A common approach to enhance patient-centered care is training care professionals. Additional training of patients has been shown to significantly improve patient-centeredness of care. In this participatory design and evaluation study, patient education and medical education will be combined by co-creating a patient-centered and interprofessional training program, wherein patients, students and care professionals learn together to improve patient-centeredness of care.In the design phase, scientific literature regarding interventions and effects of student-run patient education will be synthesized in a scoping review. In addition, focus group studies will be performed on the preferences of patients, students, care professionals and education professionals regarding the structure and content of the training program. Subsequently, an intervention plan of the training program will be constructed by combining these building blocks. In the evaluation phase, patients with a chronic disease, that is rheumatoid arthritis, diabetes and hypertension, and patients with an oncologic condition, that is colonic cancer and breast cancer, will learn together with medical students, nursing students and care professionals in training program cycles of three months. Process and effect evaluation will be performed using the plan-do-study-act (PDSA) method to evaluate and optimize the training program in care practice and medical education. A modified control design will be used in PDSA-cycles to ensure that students who act as control will also benefit from participating in the program.Our participatory design and evaluation study provides an innovative approach in designing and evaluating an intervention by involving participants in all stages of the design and evaluation process. The approach is expected to enhance the effectiveness of the training program by assessing and meeting participants’ needs and preferences. Moreover, by using fast PDSA cycles and a modified control design in evaluating the training program, the training program is expected to be efficiently and rapidly implemented into and adjusted to care practice and medical education. Patient-centeredness, first coined by Balint in 1955 . A commoAlong with patient empowerment, medical education shifts towards mature roles for students in care practice . UndergrIn addition, interprofessional education is applied to enhance quality of (future) care by improving students’ attitudes towards and perceptions of other professions in healthcare, and students’ knowledge and skills with regard to collaboration in care  . Even mTo simultaneously facilitate training of patients in managing their illness and treatment and provide learning opportunities for students and care professionals, a patient-centered and interprofessional training program for patients, students and care professionals will be constructed at the Radboudumc and Hogeschool Arnhem en Nijmegen in Nijmegen, the Netherlands. In the training program, patients, students of different professions and care professionals will work and learn together to exchange experiences, knowledge, and skills by combining patient education, service learning, workplace learning and interprofessional education. It is hypothesized that patient-centeredness of care will be improved by facilitating patients, students of different professions and care professionals to learn together and from each other. To design and evaluate the training program in care practice and medical education, a participatory design and evaluation study will be conducted.The concept of design-based research and the framework of the Medical Research Council  for developing and implementing complex interventions in healthcare are used in this study to guide the research design. Design-based research is used in educational research to design, evaluate and improve educational interventions for complex problems in a real life environment using a mixed-methods approach . The MRCIn this study, grounding for the design of the training program will be obtained by performing a scoping review of the scientific literature regarding interventions and effects of student-run patient education, and focus group studies regarding the preferences of patients, students, care professionals and education professionals on the structure and content of the training program. Based on the results of the scoping review and focus group studies, an initial intervention plan of the training program will be constructed. The intervention plan will consist of the structure, content and theoretical principles of the program. Elements of the intervention plan will be tested in practice in a small scale pilot Fig. .Fig. 1OvThereafter, the intervention plan of the training program will be evaluated in care practice and medical education using process and effect evaluation in short plan-do-study-act cycles of 3 months to ensure rapid adaptation of the training program to experiences of participants, observations of the training program in practice and effects on participants. In addition, the process and effect evaluation will be used to update theories in the field of patient-centered care and medical education.Moreover, an advisory board of patients, students, care professionals and education professionals will be shaped at the start of the project to ensure involvement of participating groups and education professionals in all phases of designing and evaluating the training program.To examine known interventions and effects of student-run patient education by means of a scoping review (phase 1.a).To assess the preferences of patients, students, care professionals and education professionals regarding the structure and content of the training program in focus group studies (phase 1.b).To combine the results of the scoping review and focus group studies into an initial intervention plan of the program (phase 1.c).To pilot-test and evaluate the initial intervention plan with experienced patients, students and care professionals (phase 1.d).To perform process and effect evaluation of the training program in plan-do-study-act cycles as executed with patients with a chronic disease, medical students, nursing students and care professionals (phase 2.a).To perform process and effect evaluation of the training program in plan-do-study-act cycles as executed with patients with an oncologic condition, medical students, nursing students and care professionals (phase 2.b).The scientific literature regarding interventions and outcomes of patient education as performed by undergraduate medical students will be examined. Four databases will be searched  for studies reporting patient education as performed by undergraduate medical students.Studies that 1) involve undergraduate medical students in providing patient education, 2) are aimed at patient education for real patients, and 3) are aimed at patient-centered outcomes of patient education, that is health attitude, self-care, health literacy, treatment compliance, patient empowerment, students’ communication skills, shared decision-making, and relations between (upcoming) care professionals and patients , 20, wilSelection and inclusion of studies will be executed by two independent researchers. Differences in judgment will be discussed to reach final agreement. Finally, references of included studies will be searched for other articles meeting the inclusion criteria.The quality of included studies will be assessed using the Quality Assessment Tool for Quantitative Studies . ConstruIn addition, the patient education intervention method, effects on patients and students, patient education content, patient target group and students’ stage in medical education of the included studies will be characterized using the Kirkpatrick model. The Kirkpatrick model differentiates the extent to which a training program influenced learners on four levels: satisfaction, learning goals, behavior and impact on practice .Finally, an assessment tool will be designed based on the Learning System Transfer Inventory (LTSI). The LTSI is designed for assessing the transfer of training efforts to work practice, and will be applied in this review to assess facilitators and barriers with regard to organizing and implementing practice-based learning in student-run patient education .To include relevant perspectives in designing the training program, nine focus group interviews with patients, students, care professionals and education professionals will be performed Table . StudentFocus group transcripts will be examined using inductive thematic analysis with coding software Atlas.ti to induce semantic themes from the data based on the questions of the topic guide without using a predefined theory or framework. Thematic analysis is a search for themes that emerge as being important to the description of the phenomenon. It involves careful reading and re-reading of the data in order to identify themes, without using a predefined theory or framework in order to capture all relevant information . Two codResulting themes and categories will be compared between focus groups to analyze different perspectives on the training program. Moreover, differing and overlapping themes and categories between subgroups will be analyzed, for example comparison between the perspectives of patients with a chronic disease and the perspectives of patients with an oncologic condition, and comparison between the perspectives of medical students and the perspectives of nursing students. By comparing between subgroups, we aim to adapt the training program more specifically to the needs and preferences of participants of the training program.A concept map will be created based on the scoping review and focus group studies to structure the results of the scoping review and focus group studies. Concept mapping was developed by Joseph Novak and can be used to design complex structures based on knowledge . One resBased on the concept map, facilitators and barriers on learning effectiveness of student-run patient education from the scoping review will be compared with the preferences of participating groups and education professionals as obtained in the focus group studies; corresponding items will form the basis for the design process.Subsequently, the research team  will together assess individual aspects of the concept map and make decisions on the conceptual structure of the program. In the decision process, the preferences of patients, students, care professionals and education professionals, as obtained in the focus group studies, will be used to select items on the structure of the training program which resulted from the scoping review and focus group studies. After that, the conceptual structure will be presented to the advisory board and discussed step-by-step to adapt it to the needs and preferences of participants.The content of the program will be developed using the Dick and Carey model , which dFinally, the conceptual structure and content of the program will be matched with theories in the field of patient-centered care and learning theories to form the theoretical underpinning for the intervention plan of the program.n = 6), clinical stage medical students (n = 6) and a care professional in the field of rheumatoid arthritis. During the pilot study, learning modules consisting of essential parts of the initial intervention plan of the training program will be provided and evaluated. Learning modules will form the building blocks of the program and consist of educational meetings wherein patients, students and care professionals learn together to reach a specific learning goal of the program.To test the initial intervention plan of the training program, a pilot study of the training program will be delivered with expert-by-experience patients who have rheumatoid arthritis for at least more than 10 years  to simulate and evaluate the interaction which took place during the pilot by facilitating discussion about the program between patients, students and care professionals, 2) a group of four students (n = 4) and 3) a group of four patients (n = 4) to address the specific perspectives of participants regarding the structure and content of the pilot. Focus group interviews will be audio recorded and transcribed verbatim.In addition, focus group interviews will be held with participants after executing the pilot to assess their experiences regarding the pilot. The topic guides of the focus group interviews will revolve around the organizational process of the program, experiences of participants, interactions between participants, expectations of participants versus reality, and privacy and safety aspects. Three focus group interviews will be held with 1) a mixed group of two patients, two students and one care professional  will be applied. PDSA is a quality improvement strategy, originating from the engineering industry , which eTo perform process evaluation, the implementation process, mechanisms of impact and influence of contextual factors on the process will be examined using quantitative and qualitative research methods .Detailed modeling of variations between participants, for example in terms of age, educational level, ethnicity and socio-economic status, will be performed to enhance the process and effect evaluation of the program. In addition, program records on the dose and reach of the program, that is number of sessions, duration of sessions and preparation assignments, participation rate and drop-outs, will be made during execution of the program .A custom-made survey with open-ended and closed-ended questions will be administered to participants after they participated in the program to evaluate participants’ experiences with regard to the training program. Moreover, two qualitative research strategies will be applied during and after the PDSA-cycles to assess the implementation process and fidelity of the program : observaNon-participatory observational research will be performed during the training program’s learning modules by taking observational notes on the execution of the program. Observational notes will aim at the organizational process, interactions between participants, integrity and safety aspects, and general remarkable events during the execution of learning modules.Individual exit-interviews or focus group interviews will be held with participants after each cycle of the training program. The topic guides of individual interviews or focus group interviews will revolve around achieving personal goals during the program, experiences of participants, interactions between participants, expectations of participants versus reality, and privacy and safety aspects. In addition, time will be spend during the exit-interviews or focus group interviews on open comments about the training program.It is hypothesized that patients are affected by the program in terms of enhanced disease knowledge, self-efficacy towards care providers, self-efficacy towards chronic diseases, health literacy and patient activation. In addition, it is hypothesized that patients, students and care professionals are affected by the program in terms of a shift of their attitude towards patient-centeredness. Moreover, it is hypothesized that students and care professionals gain more trust in patients whilst participating in the program. Finally, it is hypothesized that interprofessional parts of the program will enhance both medical and nursing students’ attitude towards other care professions and their team skills.The effects of the training program on patients’ knowledge, attitude, self-efficacy, skills and behavior, and students’ and care professionals’ attitude and skills, will be evaluated by performing before-and-after outcome measures. Based on the above-mentioned hypothesized effects of the training program, reliable and validated measurement instruments are selected for each group and will be used to evaluate the effects of the training program Table .Table 2MProcess data will be evaluated before the effect evaluation is completed to prevent bias in the interpretation of qualitative evaluations regarding the process. In addition, quantitative and qualitative research methods which are used in process and effect evaluation will build upon another to enhance the evaluation . TheoretObservations will be used to monitor the training program in practice and quickly adapt the training program to participants’ needs and preferences. To do so, observations will be discussed within the research team between learning modules in a PDSA-cycle to examine the implementation process of the training program and adapt the learning modules, if necessary .In addition, observational notes and results of individual exit-interviews or focus group interviews will be assessed in more depth after execution of one PDSA-cycle of the training program. Two coders will independently code and categorize the observational notes and focus group transcripts using thematic analysis to induce semantic themes from the data based on the questions of the topic guide without using a predefined theory or framework , and disBefore-and-after outcome measures will be compared to evaluate the effects on patients, students and care professionals using descriptive statistics and multi-level logistic regression analysis. The results of the Patient-Practitioner Orientation Scale will also be compared between participants to compare the effects on attitude towards patient-centeredness between participating groups. In addition, individual questions, items and sub-scales from the measurement instruments will be compared in combination with the process evaluation to assess specific effects of the training program.All results will be discussed during learning meetings between PDSA-cycles with the research team and the advisory board to examine the implementation process, mechanisms of impact, influence of contextual factors and outcomes of the program, and improve the structure and content of the subsequent PDSA-cycle of the training program Fig. .Finally, process and effect evaluation will be compared with theories in the field of patient-centered care and medical education to update theoretical principles and enable generalization of the results of our study to other situations.A modified control design will be used for two groups of students per two PDSA-cycles to ensure that students who act as control for the intervention group will benefit from participating in the program in a subsequent PDSA-cycle of the program Fig.  33].Fig.Fig33].FIn the modified control design, two student groups simultaneously enter the research program. Student group 1 participates in the program next to the regular curriculum in the first PDSA-cycle and follows only the regular curriculum in the second PDSA-cycle. Student group 2 follows only the regular curriculum in the first PDSA-cycle and participates in the program next to the regular curriculum in the second PDSA-cycle. The process of and effects on student group 1 are evaluated by a pre-test measure with measurement instruments at the start of the PDSA-cycles (T-0), a post-test measure with measurement instruments and exit-interview after following the program (T-1), and a follow-up measure with measurement instruments 3 months after participation (T-2). The process of and effects on student group 2 are evaluated by a control measure with measurement instruments at the start of the PDSA-cycles (T-0), a pre-test measure with measurement instruments before following the program (T-1), and a post-test measure with measurement instruments and exit-interview after following the program (T-2).Comparison between the outcome measures of both groups at time-points T-0 and T-1 enables controlled evaluation of the effects of the program on student group 1. The outcome measures on student group 1 at time-point T-2 enable uncontrolled follow-up evaluation of the effects of the program on student group 1, 3 months after participation in the program. The outcome measures on student group 2 at time-point T-1 and T-2 enable uncontrolled evaluation of the effects of the program on student group 2.For focus group interviews in phase 1.b, we chose to include 4–6 participants per focus group interview since it can be practically challenging to find participants and we want to have a broader range of focus group interviews. For the pilot in phase 1.d, we chose to include six patients, six students and one professional to enable intensive interaction between participants and support the educational nature of the program.The number of participants in phase 2 will not be calculated using a power calculation due to the explorative nature of the study. We will involve 20–30 participants per cycle to enable interaction between participants in thorough manner and support the educational nature of the program. In addition, we aim to include as many patients as students to facilitate equity between these participating groups. Partially due to the low number of participants and exploratory nature of the protocol, evaluation of the program using descriptive statistics will be aimed at describing the process and effects of the program, instead of explicitly proving the effects of the program.To assess the feasibility of the training program in improving knowledge, attitude, self-efficacy, skills and behavior of chronic patients, patients with rheumatoid arthritis will be included in the first PDSA-cycle of the training program. Patients will participate next to receiving regular care or support. Detailed inclusion criteria for the first cycle and subsequent cycles will be based respectively on the focus group studies, and process and effect evaluations of PDSA-cycles.After performing process and effect evaluation of the first PDSA-cycle and improving structure and content of the program, a second cycle of the training program will be performed, wherein we plan to include patients with rheumatoid arthritis, diabetes mellitus and hypertension.Oncologic conditions have a different course of disease and influence of the disease on personal life compared to chronic diseases. It is hypothesized that patients with an oncologic condition require a different configuration of the training program. Therefore, after evaluating the training program with chronic patients, the feasibility of the training program in improving knowledge, attitude, self-efficacy, skills and behavior of patients with an oncologic condition, that is colonic cancer and breast cancer, will be evaluated. To do so, patients with an oncologic condition, students and care professionals will participate in subsequent PDSA-cycles of the training program. Patients will participate next to receiving regular care or support.To enable students to learn about diseases, the influence of a disease on people’s lives and care processes from the patients’ perspective, medical students and nursing students will participate in the training program.Medical students will participate in the training program as part of their medical education in the patient-centered medical curriculum of the Radboudumc. Moreover, starting from the second PDSA-cycle, nursing students will be involved in the training program as part of their education at the Hogeschool Arnhem en Nijmegen.Finally, medical and nursing students will be involved in designing and evaluating the training program by participating in the advisory board and focus group studies. Student internships will be offered to students, in which they contribute to the organization and evaluation of the training program, for example by performing observational research during the PDSA-cycles or contributing to the practical organization of the training programs’ modules.Besides patients and students, the training program is hypothesized to affect the attitude towards patient-centeredness of care professionals who participate in the training program, for example by enhancing their knowledge regarding the patients’ perspective. To ensure connection with clinical practice, care professionals who work in the field of chronic diseases and oncologic conditions at the Radboudumc will be involved in the training program by participating in the advisory board, the focus group studies, and the training program itself.To support ethical issues regarding this study protocol, ethical approval of the study protocol has been obtained from the Medical Ethical Committee of the Radboud university medical center for the study parts that include patients. Moreover, ethical approval has been obtained from the Netherlands Association for Medical Education for study parts that include students.The informed consent procedure will include information briefing prior to inclusion for both patients and students. All participants will have enough time to decide on participation.All participants will have the possibility to exit the program and/or investigation at any time during execution. Research data obtained until that moment will be deleted.In addition, interim analyses will be performed after each learning module and PDSA-cycle to decide on continuation of process and effect evaluation by the research team in case of unsafe conditions. Unsafe conditions are mainly possible in psychosocial sense, for example regarding personal information which is communicated during the program or highly emotional issues regarding diseases and treatment. We will monitor execution of the program closely and guide participants during execution by an experienced moderator. Moreover, a safe atmosphere will be created by preparing patients, students and professionals for participation by explaining privacy issues and providing general “rules” of interaction between participants during the program, for example regarding integrity and privacy of communication.Research data will always be analyzed anonymously. In addition, research data will be stored securely on the server of the department. Personal information will be separated from research data and coded. Only the research team has access to the data.Our participatory design and evaluation study provides an innovative approach by including various participants in rapid design and evaluation of an educational and therapeutic intervention in care practice and medical education. The participatory approach is expected to enhance the effects of the training program on patients, students and care professionals by meeting participants’ needs and preferences Table , Fig. 4.Participatory medicine and coproduction of healthcare services are increasingly applied in designing and improving health care. It has been suggested that cooperation between users and providers in medicine will self-evidently improve quality, safety and value of care . In our During the process and effect evaluation, a large amount of data will be collected on the implementation process, the mechanisms of impact, the influence of contextual factors and the outcomes of the program. By evaluating the process and effects of the program in broader sense by using various outcome measures, we aim to assess the process and effects of the program in more extent than when only focusing on specific effects. We believe that evaluating only specific effects will not provide in depth insight into the complex learning process that is expected to occur in the program.By enabling students to meet and interact with patients in an early stage of their educational career, we hypothesize that their attitude towards patient-centeredness and trust in patients will be enhanced Table . In addiIn addition, our training program offers patients the opportunity to interact with each other to exchange knowledge and to find support, to obtain personalized information regarding their disease and treatment from students and care professionals, and to improve care services by sharing their experiences with students and care professionals. We expect that the program will improve patients’ knowledge, attitude, self-efficacy, skills and behavior regarding their disease and treatment Table , which cFinally, interaction between care professionals and patients and students in the program is expected to enhance the attitude of care professionals with regard to patient-centeredness Table . AlthougOur study protocol is based on the concept of co-production. We will involve patients, students and care professionals in all phases of designing and evaluating the training program. However, co-production in its purest form would also include patients, students and care professionals executing or analyzing for example focus group interviews, observational notes, and/or results of measurement instruments. Since it is a practical challenge to involve all target groups in all phases of executing this protocol, we incorporated specific measures to involve participating groups as much as possible in the design and evaluation of the program, for example by shaping an advisory board of participating groups to assess results of evaluations, and enabling students to organize the program. In addition, since this study protocol is aimed at designing and evaluating the training program in its earliest phase, we expect to provide more intensive and purer co-production at a later stage of implementing the program, for example by involving former participants in producing, implementing and evaluating the program.Personalizing the training program to the individual needs and preferences of each participant would require and intensive amount of time, money and effort. In addition, knowledge and skills differ between patients and between (future) care professionals, and it is expected to be a challenge to fit the training program to the capacities of all patients, students and care professionals. We will differentiate between participant subgroups in designing and evaluating the program to fit the training program to the needs, preferences and capacities of individual participants as much as possible. In addition, we will assess if the program fitted participants’ personal needs, preferences and capacities during program evaluation, and use these experiences to improve the next cycle of the program.In addition, prioritizing the experiences and opinions of participants as presented during the program evaluation will be essential to be able to improve the training program in the PDSA-cycles. To be able to apply the preferences of participants in improving the training program, we will discuss and prioritize the evaluations with the advisory board.Since the program is evaluated in one setting, the transferability of the results of our study towards other settings might be limited. To address the transferability, we will use theoretical principles to ground the intervention plan and explain the results of process and effect evaluation. In addition, we will describe the participants, the context of the learning environment of the program and our analytic approach in depth to enable comparison of our results to other situations .Design-based research can be risky due to uncertainties in participant behavior and circumstances in the learning environment, and complicated in the sense of combining theory and practice while involving various stakeholders during all steps of designing and evaluating an intervention . To addrFinally, medical and nursing students are commonly prepared for ethical and moral aspects of care practice at the end of their educational career. However, since undergraduate medical and nursing students are not yet fully prepared and equipped for these aspects of care practice, it is essential to monitor the integrity and safety of the training program. In addition, discussing severe diseases and the influence of a severe disease on the lives of patients between patients, students and care professionals can have psychological impact on both patients and students. To ensure the integrity and safety of both patients and students, we will pay attention to the psychological and social aspects of participating in the training program during observational research and program evaluation. Moreover, to ensure an ethically safe design of the training program, ethical approval will be requested for both patient and student participation in the project from respectively the ethical committee of the Radboudumc and the ethical committee of the Dutch Association for Medical Education.To summarize, in our participatory design and evaluation study, an innovative patient-centered and interprofessional training program is co-created together with patients, students and care professionals. By embedding the perspectives of participating groups in all phases of designing and evaluating the training program, we aim to meet the needs and preferences of patients, students and care professionals and enhance the effectiveness of the training program. Moreover, by using fast PDSA-cycles and a modified control design in evaluating the training program, we aim to adjust the training program rapidly to process and effects evaluation, and efficiently evaluate and optimize the program in care practice and medical education.


In this article, we examined the productivity and welfare effects of the program using household-level data from rural Nigeria. The article employed instrumental variable regression approach to control for the potential endogeneity of the input subsidy program. Our results suggest that the program is effective in improving productivity and welfare outcomes of beneficiary smallholders. The size of the estimated effects suggests a large improvement in productivity and welfare outcomes. Moreover, the distributional effects of the program suggest no heterogeneity effects based on gender and farm land size. These results are robust to using alternative measurements of program participation. The benefit–cost ratio of 1.11 suggests that the program is marginally cost-effective. Overall, our results suggest that while improving average productivity is a good outcome for improving food security, improving the distributional outcome of the program by targeting the most disadvantaged groups would maximize the program’s contribution to food security and poverty reduction.In an attempt to go beyond the so called “ In an effort to promote adoption of yield-increasing technologies such as inorganic fertilizer and improved seed, many sub-Saharan African (SSA) countries implemented universal large-scale input subsidy programs throughout the 1970s and 1980s . However1Like many SSA governments, Nigeria has since then implemented a large-scale targeted input subsidy program called the Growth Enhancement Support Scheme (GES) in 2012. The program was implemented with the broad official objective of promoting agricultural productivity and food security by making fertilizer and improved seed more affordable and accessible to smallholders . The GESSince the GES program outsources the subsidy to private agro-dealers, it is safe to assume that the scheme will have a crowding-in effect on the supply side of fertilizer and improved seed markets in terms of private sector sales. However, farmers could still use subsidized inputs provided through the GES in place of some or all of their commercial purchases, leading to crowding out of commercial inputs on the demand side of the market. Regardless, there is little empirical evidence on the impact of the program to inform on-going debates on how effectively the GES program increases agricultural productivity and welfare of poor and food insecure households. In this study, we empirically test whether a mobile-based e-voucher system for fertilizer and improved seed subsidies in Nigeria improves productivity and welfare outcomes. Maize yield and income from maize production are used as a proxy for productivity outcomes in this article, while per-capita food, total, and non-food expenditure are used as indicators for welfare outcomes. We focus on productivity and welfare outcomes as they are the most important indicators given the stated objectives of the GES.ceteris paribus, only improve the income of smallholders. However, leakages and imperfect targeting may divert subsidies away from the intended beneficiaries. Under such circumstances, the GES may become beneficial on average by improving the productivity of commercial farmers albeit ineffective in addressing the needs of smallholders. This paper therefore addresses this issue by estimating the overall average effect of the program as well as its distributional effects. In estimating the overall average and distributional impacts of the GES program, we control for the potential endogeneity of participation in the GES using Instrumental Variable (IV) regression approach. We also examined the robustness of estimated impacts by constructing alternative measures of participation in the GES program. Finally, in an attempt to provide an overall effectiveness of the program, the paper undertakes a benefit–cost analysis based on observed direct costs and benefits. The rest of the paper is organized as follows: Section . Data sources and the econometric strategy are presented in Section This article contributes to the literature on input subsidies in the following ways: First, by focusing on a country that implemented the most expensive input subsidy program in SSA, it investigates the enduring question of whether and to what extent a smart input subsidy program such as the GES impacts productivity and welfare outcomes. To date, there is not a single study that evaluated the impact of the GES program on productivity and welfare of smallholders in Nigeria. In addition, this article is the first to evaluate the effectiveness of an e-voucher input subsidy program. Second, in an attempt to provide beyond average treatment effects, we examine the distributional impacts of the GES program focusing on two sources of heterogeneity: gender and farm land size. In principle, the GES should, 2Although the vast majority of Nigeria’s rural population engages in agriculture, the sector has been in the periphery of government priorities over the past 30 years. As a result, the rate of rural poverty and food insecurity has increased substantially over that time period. For instance, rural poverty measured at the food poverty line has increased from 33.6% in 2004 to 48.3% in 2010 . MoreoveThe GES has been implemented with the intention to improve the efficiency of fertilizer and improved seed distribution to smallholders. By deregulating seed and fertilizer markets as well as through well-targeted fertilizer and improved seed subsidies, the GES aims to increase the productivity of smallholders. It was specifically designed to minimize leakages and to ensure that subsidies are provided only to intended farmers. In addition, the procurement and distribution of fertilizer and improved seeds is outsourced to private agro-dealers. The GES intends to provide improved seed and fertilizer to 20 million farmers within five years . In addismarter”, the initial list compiled at the village level was transferred to an electronic database. Moreover, each farmer was given a unique identifier with the help of National Identity Management Commission (NIMC). After registration was completed, eligible farmers received an e-wallet (an electronic voucher) notification through their phone. The e-wallet specifies the total quantity of fertilizer and improved seed allocated to the farmer as well as the designated redemption center for collection. According to In principle, the GES targets only fulltime and non-commercial farmers. However, there is no database of farmers to verify eligibility and most of the demographic information provided by farmers was self-reported. Registration of eligible farmers was carried out manually, with completion of forms at village level with the help of village leaders . In orde3(a)This study uses a household survey data collected by the International Institute of Tropical Agriculture (IITA) in 2015 as part of an on-going effort to evaluate the impact of adoption of drought tolerant maize varieties and the GES on productivity and welfare outcomes. A multi-stage-stratified sampling procedure was employed to select Enumeration Areas (EAs) from each Local Government Areas (LGAs), and households from each of the selected EAs. The list of all EAs was obtained from the National Population Commission (NPC) of Nigeria. The EAs were then divided by the number of LGAs in each of the selected states to obtain the number of EAs per LGA. Following the National Bureau of Statistics (NBS) recommendation for a nationally representative data collection, 10% of the LGAs in each of the selected States and 5% of the total EAs per LGA were randomly selected. Finally, from the households in each of the selected EAs, five farming households were randomly selected, resulting in a sample size of 2,305 households.surveybe” software.The data were collected using structured questionnaire which was pre-tested twice by trained and experienced enumerators. The survey questionnaire was designed to gather detailed information on socio-economic characteristics of households, expenditure on food, and non-food items, input use and allocation, crop and livestock production, output for maize, and other notable crops and participation in the GES program. In addition, extensive village-level data were collected on the incidence of shocks, prices of key inputs and crops, among others. In terms of participation in the GES, relevant data were collected on the level of awareness about the GES program as well as on farmers' decision to register for the GES program. In addition, data were collected on the quantity of seed and fertilizer allocated to registered farmers as well as the final quantity collected and the price paid by the participants of the GES program. To minimize errors usually encountered with the use of paper questionnaire, the data for this study were collected electronically using the “(b)Like any evaluation program, establishing the causal impacts of an input subsidy program on various outcomes of interest is in fact a “wicked problem”  is then computed as the difference between Eqns. However, casual identification requires controlling for both observable and unobservable factors that influence participation in the GES and productivity and welfare outcomes. Hence, estimates of Eq. However, finding an instrument that satisfies the orthogonality condition is not a trivial matter. Most of the studies that evaluated the impacts of input subsidies on such outcome indicators have used the variable “number of years the household head has lived in a village” as an instrument . Followi4i’s characteristics such as household size, age, education that affect participation in the GES. iS captures participation in social network activities such as membership in cooperatives and labor-sharing arrangements The outcome indicators are related to productivity and welfare. Our first productivity outcome-related indicator is maize yield. Although the GES does not require participating farmers to use the subsidized inputs on a particular crop, we opt to consider maize yield as a productivity outcome variable as maize is one of the most important food crops in Nigeria. In fact, Nigeria is the largest maize producer in West Africa. In addition, maize also stands to benefit the most from fertilizer subsidies as response rate of improved maize is higher than most other crops. According to our data, average maize yield in the study area stands at 2,006 kg/ha. However, average maize yield for GES participants 2,205 kg/ha) is significantly higher than for non-participants  and the difference is statistically significant at 1% significance level see . Our sec kg/ha isOur welfare-related indicators include food expenditure, non-food expenditure, and total expenditure, all measured on per-capita basis. In addition to expenditure indicators, we also used headcount poverty ratio as an additional welfare indicator. Total expenditure is calculated by summing food and non-food expenditure values. A household’s food consumption expenditure is comprised of monetary expenditures on purchased food and the imputed values of consumption from own harvest. Looking into the distribution of consumption expenditures, the average per capita total consumption expenditure is about ₦112,136 per year.r capita .7I(.) i(b)In the household survey, we collected detailed information regarding the awareness and registration process of the GES. More specifically, first we asked households if they were aware of the GES program. Second, we asked those who responded in the affirmative if they had registered in the GES program. Third, we asked those who responded to the registration question in the affirmative if they had received mobile alert. Finally, we asked those who were notified of the e-voucher through the mobile alert if they had actually collected the subsidized inputs and the quantity of seed and fertilizer allocated to them as well as the final quantity they collected. We used the above sequence of questions to construct dummy variables for our sequential probit model. According to the survey, about 65.5% of the households were aware of the GES program and only 64% of them registered for the GES. However, our survey further revealed that only 76% of the registered households actually received mobile alerts.Since our main objective is to evaluate the overall effectiveness of the GES program on productivity and welfare outcomes, we used registration to the GES program as our main treatment variable. In particular, participation in the GES is measured by a dummy variable which takes a value of one if the household is registered to the GES and zero otherwise. Note that, in the robustness section, we used receiving a mobile alert as well as actual collection of subsidized fertilizer and improved seed as our treatment variables. In addition to household characteristics, we also included state dummies to control for state-level fixed effects. We further have controls for general conditions such as access to electricity. Finally, the number of years of residence in the village serves as an instrument for participation in the GES. 4In this section, we present the results of our econometric analysis. Firstly, we report the effect of the GES program on productivity, maize income, and welfare outcomes using matching techniques in (a)p-value = 0.543) while the joint significance of covariates was not rejected before matching . Moreover, due to matching, the pseudo-R2 declined from 15.2% to 1.1%.The reliability of the PSM and IPWRA results depends on the quality of our matching. We therefore provide some details on the overall covariate balancing and common support. R2, and significant reduction in the mean standardized bias are indicative of successful balancing of the distribution of covariates between participants and non-participants of the GES. The common support region is presented in The high total bias reduction, the insignificant p-values of the likelihood ratio test after matching, low pseudo-(b)(i)As mentioned in the methodology section, we used a sequential probit model to examine the determinants of participation in the GES due to the sequential steps involved in the GES program. In our setting, first we estimate the determinants of awareness to the GES. We then estimate the determinants of registration to the GES conditional on awareness. Finally, we estimate the determinants of receiving a mobile alert conditional on registration. We followed this step as registration is a strict subset of awareness. Similarly, receiving a mobile alert is a strict subset of registration. We did not include the decision to collect allocated quantities of fertilizer and improved seed in our sequential probit model as it is not a strict subset of receiving a mobile alert.10Number of years of residence in the village) affects the probability of becoming aware of the GES and the conditional probability of registration to the GES conditional on awareness but not the conditional probability of receiving a mobile alert given registration in the GES No control” present a parsimonious specification for maize yield and income that includes only the treatment variable (registration for the GES) along with state-level fixed effects. Estimates of “With control”, present results where standard controls for maize yield and income are included. Estimates of “With IV” present the results of the IV specification in which participation in the GES program is treated as endogenous. We specify a log-linear functional form for maize yield and income from maize production is estimated at levels.The result showing the effects of the GES program on maize yields and maize income is presented in The results presented in land category” which takes on a value of one if a household owns less than 3 hectares of farm land and zero otherwise.In our subsequent discussion, we base all our interpretations based on our preferred specification (IV specifications). The results in (iii)This section presents and discusses the welfare effects of the GES program. We used per-capita total expenditure, food expenditure as well as poverty headcount ratio as indicator for welfare. In our estimation, total expenditure and food expenditure are measured on per capita basis and estimated using a log-linear functional form. Results are reported in On average, per-capita total expenditure increased by 30.7%. Similarly, as a result of participation in the GES program, per-capita food consumption expenditure increased by 39.4%. These results are consistent with previous studies in Nigeria. For instance, The final welfare indicator, headcount poverty ratio, is a binary variable and hence the effect size can be estimated using a probit model specification. However, the parameter estimates for GES will only represent changes in the probability of poverty instead of actual poverty reduction rates. Estimating the effect of GES on poverty reduction instead of changes in the probability of poverty reduction requires examining the distribution of observed poverty of GES participants and the distribution of the counterfactual poverty of GES participants had they not participated in the GES program. In other words, we need to examine the poverty reduction effects of the 30.7% per-capita total expenditure growth reported in (c)In this section we present robustness cheeks for alternative measures of participation in the GES program.(i)In our main analysis, we measure participation in the GES by registration status. Our data show that only registered farmers have received mobile alerts. However, of the registered farmers, only 76% have received mobile alerts. As a robustness check, we define treatment based on receiving a mobile alert. In particular, we created a dummy variable which takes a value of one if the household has received a mobile alert and zero otherwise.Results are reported in (ii)Our second robustness check is based on actual collection of subsidized fertilizer and improved seed by farmers. Our data show that only registered farmers have managed to collect subsidized fertilizer and improved seed. However, only 69% of the registered farmers have collected subsidized fertilizer and improved seed. Similarly, 3.7% of the registered farmers have managed to collect subsidized fertilizer and improved seed without receiving a mobile alert. The second case may arise due to network coverage or mobile phone ownership issues. The program clearly stated that when the use of mobile phone is not tenable, farmers can claim benefits using scratch cards or GES identification cards. As such the second group of the beneficiaries may have collected their share of fertilizer and improved seed through scratch cards or GES identification cards. However, the first group of households may have failed to collect their share due to liquidity constraint as farmers are expected to pay the subsidized price to private agro-dealers or the redemption centers may have been far away which makes the final price expensive due to high transaction costs. Nonetheless, these two issues will introduce measurement errors. Herein, we probe the robustness of our results by measuring treatment by a dummy variable which takes on a value of one if the household has collected subsidized inputs and zero otherwise as a measure of program participation. We focus on maize yield and poverty outcomes. Results are reported in (iii)Herein, we focus on registration without receiving a mobile alert or collecting subsidized fertilizer and improved seeds from redemption centers as a falsification test to examine if our reported results , Table 8(iv)Herein, we provide benefit–cost ratios albeit without considering indirect benefits and costs. For the purpose of calculating the effectiveness of the program, we collected data on the quantity of seed and fertilizer allocated to farmers as well as the final quantity collected and the price paid by farmers. We calculated the cost of subsidy per kg of fertilizer and improved seed as the difference between the market price and the subsidized price of fertilizer and improved seeds. However, data on registration, administrative, and logistic costs of the GES program are not available despite our best efforts to obtain it. Since costs for registration, transportation, storage, procurement, and administration are likely to be significant; we took some of the cost components of the Malawi input subsidy program from 13It is worth noting, however, that our calculation is based on the so called “production-based” approach and ignores indirect benefits . Using t5In Nigeria, improving agricultural productivity through the use of fertilizer and improved seeds is imperative to improve food security and reduce the pervasive nature of rural poverty. However, the use of such key agricultural inputs is rather low even by SSA standard as a result of pervasive input and credit market imperfections. With the premise of improving the use of improved seed and inorganic fertilizer, the government of Nigeria embarked on a mobile phone-based input subsidy program in 2012. Using a unique household-level data from rural Nigeria, this paper examined the productivity and welfare effects of the GES program. In particular, the study provides insights into how effective the program was in enhancing productivity and improving welfare outcomes. The study employed instrumental variable regression approach to control for the potential endogeneity of participation in the GES program.Our main empirical findings are as follows. First, farmers who participated in the GES increased their maize yield by 26.3%. Similarly, maize income of GES participants increased by ₦19,730. These results suggest that the GES enabled farmers to improve their productivity and income from maize production, which is a case for justifying the intervention. Second, in terms of the welfare outcomes, the GES has a positive and statistically significant effect on per-capita total, food, and non-food consumption expenditures. The size of the estimated effects suggests a large improvement in welfare as a result of participation in the GES program. Specifically, GES participants increased their per-capita total consumption expenditure by 30.7%. As a result of this consumption growth, poverty headcount ratio has declined by 17.7% points among participants of the GES. Third, the effect of the interaction term between participation in the GES and farm land size as well as GES and gender is insignificant suggesting the absence of heterogeneity effects based on gender and farm land size. Fourth, the benefit–cost ratio of the program, valued at market prices and without accounting for economy-wide effects, is about 1.11. Each unit of dollar that the government spends as a subsidy yields a return of 1.11 dollars.The results presented in this paper should be interpreted with caution. First, our identification strategy relies on cross-sectional data which limits the generalizability of the results beyond one agricultural production year. The use of panel data and fixed-effects would be an important extension in the future. Second, our benefit–cost ratio calculation does not take into account indirect benefits and costs. Moreover, in estimating impacts on productivity and welfare, we did not consider the possibility of farmers re-selling their fertilizer and improved seeds due to lack of data. Although the GES strictly prohibits re-selling of the received inputs, we cannot rule out the possibility of some recipients selling fertilizer and improved seeds in the local market or at the redemption centers. When subsidized inputs are re-sold at the local market, it will definitely introduce a crowding-out effect. Examining the crowding-out effect of the program will therefore be an important extension.


American Indian and Alaska Native (AI/AN) youth face multiple health challenges compared to other racial/ethnic groups, which could potentially be ameliorated by the dissemination of evidence-based adolescent health promotion programs. Previous studies have indicated that limited trained personnel, cultural barriers, and geographic isolation may hinder the reach and implementation of evidence-based health promotion programs among AI/AN youth. Although Internet access is variable in AI/AN communities across the United States, it is swiftly and steadily improving, and it may provide a viable strategy to disseminate evidence-based health promotion programs to this underserved population.We explored the potential of using the Internet to disseminate evidence-based health promotion programs on multiple health topics to AI/AN youth living in diverse communities across 3 geographically dispersed regions of the United States. Specifically, we assessed the Internet’s potential to increase the reach and implementation of evidence-based health promotion programs for AI/AN youth, and to engage AI/AN youth.This randomized controlled trial was conducted in 25 participating sites in Alaska, Arizona, and the Pacific Northwest. Predominantly AI/AN youth, aged 12-14 years, accessed 6 evidence-based health promotion programs delivered via the Internet, which focused on sexual health, hearing loss, alcohol use, tobacco use, drug use, and nutrition and physical activity. Adult site coordinators completed computer-based education inventory surveys, connectivity and bandwidth testing to assess parameters related to program reach , and implementation logs to assess barriers to implementation (program errors and delivery issues). We assessed youths’ perceptions of program engagement via ratings on ease of use, understandability, credibility, likeability, perceived impact, and motivational appeal, using previously established measures.Sites had sufficient computer access and Internet connectivity to implement the 6 programs with adequate fidelity; however, variable bandwidth  and technical issues led some sites to access programs via back-up modalities . The number of youth providing engagement ratings varied by program . Across programs, youth rated the programs as easy to use (68-91%), trustworthy (61-89%), likeable (59-87%), and impactful (63-91%). Most youth understood the words in the programs (60-83%), although some needed hints to complete the programs (16-49%). Overall, 37-66% of the participants would recommend the programs to a classmate, and 62-87% found the programs enjoyable when compared to other school lessons.Findings demonstrate the potential of the Internet to enhance the reach and implementation of evidence-based health promotion programs, and to engage AI/AN youth. Provision of back-up modalities is recommended to address possible connectivity or technical issues. The dissemination of Internet-based health promotion programs may be a promising strategy to address health disparities for this underserved population.Clinicaltrials.gov NCT01303575; https://clinicaltrials.gov/ct2/show/NCT01303575 (Archived by WebCite at http://www.webcitation.org/6m7DO4g7c) As of 2012, an estimated 5.2 million individuals in the United States identified as American Indian and Alaska Native (AI/AN) alone or combined with other races, comprising 2% of the nation’s population ; howeverAI/AN youth also face disparities related to obesity and diabetes. Previous studies have indicated that 20-30% of AI/AN children are obese , comparereach to their intended audience, be implemented as intended in the real world, and adequately engage their audience [These health disparities could potentially be ameliorated by the dissemination and implementation of evidence-based adolescent health promotion programs. The United States Department of Health and Human Services’ Office of Adolescent Health, Substance Abuse and Mental Health Services Administration, and Centers for Disease Control and Prevention (CDC) have identified adolescent health promotion programs proven to impact behavior change across various health domains, including sexual health, violence and substance use prevention, physical activity, and nutrition -14. Howeaudience .Limited data exist regarding the reach and implementation of evidence-based health promotion programs among AI/AN youth. The Bureau of Indian Education (BIE) supports 183 primary and secondary schools in 23 states, serving approximately 50,000 students. A school health assessment of BIE schools conducted in New Mexico in 2006 reported that 38 of 39 schools (97%) provided health education and/or health promotion activities, and 67% used a comprehensive health education curriculum . CurricuTechnology-based programs may offer a viable strategy to increase the reach and implementation of evidence-based health promotion programs in this underserved population . FurtherRecently, Internet-based sexual health promotion programs have been specifically developed or adapted for AI/AN youth, with high satisfaction ratings reported ,24. The This study presents a secondary analysis of data collected during the implementation phase of a randomized controlled trial  that assessed the effectiveness of Native It’s Your Game  relative to a comparison suite of 5 evidence-based Internet-based health promotion programs, across 3 geographically dispersed regions in the United States. A detailed description of the adaptation process for Native IYG is provided in a supplemental file . PrimaryParticipants were primarily self-identified AI/AN youth aged 12-14 years and adult site coordinators  that were recruited from 25 study sites. The sites were located in 13 urban and 12 rural/tribal settings in Alaska, Arizona, and the Pacific Northwest , and comprised schools, tribal community centers, after school programs, and summer youth programs. Given the importance of confidentiality when partnering with AI/AN communities, specific tribal names have been withheld. The study was approved by the Alaska Area Institutional Review Board (IRB), the Portland Area Indian Health Service IRB, the University of Texas Health Science Center at Houston  IRB, and 16 tribal organizations .Study activities were coordinated regionally by 3 organizations that collectively serve 295 federally recognized AI/AN tribes. Regional staff used convenience sampling to recruit tribal communities that were interested in participating in an early adolescent sexual health study. Regional staff sent flyers to schools, tribal community centers, after school programs, and summer camp programs, and advertised on organizational websites, social media outlets, and/or via newsletters. Participating sites were randomized to a treatment condition  or a comparison condition (n=11) featuring a suite of 5 evidence-based Internet-based health promotion programs that were not focused on sexual health.Site coordinators at each study site completed the Collaborative Institutional Training Initiative Program’s online certification in human subject research and a live webinar (tailored for treatment or control conditions) coordinated by UTHealth research staff, which explained intervention content and protocols for logging-in youth, documentation, and maintaining confidentiality.It’s Your Game-Tech (IYG-Tech) [Native IYG is a 13-lesson, multimedia sexual health education curriculum for AI/AN youth (aged 12-14 years). The curriculum was adapted from an Internet-based curriculum for urban middle schools titled YG-Tech) . LessonsYG-Tech) .The 5 evidence-based, Internet-based programs that comprised the comparison suite addressed hearing loss (Dangerous Decibels), alcohol use (N-Squad), tobacco use , drug use (Reconstructors), and physical activity and nutrition (The Quest to Lava Mountain). Each program has undergone usability testing with non-AI/AN youth as part of its own formative development, and has demonstrated efficacy to positively impact health behaviors and/or related psychosocial factors in other adolescent populations. The Dangerous Decibels Virtual Exhibit was developed by the Oregon Museum of Science and Industry as an online component of a public health campaign to reduce the incidence and prevalence of noise-induced hearing loss and tinnitus (ringing in the ear) by improving knowledge, attitudes, and protective behaviors of school-aged children . N-SquadSite coordinators logged participants onto the programs on desktop or laptop computers located in quiet locations . Sites with insufficient bandwidth to accommodate simultaneous Internet access by multiple users were provided with uploadable versions of their respective programs on a Universal Serial Bus (USB) drive or digital video disc (DVD).Prior to implementation, site coordinators completed a computer-based education inventory survey  and connEase of use was based on how easy it was to use the program, using a Likert-type 3-point scale (very easy to kind of hard). Understandability was based on whether youth understood the words used and if they needed hints from an adult to play the game, using a Likert-type 3-point scale . Credibility was based on youths’ perceptions of content correctness, using a Likert-type 3-point scale  and trustworthiness . Likeability was based on how much youth liked the program activities, using a Likert-type 5-point scale (dislike a lot to like a lot). Perceived impact was based on whether youth thought the program would help them make healthy decisions, using a Likert-type 3-point scale . Motivational appeal was based on whether youth would play more program lessons if available, if they would recommend the program to classmates, and whether the program was as much or more fun than other lessons at school, including other health lessons, computer-based lessons, and their favorite video game, using a Likert-type 3-point scale .We used Likert-type scales adapted from previous studies to assess youths’ perceptions of engagement -42. EaseRatings were collected via an Internet-based Qualtrics usability survey administered at the completion of each program. Demographic characteristics  were collected during the study’s baseline survey, using an Internet-based Qualtrics self-report survey . Upon enWe used descriptive statistics  to summarize data on reach parameters  and implementation . Regarding youth engagement, for each parameter we calculated the percent of youth who rated each program favorably, and the range of ratings across all 6 programs, from lowest to highest.Twenty-four site coordinators  provided complete or partial information related to Internet reach parameters. Eighteen computer labs, one classroom, and one after school classroom across the 3 regions were primarily composed of personal computers  and Mac computers , were mostly wired , and most had access to the Internet . Primary Web browsers included Chrome , Safari , Internet Explorer , Firefox , and Mozilla . Download speeds ranged from 0.24 megabits per second (Mbps) to 93.5 Mbps .At some sites, the method of program delivery changed during implementation. Treatment sites commenced the study accessing Native IYG as an online streaming program (n=12) or as an uploadable program from a USB drive (n=2). During the study, several sites that initially accessed Native IYG as an online streaming program converted to uploading Native IYG from a USB drive (n=4) due to the inability of local bandwidth to accommodate larger Native IYG video files while providing simultaneous streaming for multiple youth.Comparison condition sites commenced the study by accessing the suite of health promotion programs via online streaming (n=8) or a combination of online streaming and an uploadable program from DVDs (n=2). Information regarding program access was missing from one site. During the study, most sites continued to access these programs via Internet connections (n=8).The most commonly reported problems that were documented by site coordinators during implementation included frozen screens (4/6 programs), activities taking a long time to load (3/6 programs)—both of which were related to multiple simultaneous users—and trouble navigating the programs (3/6 programs).During implementation, 387 youth received Native IYG, of whom 191 (49%) provided feedback; 136 youth received the comparison suite of programs, of whom 108 (79%) completed at least one feedback survey. Across programs, participants were 48-60% female, with a mean age of 13.1-13.3 years, and 85-90% self-identified as AI/AN .correct (58-90%) and trustworthy (61-89%), and 63-91% reported that the programs would help them make better choices. Regarding likeability, 59-87% of youth liked the programs a little or a lot. In terms of motivational appeal, 35-63% of youth reported that they would play more lessons from each program, if available; 37-66% would recommend the programs to a classmate. Although fewer youth considered the programs as much or more fun than their favorite video game (25-61%), youth stated that the programs were as much or more fun than other lessons at school (62-87%), other health lessons at school (61-79%), and other computer-based lessons at school  and the majority understood the words in the programs (60-83%). However, some participants needed adult assistance or hints to complete the programs (16-49%). Over half of the youth reported that the program content was credible, rating it  57-85%; .AI/AN youth face multiple health challenges compared to youth of other racial/ethnic groups. Viable program delivery strategies that overcome limited personnel with training in health education, cultural barriers, and geographic isolation  are needed to increase the reach and implementation fidelity of evidence-based adolescent health promotion programs in tribal communities. We examined the potential of using the Internet to deliver 6 evidence-based health promotion programs to AI/AN youth living in urban and rural settings in 3 geographically diverse regions of the United States. The health topics addressed included sexual health, hearing loss, substance use, physical activity, and nutrition. Despite variability in connectivity and bandwidth, most sites were able to access the programs via the Internet. However, technical and connectivity issues led some sites to access the programs via back-up modalities . Practitioners interested in implementing Internet-based programs in tribal communities are advised to provide contingency plans as back-ups to technical failures. We also recommend conducting bandwidth assessments, especially when dealing with multiple simultaneous users, prior to implementing an Internet-based program.Adult site coordinators from each tribal community  facilitated youths’ access to the Internet-based programs. Regarding implementation fidelity and program errors, site coordinators reported issues with frozen screens (4/6 programs), activities taking a long time to load (3/6 programs), and trouble navigating the programs (3/6 programs). Given that 16-49% of youth needed assistance to complete the programs, some adult oversight is recommended when implementing Internet-based programs for youth. Although the site coordinators received webinar training prior to program implementation, the training focused primarily on research study-specific protocols . The training related to actual program implementation, such as reviewing specific program content, was limited to approximately one hour, indicating that a broad range of personnel  may be able to implement Internet-based health promotion programs.as engaging as their favorite video game , over 60% stated that the programs were as much or more fun than other lessons at school. These findings indicate that Internet-based health promotion programs are engaging to AI/AN youth in the diverse settings of both rural (reservation and village) and urban locations. These results also support previous studies indicating that Internet-based health promotion programs provide an engaging educational format for Millennium learners. Internet-based programs are uniquely positioned to allow for: the provision of motivational learning experiences delivered via video, animated characters, and gaming formats; the provision of role modeling activities that influence normative perceptions and skills; confidential and personalized presentation of sensitive and potentially embarrassing issues ; and intervention messages that are tailored to specific user characteristics [Overall, AI/AN youth rated the programs favorably. Although fewer youth rated the programs as being eristics ,28. ThesIt is worth noting that youth rated Native IYG most favorably across all programs on 10 of the 13 usability parameters, possibly because this program was specifically adapted for AI/AN youth. This finding aligns with previous studies that point to the value of cultural tailoring . Incorpoas much or more fun than other lessons at school) suggest that the programs would be engaging for AI/AN youth in school, after school, or in community-based settings.Across all programs, we experienced attrition in the number of youth who received the programs compared to those who completed a feedback survey. This attrition may have been due to respondent burden or fatigue in completing surveys after each program. However, the relatively high motivational appeal ratings across programs , as they do not require statistical significance to determine major usability problems . In contDespite these strengths, several limitations should be noted. First, the sample was restricted to early adolescent AI/AN youth, aged 12-14 years; thus, findings may not apply to older AI/AN youth. Second, social desirability may have biased youths’ ratings of the programs; however, the fact that some items scored lower than others  suggests that youth answered honestly, based on their experience with each program. Third, the intervention program, Native IYG, was specifically adapted for AI/AN youth. In contrast, no attempt was made to adapt the comparison group programs for AI/AN youth; this factor may have negatively impacted program ratings relative to Native IYG. Finally, although the use of percent ranges to evaluate engagement is sufficient for this kind of exploratory trial, more thorough quantitative analyses, such as appropriately powered randomized pilot tests of the programs’ impact on behavioral determinants or randomized controlled efficacy field trials, are needed to determine long-term behavioral impact.Despite these limitations, this study demonstrates the potential of using the Internet to disseminate evidence-based health promotion programs to AI/AN youth across 3 separate geographic regions. These findings may have broader implications for understanding the degree to which Internet-based programs may enhance the reach and implementation of evidence-based health promotion programs in tribal communities, and provide an educational format that is engaging for AI/AN youth.


Background. The sympathetic nervous system (SNS) is responsible for hepatic stellate cells (HSCs) activation and the accumulation of collagen that occurs in hepatic fibrogenesis. Carvedilol has been widely used for the complication of hepatic cirrhosis in the clinic. Furthermore, it has powerful antioxidant properties. We assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may further enhance its clinical benefits. Methods. Using a bile duct ligation rat model of hepatic fibrosis, we studied the effects of carvedilol on the fibrosis, collagen deposition, and oxidative stress based on histology, immunohistochemistry, western blot, and RT-PCR analyses. Results. Carvedilol attenuated liver fibrosis, as evidenced by reduced hydroxyproline content and the accumulation of collagen, downregulated TIMP-1 and TIMP-2, and upregulated MMP-13. MMP-2 was an exception, which was decreased after carvedilol treatment for 2 weeks and upregulated after carvedilol treatment for 4 weeks. Carvedilol reduced the activation of HSCs, decreased the induction of collagen, transforming growth factor-β1, and MDA content, and strengthened the SOD activity. The antifibrotic effects were augmented as dosages increased. Conclusions. The study indicates that carvedilol attenuated hepatic fibrosis in a dose-dependent manner. It can decrease collagen accumulation and HSCs activation by the amelioration of oxidative stress. Once activated, TGF-β1 binds to Smad proteins, which enhances the transcription of target genes, including procollagen I and procollagen III, and then leads to fibrosis development [Hepatic fibrosis, a reversible wound-healing response to a variety of stimuli, is characterized by the accumulation of extracellular matrix (ECM) mainly secreted by activated hepatic stellate cells (HSCs) . In normelopment .β-adrenergic blocker, carvedilol has been studied as an antioxidant [4) induced liver fibrosis, which can be explained by amelioration of oxidative stress [β-adrenoreceptor antagonist and antioxidant might be beneficial for hepatic fibrosis treatment.Oxidative stress also plays a major role in hepatic fibrogenesis, which is an important stimulus to HSCs activation . Reactivioxidant , 7. It hioxidant . Moreoveioxidant . Recentle stress . In concIn the present study, hepatic fibrosis model was established by bile duct ligation (BDL) in Sprague-Dawley (SD) rats. Carvedilol was administered in three dosages 48 hours after BDL for 2 weeks and 4 weeks, respectively. In addition to assessing the effects of carvedilol on liver fibrosis, we also investigated its potential mechanisms.Fifty adult male Wistar rats weighing 250–300 g were obtained from the Experimental Animal Center of Hebei Medical University (permission number 705188). The research was conducted in accordance with the internationally accepted principles for laboratory animal use and care as found in the US guidelines . The experiment was performed in compliance with the national ethical guidelines for the care and use of laboratory animals (certificate number 911102).−1·d−1, CAR-L), medium-dose carvedilol treatment group , and high-dose carvedilol treatment group . Rat hepatic fibrosis model was established by applying BDL. Forty-eight hours after the operation, carvedilol was administered twice a day. Each group was also randomly divided into two groups, and their liver tissue specimens were separately taken 2 weeks and 4 weeks after BDL.The rats were randomly divided into five groups (10 rats per group): sham surgery control group, bile duct ligation (BDL) model group, low-dose carvedilol treatment group , aspartate aminotransferase (AST), total bilirubin (TBil), and albumin (Alb) were detected using a fully automatic biochemical analyzer. Liver specimens were fixed for 12–24 h in 4% phosphate-buffered paraformaldehyde  and then embedded in paraffin for light microscopy examination. Tissue sections (4 μm thick) were stained with hematoxylin and eosin (H&E) for morphological evaluation and Masson trichrome (MT) for assessing the degree of fibrosis.Blood was obtained from the left ventricular apex of rats and centrifuged at 3000μm thick liver tissues embedded in paraffin were deparaffinized and serially dehydrated in ethanol. Then, they were treated with 5% hydrogen peroxide for 10 min to inactivate the endogenous peroxidase. After 20 min of blocking with PBS containing 10% normal goat serum, the sections were incubated with primary antibodies. The primary antibodies included type I, III, and IV collagen  used as a marker for collagen expression; smooth muscle actin polyclonal antibody  used as a marker of activated HSC; TGF-β1  used as marker of cytokine. After treatment with HRP-conjugated goat anti-mouse IgG and 50 μL of streptavidin-peroxidase solutions for 30 min at RT, the sections were stained with DAB and counterstained with hematoxylin. The positive areas showed the color of brown yellow. Immunohistochemical analysis was performed with Image-Pro Plus.The 3 Collagen was detected by estimating the hydroxyproline content, an amino acid characteristic of collagen. Hepatic hydroxyproline was measured using a hydroxyproline detection kit  according to the manufacturer's instructions.β-actin 1 : 5,000; mouse monoclonal antibody; Sigma-Aldrich, St. Louis, MO), anti-matrix metalloproteinase-13 , antitissue inhibitors of metalloproteinase-1 , anti-MMP-2 (1 : 300), and anti-TIMP-2 (1 : 400). All the above were from Santa Cruz Biotechnology. Then, secondary antibody (Santa Cruz Biotechnology) was added, and the reaction bands of western blot were quantified by Quantity One software  and modified by the β-actin. The values (% of control) are given as means ± SD of 5 animals.Liver samples were homogenized with lysis buffer  and centrifuged at 20,000 ×g for 60 minutes at 4°C. The resultant supernatants were used as the total liver protein and subjected to western blotting. The protein concentrations were determined by Bradford's method. Proteins were resolved by sodium dodecyl sulphate polyacrylamide gel electrophoresis and transferred to a polyvinyl difluoride membrane. Each blot was treated with the anti-b-actin antibody  by thiobarbituric acid reactive substances. The experiment was conducted according to the manufacturer's instructions . The conjugation was accompanied by an increase in absorbance at 532 nm. The cytosolic SOD activity was assayed using the SOD detection kit . The autooxidation rate of epinephrine, which was progressively inhibited by the increasing amounts of SOD in the homogenate, was monitored spectrophotometrically at 550 nm. The amount of enzyme that inhibited 50% of epinephrine autooxidation was defined as 1 U of SOD activity.P < 0.05. Results are expressed as means ± SD.Data were analyzed statistically by one-factor analysis of variance (ANOVA). Differences between experimental groups were analyzed using Student-Newman-Keuls (SNK) multiple-range test. The significant level was set at We found that the liver functions in hepatic fibrosis model groups were obviously damaged according to the expression of ALT, AST, TBil, and Alb. And the levels of ALT and AST in CAR-H groups were significantly lower than in model groups Tables  and 2. HType I, III, and IV collagen expressions were detected by immunohistochemistry staining. It was demonstrated that the expressions of type I, III, and IV collagens in carvedilol-treated groups were markedly reduced compared to BDL group, while no marked differences were found among the three carvedilol-treated groups Figures .μg·mg−1, 0.279 ± 0.031 μg·mg−1 versus 0.363 ± 0.027 μg·mg−1; P < 0.01, P < 0.01, resp.)  (P < 0.05).Hydroxyproline is unique to collagen and thus serves as a specific biochemical marker of collagen production. Two weeks after BDL, the hydroxyproline content in BDL group was markedly higher than that in the sham group. However, it was significantly decreased in CAR-M and CAR-H groups  . Four we, resp.) . And a sα-SMA expression in CAR-M and CAR-H groups was markedly reduced compared to that in BDL group   .We investigated the changes of HSCs in the present BDL rats to examine the effect of BDL-induced overactive sympathetic tone on the activation of HSCs, the key cell for the progressive accumulation of collagen in fibrosis disease. Immunohistochemistry staining for a-SMA, the marker of the activated HSCs, was mildly increased in the BDL group compared to that in sham group and was reduced by carvedilol treatment. After the 2-week carvedilol administration, the  Figures . After t Figures . And a sα-SMA immunohistochemical double staining. Among the 2-week groups, the apoptosis index of HSC was markedly higher in the CAR-M and CAR-H groups than in BDL group   . The results suggested that carvedilol may inhibit the activation of HSCs and promote apoptosis via the antisympathetic predominance pathway.HSCs apoptosis was determined by TUNEL and  Figures . Similar Figures . And a s versus 1.24 ± 0.09; P < 0.01), but it was significantly reduced in CAR-H group (1.33 ± 0.04). After carvedilol treatment for 4 weeks, the MMP-2 protein expression in CAR-M and CAR-H group was significantly higher than that in BDL group .The degradation of the matrix components markers MMP-2, TIMP-2, MMP-13, and TIMP-1 was used for the same rats in order to evaluate the accumulation and the degradation of matrix components based on the western blot and real-time Q-PCR . Two wee versus 1.1 ± 0.11; P < 0.05, P < 0.05, and P < 0.01, resp.). Similar results were shown in 4-week carvedilol groups. And a significant difference was found between the CAR-L and CAR-H groups (P < 0.05). The MMP-2 and MMP-13 mRNA expressions showed the same tendency as the protein expression above (data was not shown).After carvedilol treatment for 2 weeks, the MMP-13 protein expression in CAR-L, CAR-M, and CAR-H groups was significantly higher than that in BDL group . In the 4-week groups, TIMP-2 in CAR-L, CAR-M, and CAR-H groups was significantly reduced compared with that in the BDL group  . The results determined by RT-PCR were the same as the results above (the data was not shown). All these results suggest that carvedilol may modify the shift in the balance of the accumulation and degradation of matrix components in the BDL rats.TIMP-1 and TIMP-2, mainly produced by HSC, combine with active MMPs to inhibit their activity. Two weeks and 4 weeks after BDL, the protein expression of TIMP-1 and TIMP-2 in BDL group was increased compared with that in sham group. After BDL and carvedilol treatment for 2 weeks and 4 weeks, TIMP-1 protein expression in CAR-M and CAR-H groups was markedly reduced. In the 2-week groups, the protein expression of TIMP-2 in the CAR-H group was dramatically lower than that in the BDL group . But no statistical difference was found between the CAR-M and CAR-H groups. Four weeks after BDL, TGF-β1 expression in CAR-L, CAR-M, and CAR-H groups was significantly decreased compared with that in the BDL group  , while no statistical difference was found among the carvedilol-treated groups. Four weeks after BDL, there was no significant difference between the carvedilol-treated groups and the BDL group  showed that MDA contents in the CAR-L, CAR-M, and CAR-H groups were significantly lower than those in the BDL group , while no marked differences were found among the three carvedilol-treated groups. Similarly, four weeks after BDL, SOD activities in the CAR-L, CAR-M, and CAR-H groups were higher than those in the BDL group   .Carvedilol is a nonselective beta-blocker with potent antioxidant and free radical scavenging properties, which is used in the treatment of portal hypertension commonly associated with chronic liver diseases. Considering these powerful antioxidant properties of carvedilol, we predicted that carvedilol may exert an antifibrotic effect on chronic liver injury. This means carvedilol has additional clinical benefits. So, in the present study, we investigated the efficacy of carvedilol on BDL-induced hepatic fibrosis and the potential mechanisms involved. Three dosages of carvedilol treatment for 2 weeks and 4 weeks were used, which was beneficial for observing the curative effect on different stages of fibrosis.β is the mostly potent fibrogenic cytokine, which has three major isoforms . TGF-β1 is the principal isoform implicated in liver fibrosis. The activated TGF-β1 combines with Smad proteins via its cognate receptors, which enhances the transcription of target genes, including collagens I and III [β1 expression. Therefore, we inferred that the inhibition of TGF-β1 by carvedilol was one of the pathways for decreasing collagen expression.In the study, H&E and Masson staining confirmed the established hepatic fibrosis model. The liver inflammatory and fibrous formations were markedly alleviated by carvedilol treatment. Hepatic fibrosis is characterized by abnormal accumulation of ECM, which is changed not only in quality but also in quantity. In normal liver, the low-density basement membrane-like matrix in the space of Disse is mainly composed of collagens IV and VI. However, the fibrillar collagens including collagens I and III and fibronectin are markedly increased in hepatic fibrosis . This in and III , 12. Theα-SMA by several stimuli such as cytokines and inflammatory mediators. Activated HSCs migrate to and proliferate in sites of liver injury, synthesize ECM components, and upregulate the expression levels of α-SMA and collagen matrices [α-SMA is a marker of HSC activation and proliferation. The results of α-SMA expression showed that carvedilol administration inhibited HSC activation. Furthermore, α-SMA and TUNEL double staining demonstrated that carvedilol increased the apoptosis of activated HSC. Regulating the biologic behavior of HSC may be one of the reasons for carvedilol to prevent the progression of hepatic fibrosis.HSCs are typically found in the space of Disse in a quiescent state . HSCs mamatrices . Hence, Hepatic fibrosis occurs because of the synthesis and excessive deposition of ECM in the space of Disse along with insufficient ECM degradation. The equilibrium between MMPs and TIMPs mainly determines the homeostasis of ECM. MMPs are the main enzymes responsible for ECM degradation and TIMPs are their specific inhibitors . In the Bile duct ligation is an established method for investigating cholestasis and hepatic fibrosis, which leads to changes in the equilibrium between antioxidant and prooxidant activities . The depβ1 expression, increased HSCs apoptosis, and increased ratio of MMPs/TIMPs, as well as its antioxidant property. Consequently, carvedilol treatment as early as possible in the maximum dosage that patients are able to bear may be beneficial for preventing hepatic fibrosis progression.In summary, carvedilol plays a preventive role in a dose-dependent fashion in the progression of hepatic fibrosis induced by BDL, which is associated with decreased TGF-


Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. Mttp mRNA and protein levels of Shp−/− mice were similar to those of wild-types; however, those of Chrebp−/−Shp−/− and Chrebp−/− mice were significantly much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp−/− mice were similar to wild-types but were much lower in Chrebp−/− and Chrebp−/−Shp−/− mice. These findings suggest that ChREBP, rather than SHP, regulates VLDL secretion under normal conditions and that ChREBP and SHP do not affect the transcriptional activities of each other.The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP).  Mttp deficiency causes hypolipidemia and fatty liver  knockout (Chrebp−/−) mice [Mttp transcription in cooperation with ChREBP.As with the effects of nutritional conditions on Mttp expression, high fat diets and high carbohydrate diets induce Mttp expression, resulting in hyperlipidemia ,18. Highpromoter . High su/−) mice . ChREBP /−) mice ,21,22,23/−) mice ,21,22,23/−) mice ,26,27,28/−) mice . Conside/−) mice , we specMttp expression. Using rat hepatocytes and knockout mice, we therefore evaluated the following: (1) whether ChREBP and SHP affect the transcriptional activities of each other; (2) whether ChREBP and SHP coordinately affect Mttp expression and thereby VLDL secretion; and (3) if ChREBP or SHP regulate VLDL secretion more potently. An appreciation of the roles of ChREBP and SHP in regulating Mttp and VLDL secretion will be beneficial for understanding the role of nutritional signals in the development of NAFLD and dyslipidemia. ChREBP and SHP control the regulation of −/− mice were backcrossed for at least 10 generations onto the C57BL/6J background [−/− mice were purchased from Lexicon Genetics Inc. . Shp+/− mice were backcrossed for at least 12 generations onto the C57BL/6J background. Male mice were used for all studies. Chrebp−/−Shp−/− (DKO) mice were intercrossed with Chrebp−/− and Shp−/− mice. Animal experiments were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals . All animal care was approved by the animal care committee of the University of Gifu . Mice were housed at 23 °C on a 12-h light/dark cycle. Chrebp−/−, Shp−/−, and DKO mice were housed separately with a total of three mice per cage. Body weight was measured weekly between 7 and 21 weeks of age. Mice were sacrificed at 21 weeks of age by cervical dislocation. All tissue samples were immediately placed into liquid nitrogen and stored at −80 °C until further analysis for hepatic triacylglycerol and cholesterol contents and for quantitative polymerase chain reaction (PCR).Mice had free access to water and were fed an autoclaved CE-2 diet . Wild-type (WT), ChrebpLiver lipids were extracted using the Bligh and Dyer method ; they weTotal RNA isolation, cDNA synthesis, and real-time PCR analysis were performed as previously described . Real-ti®) at Skylight Biotech Inc.  [VLDL secretion tests were performed as previously reported . Briefly, Japan) . Serum s2 and 95% air at 37 °C. After the cells had been incubated for 4 h, the medium was replaced with DMEM containing 10 nM T3. Adenoviruses harboring dominant active rat Chrebp lacking 1–196 a.a. (Ad-daChREBP) and mouse SHP full length (Ad-SHP) were constructed according to the manufacturer’s protocol . After 4 h infection with Ad-daChREBP and/or Ad-SHP, rat hepatocytes were incubated for 20 h. Mttp mRNA levels were detected by real-time PCR. Rat primary hepatocytes were isolated as previously described ,33. IsolReporter plasmids pGL3 3×LPK ChoRE, pcDNA-daChrebp, and pcDNA-empty have been previously reported ,33. pcDNp-value < 0.05 was considered to be statistically significant.All values are presented as means ± standard deviations. Data were analyzed using Tukey’s test. A Mttp and Pklr mRNA expression, while SHP suppressed only Mttp expression in primary rat hepatocytes , including the HNF4/HNF1/LRH-1 binding site, successfully suppressed PGL3-Mttp (−211 bp) luciferase activity. However, co-transfection of pcDNA-daChREBP did not reverse this effect  mice also displayed similar characteristics  higher than in WT mice  in mice. Consistent with this, we found that ChREBP interacted with SHP in the mammalian two-hybrid system, and interactions with SHP did not interfere with the binding between FXR and ChREBP in the mammalian two-hybrid system (data not shown). This indicated that SHP might not affect the interplay between ChREBP and nuclear factors such as FXR and HNF4, and therefore, that it does not modulate ChREBP transcriptional activity.Recent reports have proposed a new ChREBP regulatory mechanism (ChREBP-nuclear receptor interaction), in which nuclear factors interact with ChREBP to modify ChREBP transcriptional activity ,26,27,28pression ,26,27,28Mttp promoter (−211/+81 bp) in the present study revealed that SHP suppressed hepatic Mttp expression, but that ChREBP overexpression did not affect luciferase activity controlled by the Mttp promoter (−211/+81 bp). This supports the notion that ChREBP does not affect the role of SHP as a corepressor. Taken together with the fact that a Chrebp deletion did not affect SHP target gene (Cyp7a1) mRNA levels, this suggested that ChREBP does not modulate SHP transcriptional activity. Thus, ChREBP and SHP do not affect the transcriptional activities of each other.Reporter assays for the Mttp promoter regions, we searched for putative ChoRE motifs [Mttp. Considering that ChREBP regulates the expression of many genes [Mttp expression through the activation of other transcription factors. However, further investigation is needed to identify the mechanism underlying the ChREBP induction of Mttp expression.To evaluate ChREBP binding to E motifs ,37,38 inny genes ,37,38,39Mttp expression by modulating HNF4 and LRH-1 transcriptional activity, its effect on VLDL secretion was controversial [−/− mice on ob/ob or C57BL/6 backgrounds increased relative to WT mice [−/− mice fed a Western diet was similar to that in Shp−/− mice fed a normal diet [SHP deletion did not affect VLDL secretion in either WT or Chrebp−/− mice. Our analyses of MTTP protein levels and VLDL particle numbers also supported these data. Taken together with the fact that SHP overexpression by more than 70 times was needed to suppress ChREBP-mediated Mttp induction, these findings suggest that ChREBP plays important roles in VLDL secretion, while those of SHP are much smaller or negligible.The VLDL secretory pathway is regulated by MTTP, a rate-limiting enzyme. We previously reported that ChREBP positively regulates VLDL secretion . Althougoversial ,16. Somemal diet . Our datMttp expression [Mttp expression might deteriorate NAFLD in ChREBP−/− mice. As ChREBP−/− mice could not be fed a high carbohydrate diet such as the high sucrose diet [Mttp expression was not affected by Shp deletion. Therefore, we analyzed the effects of ChREBP and SHP deletion on Mttp expression and VLDL secretion under a normal diet condition. In this study, ChREBP and SHP independently regulated glucose and lipid metabolism. The difference in target genes between ChREBP and SHP might contribute to the different effects of ChREBP and SHP on preventing the development of fatty liver induced by high fat diets in Chrebp−/− and Shp−/− mice (Nutritional conditions affect the development of NAFLD and dyslipidemia. High carbohydrate diets and high fat diets increase Mttp expression . High capression ,18. As wpression ,40. The pression ,42,43. Dose diet ,41,42, wose diet . The Higose diet . Moreoveose diet ,43. As Sose diet , Shp delose diet . Consist−/− mice . Mttp expression, but the capacity of Mttp suppression by SHP was much lower than that of Mttp induction by ChREBP. Moreover, ChREBP and SHP did not affect the transcriptional activities of each other. Unlike many transcription factors, ChREBP was not regulated by SHP. Finally, ChREBP, rather than SHP, was shown to regulate hepatic VLDL secretion. ChREBP and SHP were shown to modulate hepatic