policy on patient safety and quality service for the attainment of sustainable development goals in South Korea's development cooperation.Patient safety is an important issue in health systems worldwide. A systematic review of previous studies on patient safety culture in Southeast Asian countries is necessary for South Korea's partnership with these countries, especially given South Korea's assistance in strengthening the health systems of these developing countries. Studies on patient safety culture in Southeast Asian countries, published in English and Thai languages, were retrieved from computerized databases using keywords through a manual search. Data extraction, quality assessment, and analyses were performed using several tools. The review included 21 studies conducted in Indonesia ( Patient safety is a global concern at all levels of healthcare systems, and its main purpose is to reduce patient risks when providing healthcare services . Since aThe recommended building blocks of health systems are outlined as healthcare providers, essential medical equipment and medicines, service delivery systems, health finance, and governance. To accomplish the improved health and efficiency of a health system, health policy on patient safety, service quality, and access and coverage are indispensable . ParticuTherefore, a systematic review of patient safety and quality in Southeast Asian countries recommended that comprehensive research on healthcare safety and quality are needed, and that patient safety interventions implemented in developed countries must also be directly applied in developing countries . In contOver the last 10 years, patient safety culture has been one of the most critical factors for studies assessing patient safety and quality of healthcare services , 11–22. The Korea International Cooperation Agency and Korea Foundation for International Health Care have been supporting developing countries' health sector since 1990. The specific areas within these health sectors include maternal and child health, school health, control of infectious diseases, and strengthening of health systems. In the last 10 years, most of the top 10 recipient countries have been Southeast Asian countries, owing to their geographical proximity, cultural similarities, and other political considerations , 26. TheThe purpose of this systematic review was to identify the current status of patient safety culture in Southeast Asian countries, which will provide evidence to develop international cooperative projects aimed at promoting patient safety culture for strengthening the health system through health policy development.This systematic review included studies on patient safety culture conducted in Southeast Asian countries published between January 2009 and March 2020.The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) checklist was applied to enhance the reporting quality of the included reviews .Medline/PubMed, Cumulative Index to Nursing and Allied Health Literature, and Embase databases were searched for potential articles. Furthermore, the WHO Institutional Repository for Information Sharing was included to retrieve any articles on patient safety issues in regional countries. A Thai database was added to include relevant studies published in domestic journals in English abstract, as well as any unpublished master's theses and doctoral dissertations identified through manual searches. Keywords for the search were followed by considering the populations, interventions, comparators, outcomes, and study designs (PICOS) in the search. For populations, we searched keywords as “Asia,” “Southeast,” (MeSH) “Southeast Asia,” , and interventions as “safety management,” (MeSH) “safety culture(s),” “hazard management,” “hazard surveillance program(s),” “hazard control(s),” “patient safety” (MeSH), “safety climate,” and “safety communication.” However, we did not apply the every steps of PICOS after receiving guidance from a senior medical librarian who has experience consulting on systematic review studies at the Medical Library of Seoul National University College of Medicine in South Korea because our study could be more broadly searched by using the populations and interventions of PICOS.Articles were included if they (a) described patient safety culture, (b) were conducted in Southeast Asian countries, (c) were written in English, and (d) were published between January 1999 and March 2020. A total of 1,413 articles were identified. Furthermore, a domestic online database in Thailand was accessed for searching related studies; then, four studies written in Thai were converted in English. After removing duplicate articles, title and abstract screening was performed for 1,251 articles; of these, 1,200 articles that did not meet the inclusion criteria were excluded. The Joanna Briggs Institute (JBI) tool, comprising eight items to determine the validity of descriptive cross-sectional studies, was used . Nine itThe extracted data were analyzed by research design, number of participants, tools, research findings, and safety culture as main variables. General characteristics of the included studies were reviewed by publication year, research field, level of research, theoretical framework, and study setting using frequencies and percentages. Measurement tools were classified by names of tools and developers, subcategories, and item numbers of tools using frequencies and percentages; their reliability coefficients were reported. The findings were then sorted by research design. All the extracted studies were descriptive research except two that employed quasi-experimental research designs. The descriptive studies were classified into cross-sectional and mixed-methods design.Suggestions for future partnership projects, recommendations, and the status of partner countries in Southeast Asia regarding South Korea's official development assistance were also comprehensively evaluated.The 21 studies were evaluated and selected for analysis in process of the quality assessment, which are summarized in n = 18), quasi-experimental study (n = 2), and mixed-methods (n = 1) designs. Studies were conducted in six Southeast Asian countries: Indonesia (n = 8), Thailand (n = 5), Malaysia (n = 3), Singapore (n = 1), Vietnam (n = 2), and the Philippines (n = 2). The reviewed studies were published between 2013 and 2020, and cross-sectional research design was applied to all reviewed ones as well as one mixed-methods design to examine the status of patient safety culture in Southeast Asia (Meeting inclusion criteria of 21 reviewed studies were summarized in ast Asia .Study settings on patient safety culture included hospital and community clinics. At the hospital level, the number of hospitals surveyed ranged from 1 to 10 hospitals. One study focused on both hospital and clinical settings .Thirteen studies measured the concept of safety culture using the hospital survey on patient safety culture ;Reviewed studies provided questionnaires to participants including healthcare providers and educators. Ten studies focused on healthcare providers' perception on safety culture in hospital settings: nine studies included those of head nurses and staff nurses , 41, 42,Different conceptual frameworks and instruments were utilized for assessing the level of patient safety culture; however, in most studies, most of the positive rated scores focused on six dimensions of patient safety culture following the HSOPSC tool. The scores were calculated by percent-positive scores which combined percentage of respondents who answered “strongly agree,” or “agree,” or “always,” or “most of the time,” following the Agency for Healthcare Research and Quality guidelines. Only studies from Thailand applied mean scores within five points see . Among tNegative dimensions were divided by analyzing the lowest dimension of HSOPSC studies and identified as handoffs and transitions , 34, 40,Twelve out of 21 studies determined factors influencing patient safety culture; consequently, five dimensions were classified as predictors: organization and management, work environment, care delivery, team factors, and individual factors. Organization and management factors included perceptions of management , adminisThe status of patient cultural safety in Southeast Asian countries was highlighted in this review. Most studies used either the HSOPSC or the SAQ to measure safety culture, which mirrored previous findings . Ten VieBased on the dimensions of patient safety culture in Southeast Asian countries, the importance of patient safety culture has been recognized in healthcare systems. However, this review showed that patient cultural safety was mentioned in five Southeast Asian countries: Laos, Cambodia, Myanmar, Brunei, and East Timor. Therefore, researchers should consider assessing patient safety culture in those countries or provide interventional programs for healthcare providers to enhance health and safety awareness among those countries. Additionally, most studies utilized a descriptive quantitative design to identify the status of patient safety culture, and only one study focused on intervention effectiveness; thus, interventional programs related to this issue need to expand into the health system in Southeast Asian countries.In this review, supervisor and/or manager expectations and actions promoted patient safety, organizational learning and continuous improvement, teamwork within units, and teamwork climate, and working conditions are a positive dimensions of patient safety culture. It was evident that healthcare providers in Southeast Asian countries are aware of the need to have supportive health organizations, team collaboration, and continue educational training. Furthermore, safety behaviors regarding stress recognition and feedback and communication about errors were concentrated to improve workplace health and safety. These findings are similar to previous studies in developed and developing countries.Teamwork within units, organizational learning, and continuous improvement have been identified as crucial dimensions of patient safety culture , 45. In Regarding the negative dimensions to patient safety culture in this review, handoffs and transitions, non-punitive responses to an error, patient safety reporting, and staffing were generally considered barriers to patient safety culture. It was evident that cultural safety activities regarding developing patient safety report systems should be promoted and cultural safety educational programs for healthcare professionals should be encouraged. Similar findings were reported by Reis et al. , who indMoreover, the overall prevalence of patient safety culture ranged from low to moderate in this review. This suggests that patient safety culture should be further promoted among healthcare providers in Southeast Asian countries. These results are like those of studies conducted in developed and developing countries. In Peru, the degree of perceived patient safety was low among healthcare providers . Mayeng This comparative analysis of 21 studies revealed that there were two factors affecting patient safety culture: systematic factors and human factors. The systematic factors included organization and management, work environment, care delivery, and team factors, while human factors included the main variables affecting safety culture. An Indonesian study reported the determinants of patient safety implementation among nurses as teamwork, safety culture, stress recognition and management, working conditions, and standard work guidelines . KuosmanThis study explored the status of patient safety culture in Southeast Asian countries to identify differences in health policy. The level of safety culture was low to moderate in the context of system and human factor dimensions. There was also low volume of research among these countries, and most was published in Indonesia and Thailand. However, this review had some limitations, such as the exclusion of research written in non-English, which could have resulted in failing to include other relevant studies. Countries with fewer reported studies on patient safety culture reveal that their safety culture is negligible, and that regulation similar to the Patient Safety Act is a requirement of public safety for their citizens.For the future consideration of future health system cooperation, WHO's recommendations for research priorities regarding patient safety, economic status, safety culture, and communication are appropriate as tracer topics on the progress of healthcare system development  because Thus, we recommend that more evidence-based proactive project planning and implementation be conducted to integrate patient safety culture into healthcare and for the attainment of sustainable development goals in South Korea's development cooperation. Although we examined the developed and some developing countries in Southeast Asia, increased policy formation regarding patient safety, raising awareness of patient safety for healthcare providers, patients and the community are needed as well. For South Korea's partner countries of official development cooperation, such as Vietnam, Lao PDR, Cambodia, and Philippines, without quality of service and patient safety, it is impossible to expect health systems to improve.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SK and N-JL conceived the study conception and design. SK and TH contributed to the data collection, data analysis, and manuscript draft. N-JL contributed to the overall quality of the draft manuscript and its revisions. All authors have read and approved the final manuscript.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.


Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM  as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusions: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions. Idiosyncratic drug induced liver injury (DILI), in short also termed iDILI, and herb induced liver injury (HILI) are complex diseases and received much attention in recent years ,6,7,8,9.The RUCAM algorithm is a structured, standardized, transparent, liver specific and quantitative diagnostic clinical scale based on key elements of liver injury, which are individually scored and provide a score for five-degree causality grading from unrelated up to highly probable causality levels . Since kIn this review article, current conditions of DILI and HILI cases assessed worldwide using RUCAM were critically analyzed. For the first time, the focus is on reports published from1993 to mid 2020 and the discussion of their potential use to describe specific features of DILI and HILI cases.The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury (iDILI); Herb induced liver injury (HILI). Key terms were used alone or in combination. Limited to the English language, publications from each search terms were analyzed for suitability of this review article. The electronic search was completed on 30 June 2020 and supplemented by a manual literature search, using also the large private archive of the authors when the publication was not yet referenced in PubMed. The final compilation consisted of original papers including individual case reports and case series, consensus reports, and review articles with the most relevant publications included in the reference list of this review.RUCAM is presented as an algorithm that requires a few criteria allowing for a final quantitative evaluation. In particular, establishing RUCAM based criteria of liver test thresholds and liver injury patterns was revolutionary at the time of first publication issued from an international consensus meeting of experts, without the requirement of a liver biopsy  with samA liver injury caused by exogenous compounds such as drugs and herbs is defined by specific threshold values established for the liver tests (LTs) alanine aminotransferase (ALT) and alkaline phosphatase (ALP), with current serum activities considered as relevant for ALT ≥ 5 × ULN  and ALP ≥ 2 × ULN  providedRUCAM was also the first CAM proposing different patterns of liver injury based on LTs  and are Liver injury is either idiosyncratic, due to the interaction between the exogenous synthetic chemical or phytochemical and a susceptible individual with some genetic factor(s), or it is intrinsic due to chemical overdose ,12,13. IThe current scientometric report from China on knowledge mapping confirmed the high worldwide interest in DILI publications and identified a total of 1995 DILI studies published between 2010 and 2019, although information on the applied method of causality assessment was not provided and will need further clarification [The worldwide impact of DILI can best be quantified by using liver injury cases assessed for causality with a robust method that allows for establishing causality gradings for each implicated drug and to exclude alternative causes unrelated to drug administration.In the current analysis, authors from 31 countries worldwide reported on cases of idiosyncratic DILI caused by multiple drugs published from 1993 up to mid 2020 and applied in all cases RUCAM to assess causality  23,24,2,179,180.RUCAM based DILI cases were mostly published by authors from university hospitals and their affiliated teaching hospitals known for their high reputation . Among tIn addition to hospitals, other sources provided RUCAM based DILI cases . Among tAmong the top 10 countries were in decreasing order China, the US, Germany, Korea, Italy, Sweden, Spain, Japan, Argentina, and Thailand, whereby the top 5 countries provided most of the DILI cases . AuthorsAnalyses of growth trends provided additional information after identification of a total 1995 DILI studies, published between 2010 and 2019 but not stratified for causality assessment using RUCAM [Considering the period from 1993 to 2019, annually published cases of RUCAM based idiosyncratic DILI ranged between 0 and 27,224 in 2019, but data of 2020 were not included because case counting stopped by end of June in this particular year . Three pPhase 1 started after the launch of RUCAM in 1993 ,47 and tPhase 2 started in 2005 with overall 7695 annually published RUCAM based DILI cases  115,126,148. AmoPhase 3 is characterized by the worldwide use of RUCAM for DILI started in 2014 with 11,525 DILI cases , mostly Over the years starting from 1993, when RUCAM was launched ,57, and Large study cohorts of RUCAM based DILI cases accumulated many different drugs and provided as expected a global information of the DILI cases due to various drugs without a detailed description of clinical features drug by drug . ConsequThere is concern how best to establish a top ranking of drugs most commonly implicated in DILI ,74. A reHighlights of liver injury cases have been reported not only for DILI but with increasing frequency also for HILI cases questionable due to lack of a robust CAM ,8,9. TheAuthors from many countries around the world reported on cases of HILI in connection with the consumption of various herbs, all published since 1993  29,37,3,254,255.Most RUCAM based HILI cases were provided by authors from university hospitals and their affiliated teaching hospitals with their departments of Hepatology and Gastroenterology, Medicine or Internal Medicine . Rare coOther sources providing RUCAM based HILI cases include the Chinese Academy of Medical Sciences in Beijing , School Among the countries presenting RUCAM based HILI cases were on top in descending order China and Korea, followed by Germany, India and the US, whereby the top 5 countries provided most of the HILI cases . AuthorsFrom 1993 to 2019, published annual cases of RUCAM based HILI ranged between 0 and 11,609 in 2019, while 57 HILI cases of 2020 were not included because case counting stopped by end of June in this particular year . Three pPhase 1 started after the launch of RUCAM in 1993 ,47 but wDuring the subsequent phase 2, the number of annual published HILI cases remained small with cases ranging from 2 to 933, considering the years from 2004 until 2016 . In 2008Phase 3 started with low HILI case numbers in 2017 and 2018 , consideOver the years starting from 1993, when RUCAM was launched ,57 and uLarge study cohorts of RUCAM based HILI cases accumulate many different herbs and provide as expected a global information of many HILI cases without a detailed description of clinical features for specific herbs . ConsequThe utility of RUCAM has been confirmed in in many liver injury cases of DILI  and HILIApart from the objective diagnostic RUCAM algorithm, a few non-RUCAM based CAMs are known, critically discussed elsewhere in detail ,15. In sThe current analysis is based on published data of DILI and HILI reports in English, or at least an abstract in English, rather than on unpublished data contained in the original data sets that were not available to the authors of the analysis for re-analysis. Although most of the published DILI and HILI cases provide excellent data, some authors forgot presenting RUCAM based causality gradings or included cases with a possible causality grading in their final evaluations of cases together with a probable or highly probable causality level. Nevertheless, a broad range of different causality gradings was commonly provided in most published cases, respective references allow for detailed information. As being outside the scope of this article, causality gradings for individual reports were not provided , but somThe perspectives using the updated RUCAM in future DILI and HILI cases are favorable because many authors including those from the US become more familiar with RUCAM and are ready to use this diagnostic algorithm , in lineFuture DILI and HILI studies should adhere on a prospective study design as strongly recommended in the RUCAM updated in 2016 because a retrospective approach may create concern on the validity of the published results due to incomplete information . NeglectThe current analysis showed a favorable run of the RUCAM algorithm globally used since its launch in 1993, considering the annually published DILI and HILI cases. Overall 95,885 liver injury cases were published using RUCAM for causality assessment, namely 81,856 iDILI cases and 14,029 HILI cases. The global use of RUCAM assessing causality in cases of DILI and HILI helps compare study results among various countries and facilitates description of typical clinical features, best derived from case reports or small case series. RUCAM solves complex conditions as an algorithm in line with principles of Artificial Intelligence. Top ranking countries providing RUCAM based DILI cases were China, the United States, Germany, Korea, and Italy, whereas most RUCAM based HILI cases were published by authors from China, Korea, Germany, India, and the United States. In term of number of cases published, there is no other causality assessment method that could outperform RUCAM evaluating DILI and HILI cases. This should encourage all the stakeholders involved in DILI and HILI to systematically use RUCAM in order to reinforce their diagnosis and take the right decisions for the benefit of the patients.


With the increasing double burden of communicable and non-communicable diseases (NCDs) in sub-Saharan Africa, health systems require new approaches to organise and deliver services for patients requiring long-term care. There is increasing recognition of the need to integrate health services, with evidence supporting integration of HIV and NCD services through the reorganisation of health system inputs, across system levels. This study investigates current practices of delivering and implementing integrated care for chronically-ill patients in rural Malawi, focusing on the primary level.A qualitative study on chronic care in Phalombe district conducted between April 2016 and May 2017, with a sub-analysis performed on the data following a document analysis to understand the policy context and how integration is conceptualised in Malawi; structured observations in five of the 15 district health facilities, selected purposively to represent different levels of care (primary and secondary), and ownership (private and public). Fifteen interviews with healthcare providers and managers, purposively selected from the above facilities. Meetings with five non-governmental organisations to study their projects and support towards chronic care in Phalombe. Data were analysed using a thematic approach and managed in NVivo.Our study found that, while policies supported integration of various disease-specific programmes at point of care, integration efforts on the ground were severely hampered by human and health resource challenges e.g. inadequate consultation rooms, erratic supplies especially for NCDs, and an overstretched health workforce. There were notable achievements, though most prominent at the secondary level e.g. the establishment of a combined NCD clinic, initiating NCD screening within HIV services, and initiatives for integrated information systems.In rural Malawi, major impediments to integrated care provision for chronically-ill patients include the frail state of primary healthcare services and sub-optimal NCD care at the lowest healthcare level. In pursuit of integrative strategies, opportunities lie in utilising and expanding community-based outreach strategies offering multi-disease screening and care with strong referral linkages; careful task delegation and role realignment among care teams supported with proper training and incentive mechanisms; and collaborative partnership between public and private sector actors to expand the resource-base and promoting cross-programme initiatives. Healthcare systems face an increasing demand for chronic care. Non-communicable diseases (NCDs) such as cardiovascular diseases, diabetes, and cancer are among the largest contributor to global mortality, and over 70% of these deaths occurred in sub-Saharan African (sSA) and other low-income settings . sSA coucoherent set of methods and models on the funding, administrative, organizational, service delivery and clinical levels designed to create connectivity, alignment and collaboration within and between the cure and care sectors …” . Commonly identified goals for integrated care are improving efficiency in the coordination and delivery of health services, enhancing quality of care, maximising access and coverage, and improving user satisfaction  who we [MoH] sit down and discuss what the partners have, and we tell them what we want … or what we are looking for, and what they are doing may not match, but because they have drugs, we can discuss with them and they help us.(KII15_Manager_District)Some of the programme coordinators interviewed spoke of the importance of coordinating the programmes and activities, which target chronically-ill patients (both those with HIV and an NCD). They reported having focal persons at the district level for HIV, NCD, palliative services, and mental health. This was aimed at facilitating coordination of chronic care interventions within facility and community settings, and delivered by Ministry of Health (MoH) personnel and district partner NGOs. Although health interventions have been organised under distinct vertical programmes as stipulated in Malawi’s essential health package , the cooCoordination of different professionals and health partners as a key mandate of the district authorities was identified needing strengthening as interviewees suggested the need for joint planning meetings especially in the formulation of district implementation plans, and increasing participation in district stakeholder meetings where all health and non-health sector stakeholders are engaged, usually organised by the District Commissioner or using other networking forums At community level, outreach clinics were organised to target hard-to-reach communities, offering care closer to patients and facilitating vertical integration. One NGO offered health promotion and curative services, including for some chronic conditions, during weekly mobile clinics. The district health office dispatched a team of clinicians to all its PHC facilities during scheduled clinical outreach visits, offering both general and specialist care. However, the regularity of these clinics depended on availability of transport, materials and on the proper publicising of these events to community members, as one respondent explains  initiated a clinic for patients with diabetes and other cardiovascular conditions, operating twice weekly with NGO support. Palliative services were initially accessible only at secondary level, but since 2017, two public PHC facilities were elevated to offer these services to cancer patients, improving access in remote settings.R: … we lack enough consultation [rooms]. The same consultation where the NCD clinics is happening … the [following] day is another clinic … if we had a little bit considerable number of consultation [rooms], then anybody can come and be provided with services …(KII19_Manager_District)Interviewees reported several factors hampering the extent of integration in delivering chronic care, especially in public PHC settings. One barrier was the limited physical space. Due to the sheer volume of HIV patients and limited consultation rooms in public health facilities, HIV clinics operated as stand-alone clinics on designated days of the week, to address challenges encountered. Consequently, this implied marshalling a substantial portion of health facility staff to run these special clinics, which restricted operation of other clinical services. One manager described this challenging situation as:… last time we had no Glibenclamide for diabetes and currently we do not have … Metformine, which means [patients] are suffering … like epilepsy, we have one drug and before five drugs were out of stock … if the Central Medical Stores [National level] does not have the drugs, we [district health team] do not have the capacity to procure …(KII15_Manager_District)Other barriers interviewees reported were linked to the non-availability of medical supplies and health service infrastructure. Most facilities lacked basic screening equipment such as blood pressure monitors, glucometers, and urine dipsticks to enable point-of-care diagnosis for NCD conditions. Hence, patients were often advised to seek these services in private PHC or referral facilities at their expense. The absence of a central HIV diagnostic and laboratory unit meant transferring samples to other districts, affecting timely analysis. A notable challenge for most public PHC facilities was the interrupted supply of essential NCD drugs, including for diabetes and epilepsy reported to last for several months, which affected availability of comprehensive services for this group of patients (see file Sn = 901) of Phalombe’s health workforce positions are filled, with a critical shortage of clinical staff Many districts in Malawi, including Phalombe, experience severe health workforce shortages. Only 55.1% , who were overstretched with other programme activities and lacked proper training in the management of chronic conditions.The necessary components for integrated care such as the provision of supportive resources, capacity-building opportunities, and a work environment that facilitates an integrationist approach were explored among health managers interviewed and in meetings with NGO representatives, who described the approaches and challenges of putting these components in place Malawi’s health sector is largely externally funded (61.6% donor funds) and funding allocation not equally matched across various programmes; for instance, of the USD 663 million total expenditure on health in the 2015/2016 financial year, over 30% was allocated to HIV compared to less than 10% to NCDs . The nat… they [patients] pay consultation fees and they have to pay for drugs and lab tests … but because it is a life-long problem for them [patients] … some of them are being assisted by their children since they are no longer productive … It [healthcare services] should be sort of like universal, irrespective of where they go; whether to a private hospital or government hospital they [patients] should get free services.(KII06_Clinican_District)Over one-third of health services in Malawi are offered by private-sector providers, and predominantly under the Christian Health Association of Malawi (CHAM) . The nat[some] of the people that access this health facility are from Mozambique … If those people were paying something, at least we might have some resources, or we could add more resources to the already few resources that we have.(KII03_Nurse_Public-PHC)… As a border district, the national ‘free’ public healthcare policy attracts patients from neighbouring country to Phalombe, which results in overstretched services within some of the public PHC facilities. Porous borders and challenges of vetting non-resident patients at the point of care puts additional pressure on district health services and budget.Our study provides qualitative evidence of the practices and complexities of optimally employing an integrated approach in delivering chronic care for HIV and NCD patients at the primary care level in a rural Malawian district. Our results show how the continued, vertical organisation of disease-specific programmes, policies, and financial allocation affected this approach. The rationale for disease prioritisation as well as the implications of such approach for African health systems have been widely documented , 45–47. The ongoing experimentation with integrated care in Malawi and surrounding countries in the region have produced important lessons on how to pursue and strengthen integrative strategies at the primary care level. With regards to system integration, our results indicate that integration is mentioned in health policy documents, however, proper implementation of integration policies requires coordination of programmes and activities, improved stakeholders collaboration and combination of both horizontal and vertical integration approaches. However enforcing system changes is a challenge in most resource constrained contexts. For instance, while the ideal is to have multi-purpose frontline health facilities, where patients’ access a continuum of services irrespective of their conditions, our results bring to the forefront challenges in the availability and organisation of resources to support integration. Studies on integrated HIV-NCD care demonstrate that improving patient flow processes such as sorting appointments and referring patients to the appropriate service stations (e.g. for drug refill or consultation with a clinician) could be beneficial to facilities experiencing high-volume patient load and operating within limited space , 34, 49.The initiation and scaling-up of integrated care strategies implies increased costs, though this should result in more efficient services, improved health outcomes, and cost-savings over time . As our This study was conducted in a single rural Malawian district, hence generalizability of findings is limited. Our study synthesized findings from healthcare providers and health managers interviews, structured observation of healthcare practices to understand features of integration in this context. However, there are important factors beyond what we studied such as patient systems, cultures and norms which influence integration practices . Our stuThe provision of integrated care for patients requiring long-term care has become an important health system reform, and there is growing evidence on how these reforms unfold in practice. Our findings point to the complexity of implementing integrative strategies within resource-limited PHC settings like rural Malawi, and to the progress made in the face of such complexities. Contextual factors, such as staffing levels and an infrastructure of vertical disease programmes influenced the practical implementation of national policies and strategies in support of integrated care provision. Further investment and support is needed towards primary healthcare provision in general and NCD services, particularly in terms of clinical resources, ensuring regular supplies, and provision of training and mentorship to frontline providers to enable them offer integrated care as close to the community as possible.Additional file 1. Interview topic guides.Additional file 2. COREQ checklist.Additional file 3. Health facility structured observation guide.Additional file 4. Additional quotes.