Influenza vaccination remains the most effective tool for reducing seasonal influenza disease burden. Few Low and Middle-Income Countries (LMICs) have robust, sustainable annual influenza national vaccination programs. The Partnership for Influenza Vaccine Introduction (PIVI) was developed as a public-private partnership to support LMICs to develop and sustain national vaccination programs through time-limited vaccine donations and technical support. We review the first 5 years of experience with PIVI, including the concept, country progress toward sustainability, and lesson learned. Between 2013 and 2018, PIVI worked with Ministries of Health in 17 countries. Eight countries have received donated vaccines and technical support; of these, two have transitioned to sustained national support of influenza vaccination and six are increasing national support of the vaccine programs towards full transition to local vaccine program support by 2023. Nine additional countries have received technical support for building the evidence base for national policy development and/or program evaluation. PIVI has resulted in increased use of vaccines in partner countries, and early countries have demonstrated progress towards sustainability, suggesting that a model of vaccine and technical support can work in LMICs. PIVI expects to add new country partners as current countries transition to self-reliance. PIVI grew from two initial vaccine donation projects in Lao Peoples Democratic Republic and Nicaragua 22.1PIVI is a unique partnership of three types of organizations: (1) national Ministries of Health, which develop influenza vaccine policies and are responsible for program implementation and evaluation; (2) industry partners that support the provision of appropriate vaccines, shipping and supplies to the program; and (3) technical partners and collaborators  that provide assistance to the Ministries of Health in planning the programs, supporting national evidence-based policy development, and program evaluations.PIVI is based at the Task Force for Global Health in Atlanta, USA, which provides overall coordination and strategic direction for the partnership, in close coordination with the U.S. Centers for Disease Control and Prevention (CDC), which is also the principal technical partner and funder. The goals of the program are to create sustainable routine seasonal influenza vaccination programs, and to build the immunization infrastructure capacity to ensure timely and effective vaccine delivery during pandemics and epidemics. PIVI’s work builds on ongoing collaborations between Ministries of Health and CDC’s Influenza Division and supports WHO’s programs that enhance influenza surveillance, laboratory and response capacities, and support vaccine policy development, program planning and evaluation activities.2.2PIVI serves as a catalyst for countries to generate data and gain experience to support the development of decisions concerning and programs to carry out sustainable influenza vaccination programs. PIVI does this primarily through time-limited provision of donated or low-cost vaccines and/or technical assistance to partner countries. Countries receiving vaccine develop a multi-year plan (based on a 5-year template) for vaccine introduction in target risk groups, focusing on risk groups identified by WHO SAGE and the partner country. Subsequently, in these countries, PIVI provides vaccines that are donated by or purchased at reduced cost from manufacturers or procured from UNICEF during the first 1–3 years of the multi-year plan. After this initial period, the country progressively increases its financial contribution to vaccine purchase and program implementation . At the A subset of PIVI partner countries receive only technical support rather than donated vaccine doses and supplies . These “2.3All countries are evaluated for PIVI partnership through a systematic process based on criteria designed to identify LMICs that are interested, ready and capable of developing an influenza vaccination program. Readiness criteria relate to the existence of high-quality influenza surveillance data, disease burden data, and a formal statement of interest from the representatives from Ministries of Health to initiate influenza vaccination in at least one SAGE target group in the country Once engaged, each country selected to receive vaccine doses develops a multi-year plan for either vaccine introduction or for expansion of an existing program, and for sustaining the programs over time. This plan outlines the country’s vaccine and supply needs and desired types of technical assistance during a five-year timeframe. For each year of the plan, the country indicates its preferred vaccine product formulation and presentation, the number of doses required each year, and the delivery date requested for vaccine shipments. These choices are based on seasonality of influenza, national vaccine target groups, vaccine coverage goals, and locally available or acceptable vaccines. Countries are encouraged to prioritize a small number of target groups based on the SAGE recommendations, and to begin the program with relatively modest vaccine coverage goals and with an aim to increase coverage over time.2.4All countries receive technical assistance based on a review of gaps in the evidence-base for influenza vaccination in the country and identified needs in planning or evaluating the vaccination program. This technical assistance is provided from CDC and other technical partners, and funding to support in-country activities. Technical assistance offered to a country is tailored to address data and program gaps expressed by local stakeholders and/or capacity improvement needs. To facilitate technical support, PIVI has developed a panel of generic tools that, alongside available WHO-developed tools 3From 2013 to 2018, 17 countries became PIVI partners . Eight c3.1Each vaccine-receiving country developed multi-year plans that summarized the annual needs for vaccine donations, the plan for country purchase of vaccine, and the timing of technical activities to provide the evidence base for program sustainability and country investment. The countries 5-year targets for vaccine coverage among risk groups was between 18% and 74%, with lower targets (4–47%) in the early years. The higher target coverage in some countries reflected health workers as an early target, which tend to be the smallest target group among SAGE-recommended groups. All 17 countries either carried out or are planning vaccination of SAGE-recommended target groups. The more commonly targeted group for vaccination has been HW (14 countries), followed by pregnant women (9) and persons with chronic diseases (7). Technical or data needs varied and were specific to each country and include activities related to estimating disease or economic burden, expected impact of vaccination, review of evidence base for vaccination, programmatic information, and program evaluation projects.All countries that received vaccine also conducted activities to plan, evaluate and improve the vaccination program. One example of the combination of vaccine donations, local purchase of vaccine and technical collaborations underlying the multi-year plan is provided by Albania . AlbaniaAmong the eight countries that have received donated vaccine since 2013, two have transitioned to country-funded vaccination programs . Each ofThe nine countries that have received only technical support (no donated vaccine) have been engaged for fewer than two years, making it difficult to draw conclusions about the value of receipt of technical assistance alone in developing a sustainable vaccination program. However, early results are encouraging. Based on evidence and experience gained from a small demonstration project among health workers using a knowledge, attitudes, perception and practices (KAPP) survey and National Immunization Technical Advisory Committee (NITAG) workshops, in 2017, Vietnam developed a national policy targeting health workers and a multi-year plan for step-wise introduction of HW vaccination countrywide. In Kenya, after NITAG strengthening supported through a CDC cooperative agreement that preceded PIVI the recent KAPP surveys, the Ministry of Health developed a national policy to vaccinate young children and will conduct a sub-national demonstration project of vaccinating children 623 months in 2019 Partner countries identified several challenges to introducing, expanding or sustaining influenza vaccination programs . Some of3.2All 17 countries have received technical and/or financial support for program and/or policy development and evaluation . KAPP suCapacity-building workshops for country NITAGs have been conducted for 6 countries since June 2017 . Trainin4During the first six years of PIVI, the program has supported 17 LMICs to initiate or expand influenza vaccination programs targeting SAGE-recommended target populations and to gather data and gain experience needed to make decisions on the value of sustaining influenza vaccination programs using national resources. PIVI has produced early evidence that a paradigm of provision of technical support and making vaccines available can result in establishing or expanding a seasonal influenza vaccine program and sustained government funding over time. Six countries that have received vaccine and technical support for at least 3 years have steadily increased their financial support of the program and are expected to be fully self-sustaining within the next 1 to 3 years. In addition, two countries that received PIVI support early in the program have transitioned to conducting annual vaccination campaigns of target groups using only national resources. Additional countries that have recently joined PIVI have received only technical support – either as a preparation for future vaccine donation or as a tool to increase efficiency or impact of their current influenza vaccination program. Experience thus far indicates that provision of expertise to address critical data gaps identified by local stakeholders has resulted in creation of national vaccine policies and plans to initiate national vaccination programs. Finally, countries participating in PIVI have developed processes and capabilities for vaccine delivery that will benefit the country in the timely and effective use of pandemic and non-influenza epidemic vaccines when needed. We note, however, that these results are early and interim, and that a better assessment of the value of this model will take several years.A central tenet of the need for seasonal influenza vaccination programs is the value of annual programs to create the national and global capacities to deploy pandemic or non-influenza epidemic vaccines quickly and effectively when needed We have learned several lessons during the initial period of PIVI. First, we have found that many LMICs are interested in initiating and expanding their seasonal influenza vaccination program, despite competing priorities for health funds in the country. Slow development of programs in many countries is based to uncertainty of the value and feasibility of influenza vaccination. By lowering the country risk to initiate or expand vaccine programs by sharing program costs with PIVI early in program development, and by facilitating technical assistance to address critical knowledge and capacity gaps, countries have been willing to institute seasonal influenza vaccination while they gather data to understand the potential costs and value of the program. In addition, creating a multi-year plan that contains modest targets for vaccine coverage of risk groups (so requires a modest number of doses) with gradual increases somewhat reduces concerns of affordability and sustainability. Second, all countries requested technical support to plan, conduct, or evaluate their program. By having available generic protocols and data collection tools for the various types of technical assistance, PIVI can be efficient in providing this support. Close coordination and communication with WHO and WHO Regional Offices and other experts has been important for development and testing of technical support tools It is worth noting how this influenza vaccine donation program, or any influenza vaccine donation, meets or fails to meet requirements established for vaccine donation by WHO and UNICEF While the first 17 PIVI partner countries have been a source of lessons learned, expansion to the next group of countries, especially lower income countries, may require different approaches. Lessons from Gavi and other recent vaccine introductions will be helpful to develop support for these countries PIVI uniquely fills critical gaps in global influenza prevention and control and pandemic preparedness. Seasonal influenza vaccination remains the best current tool to reduce the 290,000–650,000 influenza-associated deaths each year in the world Centers for Disease Control and Prevention, Atlanta, GA, USA [CDC-RFA-IP16-1607] and the Bill & Melinda Gates Foundation, Seattle, WA, Seattle, WA, USA [OPP1088249]This work was supported by The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Reducing injuries in adults requires work with diverse stakeholders across many sectors and at multiple levels. At the local level, public health professionals need to effectively bring together, facilitate, and support community partners to initiate evidence-based efforts. However, there has been no formal review of the literature to inform how these professionals can best create action among community partners to address injuries in adults. Thus, this scoping review aims to identify theories, models or frameworks that are applicable to a community-based approach to injury prevention.Searches of scientific and less formal literature identified 13,756 relevant items published in the English language between 2000 and 2016 in North America, Europe and Australia. After screening and review, 10 publications were included that (1) identified a theory, framework or model related to mobilizing partners; and (2) referred to community-based adult injury preventionFindings show that use of theories, frameworks and models in community-based injury prevention programs is rare and often undocumented. One theory and various conceptual models and frameworks exist for mobilizing partners to jointly prevent injuries; however, there are few evaluations of the processes to create community action.Successful community-based injury prevention must build on what is already understood about creating partnership action. Evaluating local public health professional injury prevention practice based on available theories, models and frameworks will identify successes and challenges to inform process improvements. We propose a logic model to more specifically guide and evaluate how public health can work locally with community partners. Unintentional injuries, such as those from falls, motor vehicle collisions, poison, drowning, and burns, kill more than 10,000 Canadians each year . To reduTwo approaches have been useful in preventing injuries: universal and targeted. Universal approaches, such as national building codes for stairs, provincial safety standards for motor vehicles, and pool fencing bylaws in municipalities, improve cause-specific safety for the population by addressing injury determinants broadly . TargeteOur prior projects examined local partnerships between Public Health Units in Ontario and community services addressing falls in older adults, including both health  and non-health  sectors. The findings show that the community partners had insufficient resources to implement fall prevention strategies alone , despite awareness, intention, and organizational support . AdditioOntario Public Health Standards for injury prevention  require Thus, the purpose of this paper was to conduct a scoping review to identify theories, frameworks, and models (TFM) that clarify how to mobilize partners in community-based adult injury prevention and to what effect, seeking evidence from a range of real-world sources rather than being limited to any particular quality standard . Given there are no published literature reviews, a scoping review is a systematic way to scan and aggregate existing literature to further articulate the concept of mobilizing partners, identify knowledge gaps and inform future directions related to community-based adult injury prevention.This project involved a multidisciplinary team including nine public health professionals from Ontario public health units, two academics, an academic librarian, a graduate student, and a research consultant, with collective expertise in injury prevention, scoping reviews and knowledge translation activities. Member engagement varied, with two project leads managing the collaboration, the consultant coordinating the research project, 6 team members reviewing literature, and knowledge users providing stakeholder advice. All members participated in bi-weekly teleconferences, building relationships to integrate knowledge translation between researchers and practitioners. In addition, three face-to-face meetings actively involved end-users at the various stages of the research, with each contributing their own distinct expertise and experience to the process.A methodological framework, developed by prior authors, guided our scoping review process , 18. TheOur literature search included documents of any study design and publication type. Articles were selected based on the following inclusion criteria: 1) published between 2000 and 2016; 2) published in the English language; 3) related to community-based injury prevention among community dwelling adults; 4) presenting one of a TFM for mobilizing community partners; and 5) based on literature in developed countries similar to Canada such as the United States, Australia, New Zealand and high income European nations. We excluded articles that were 1) book reviews, editorials or commentaries; 2) not in a developed high income country; 3) without any TFM for mobilizing community partners; 4) not related to community-based injury prevention; and 5) not addressing an adult population of 18 years and older.The librarian member developed search strategies to identify relevant articles in consultation with Public Health Ontario researchers and Shared Library Services. Subject headings and keywords included: 1) theory/framework/model ; 2) mobilization ; and 3) injury prevention . The first search stage included databases such as Ovid MEDLINE (including In-Process & Other Non-Indexed Citations and Epub Ahead of Print), EBSCO CINAHL, ProQuest PsycINFO, ProQuest Sociological Abstracts. The second stage of searching included Theses Canada, DART Europe E-theses Portal, EThOS (UK e-Theses online), TROVE , Public Health Databases and Grey Literature Repositories , Custom Search Engines . The third stage of searching consisted of websites suggested by project team members . Hand searches were also performed using 1) the reference lists of the included items; 2) the tables of contents of three journals that publish articles related to injury prevention and public health ; 3) additional suggestions made by project team members; and 4) publications of eight well-known authors in the field of community health partnerships identified by our academics .Fig 1, the initial search yielded 13,756 sources of literature. A database management system (EndNote) removed 2371 duplicates. We established a reviewer group that included the research consultant, an academic, a graduate student, and three public health nurses. We calibrated consistency in determining study inclusion and exclusion was among all reviewers, first through independent assessments  of 25 random abstracts followed by paired assessments of 75 random abstracts. Reviewers agreed on 83% of the abstracts to be included. We discussed and agreed upon differences via consensus. Following these exercises, we distributed all titles and abstracts among the reviewer group to screen for inclusion by asking two questions: “Does the title or abstract identify a theory, framework or model related to mobilizing community partners?” and “Does it refer to community-based adult injury prevention?” Reviewers excluded all but 251 items and these advanced for a more in-depth review of their full text. We then distributed full-text articles among the reviewer group to determine further exclusions using the screening criteria as well as an additional criteria “Is the context of development and/or implementation of models, theories and frameworks in a developed country similar to Canada ”, which may not have been apparent from the title or abstract alone. Any full text articles rated as “unsure” by the first reviewer were assigned to a second reviewer and discussion determined final eligibility for inclusion. Reviewers presented the 10 publications that satisfied our criteria for inclusion to the full project team to verify perceptions of relevance to our research question and applicability within public health practice, as well as for knowledge exchange.As shown in A data extraction tool captured the reference source, literature type, study design, and the identified TFM and incorporated a critical appraisal tool for the included literature. The MetaQAT or the Public Health Ontario Meta-tool for Quality Appraisal of Public Health Evidence  is a novAs not all included articles provided complete descriptions of the identified TFM, supplementary sources provided the full list of key elements comprising each TFM . Two project team members  pragmatically sorted the elements of each TFM into three broad categories related to 1) prerequisite conditions for community partner activity (e.g. formation as a group), 2) results of community partner activity (e.g. achievements), and 3) neither prerequisite or resultant, thereby distinguishing transitional elements to conceptualize partner mobilization. Subsequently, the full multidisciplinary team reviewed, refined and confirmed the associated categories.The ten sources collectively identified one theory, seven frameworks, and six models for mobilizing partners. Three publications identified more than one framework or model , 25, 26.Five of the ten sources were secondary literature: four reviews (three narrative reviews and one scoping review) and one synthesis of evidence for community action. One author presented 5 components and 12 processes to guide communities’ capacity to improve their health based on the Collaborative Public Health Action Framework . AnotherOne of the ten sources was tertiary: an online brochure for community health improvement using the model of “Mobilizing for Action through Planning and Partnerships” . Table 3Partnership Start-up. All but one TFM noted the importance of developing partnerships. However, the literature had different accounts of what aspects were critical to developing partnerships. United in commitment was most frequently mentioned (86%), followed by structured meetings (71%), recruitment of stakeholders and key organizational members and partners (57%) and skill building activities (43%).Community Assessment. Twelve of the TFM noted the importance of performing community assessment, defined as determining priority areas for intervention, as part of building productive partnerships. Most noted understanding the issue or problem, and the sharing of resources and active participation , 64% and 71% respectively, in all the TFM’s.Strategic Planning. Strategic planning consists of determining how an intervention developed through partnership work will result in improved outcomes. While 64% found that planning and adaptation  was an important pre-mobilization activity, only 21% of the TFMs mentioned the need for a logic model to guide programs and services.Ongoing involvement. More than half (57%) of the TFM identified ongoing involvement with community members, partnerships and stakeholders, categorized as participation (43%), commitment (29%), leadership (21%), and collective aim (14%). One theory, three frameworks, and two models identified member participation. One theory, two frameworks, and one model identified member commitment (29%) as engagement, empowerment, and high quality, trusting relationships.Instrumental supports. More than half (57%) of the TFMs identified instrumental supports, categorized as collective resources (57%) and public support (21%). One theory, five frameworks, two models identified collective resources, including material resources such as data and sustained funding, human resources such as a designated implementation team, and relational resources such as additional partners outside the partnership that can help with mobilization efforts with the greater community. These resources among core members or across the broader partnership should be shared for mutual benefit and common purpose. One theory, one framework, and one model identified public accountability, including context and community support that could be generated generically through grassroots development and community organizing or specifically through messaging, networking, reaching out and staying visible in the media.Planned Action. More than half (64%) of the TFMs identified planned action, categorized as planning (57%) and implementation (43%). One theory, four frameworks, three models identified planning, as designing outputs such as effective policies, services and environments, designing processes such as strategies for change, communication, and social marketing, and designing actions such as implementation and program operation. One theory, two frameworks, three models identified implementation related to what was designed: effective policies, services and environments, strategies, actions, a sustainability plan, program operation (e.g. implementation).Evaluation. Post-mobilization activities consist of evaluating to determine whether an intervention, program or service has had positive effects on the population of interest. Only 50% of the TFMs identified evaluation activities post mobilization including carrying out evaluations plans (36%), evaluating the implementation of a program or service (21%) and sustaining service delivery (21%).Although none of the TFM includes all the components necessary for forming and sustaining productive partnerships , the finFig 2) to articulate what a partnership effort needs, what it expects to do, how it will work and what success it hopes to achieve.Our findings also suggest there is less attention dedicated to maintaining and evaluating community-based adult injury prevention work, particularly in the mobilization and post-mobilization phases. We found only one process or outcome evaluation among the studies reviewed indicating a lack of evidence to support investment in such partnership work similar to a prior review that found that behavioural and social science theories and models are seldom represented within injury prevention research . AlthougThe prerequisite conditions for community-based injury prevention initiatives form the logic model inputs, and include partnership set-up, community assessment, and evidence-based strategic planning. Involvement from the outset can result in trust building, membership, and ownership among partners for better program implementation . Of the Partner mobilization forms the logic model outputs, and includes ongoing involvement, instrumental supports, and a detailed course of action, within an ecological framework of the community organizations and networks that can contribute to the context for injury and its prevention among community-dwelling adults. Application of the ecological model in injury prevention holds the most promise in regard to fall and traffic injury prevention, as well as community safety promotion programs . ResultsOur logic model is consistent with a recent literature review of the components for developing and reinforcing positive partnerships. Partnership start-up includes shared mission, trust and shared power, clarity of roles and structure and appropriate communication. Sustained active involvement includes collaborative leadership. Instrumental supports include active contribution of financial and human resources and consideration of context. A prepared course of action balances maintenance and production. The logic framework format supports evaluation of outputs and outcomes .Mobilizing partners requires attention to sustaining their involvement, obtaining the resources needed (including time and knowledge), and having a clear course of action acceptable to the adult community. In an evaluation of the Healthy Communities movement, findings show that initiatives often rely on community volunteerism and lack the well-supported infrastructure that is essential to successfully maintain ongoing partner involvement . InstrumWhile it is clear that evaluation-based activities are needed to assess short and long-term outcomes of partnership development, measuring the success of both partnership formation and project management is essential to injury prevention initiatives. This model provides a framework for fully measuring the success of building productive partnerships with definitive outcomes related to injury prevention.Evidence from measuring the success of community-based partnership development and resulting action is required to justify further public health expenditures. Without literature evaluating community-based adult injury prevention through partnership, public health practitioners will continue to struggle to mobilize and evaluate partnership work with reduced resources. Under these conditions, it is not surprising that intersectoral collaboration is a challenge to maintain, particularly as other non-profit organizations, businesses and health care providers also need evidence to justify investment as a community partner. Now more than ever, community partnerships and local based programs are needed given the high financial strain on the health care system from unnecessary injury related hospital visits. Future work in this field requires a greater emphasis on measuring short and long-term outcomes related to community-based injury prevention initiatives, as well as public health efforts to collaborate with multi-sector partners, to enhance both the reliability and validity of such mobilization and programmatic efforts.Although our team members followed a collaboratively developed and refined the search protocol (inclusion and exclusion criteria), it is possible that we missed some sources of literature, particularly as we searched through multiple large bodies of sources. Additionally, we may have missed sources of literature published prior to 2000. We also did not provide evidence ratings of each included article, however, we did provide qualitative feedback using the MetaQAT. This alone should help in assessing reliability and validity, and evidence ratings could be a valued contribution when a more guided systematic review is performed in the future.In summary, this scoping review synopsized the theories, frameworks and models (TFM) related to community-based injury prevention found in the available literature. We propose a logic model that combines important components from all the included TFMs into a promising process that better underscores the inputs and activities needed for public health practitioners to build and sustain partnerships active in preventing injuries, as well as plan for evaluating their success.


National deworming programmes rely almost exclusively on mass drug administration (MDA) to children to control morbidity caused by these parasitic infections. The provision of other interventions, consisting of preventive chemotherapy at high population level coverage together with water, sanitation and hygiene (WaSH) and changes in risk behaviour, should enable sustainable control of soil-transmitted helminths (STH) and schistosomiasis and ultimately interrupt transmission.Two interventions will be implemented by the project: (i) community-wide biannual albendazole and annual praziquantel treatment with a target of 80–90% treatment coverage (“expanded MDA”); and (ii) provision of WaSH with behaviour change communication (BCC), within the Wolaita zone, Ethiopia. The project has three study arms: (i) expanded community-wide MDA, WaSH and BCC; (ii) expanded community-wide MDA only; and (iii) annual school-based MDA . The impact of these interventions will be evaluated through prevalence mapping at baseline and endline (after four rounds of MDA), combined with annual longitudinal parasitological surveillance in defined cohorts of people to monitor trends in prevalence and reinfection throughout the project. Treatment coverage and individual compliance to treatment will be monitored by employing fingerprint biometric technology and barcoded identification cards at treatment. WaSH utilisation will be evaluated through school and household level observations and annual WaSH assessment survey. Complementary qualitative surveys will explore practices, cultural and social drivers of risk behaviours, uptake of WaSH and treatment, and assessing the impact of the BCC.The study has the potential to define an ‘End Game’ for STH and schistosomiasis programmes through provision of multiple interventions. Interrupting transmission of these infections would eliminate the need for long-term repeated MDA, lead to sustained health improvements in children and adults, thereby allowing health systems to focus on other disease control priorities. Ascaris lumbricoides, Trichuris trichiura, Necator americanus and Ancylostoma duodenale) and two most common schistosomes (Schistosoma mansoni and S. haematobium), as these account for most of the helminth disease burden.Neglected tropical diseases (NTDs) are a group of infectious diseases that affect over 1.4 billion people globally –4. WhilsThe most marked epidemiological attributes of human helminth infections are their highly aggregated distributions so that few individuals harbour a disproportionate number of worms, predisposition of certain individuals to infection, rapid reinfection after treatment with no evidence of strong acquired immunity, and age-intensity profiles that typically show highest infections in school-aged children (SAC) , 9. HookWithin the past decade, through the direction of the World Health Organisation (WHO), significant progress has been made in implementing large-scale drug treatment programmes targeting STH and schistosomiasis typically through school-based drug administration. The SAC-targeted treatment approach was formulated by the WHO two decades ago when focus was given to age groups with the highest prevalence of STH and schistosomiasis infection and the greatest morbidity burden. Whilst SAC-targeted preventive chemotherapy (PCT) has resulted in a large decline in STH  and schistosomiasis prevalence and morbidity, recent research suggests that transmission of these parasites cannot be interrupted without expanding treatment to all age groups except in low transmission settings –13. In tWhile PCT can greatly reduce morbidity from helminth infection, reinfection typically occurs rapidly after treatment due to the absence of effective acquired immunity . The timProvision of safe water, sanitation and hygiene (WaSH) is one of the five key interventions within the global NTD roadmap leading to long-term control and eventual elimination . In the To fill this gap, the central aim of the Geshiyaro Project is to provide an evidence-base for a scalable model of interventions for the interruption of STH and schistosomiasis, leading to the cessation of MDA. The Geshiyaro Project will be implemented in Wolaita zone in Ethiopia and will investigate the impact of two sets of interventions: anthelmintic PCT (implementing more frequently and/or extended treatment to the entire population rather than the current school-based programme) and provision of safe water and sanitation alongside behaviour change communication (BCC).The specific aims are to (i) demonstrate whether planned interventions to control STH and schistosomiasis  can feasibly break transmission ) in a focal geographical area of Ethiopia; (ii) identify effective interventions with an understanding of the associated costs, motivators and barriers associated with each strategy; (iii) assess the feasibility of the different interventions as large-scale control efforts of STH and schistosomiasis, including costs, appropriate use of diagnostics and lessons learned.The specific objectives are to (i) quantify overall achieved reductions in infection prevalence and average intensity stratified by age (from pre-SAC to adult) within and between the study arms from baseline to endline as measured by Kato–Katz, POC-CCA, haemastix, urine filtration and qPCR; (ii) determine yearly patterns of intervention impact through annual changes in prevalence and intensity of infection in longitudinal sentinel sites within and between the study arms by standard diagnostics  across all age groups; (iii) evaluate levels of treatment coverage using fingerprint biometric technology (hereafter biometrics), study ID cards, as well as WHO independent coverage surveys, and the effect on transmission; (iv) identify serial non-complying groups of the population who do not regularly partake in MDA through use of the participants fingerprint; (v) assess the annual change in knowledge on schistosomiasis and STH, and the impact of subsequent behaviour change on transmission; (vi) evaluate the change in access to WaSH, and the impact on transmission; (vii) test and evaluate the more sensitive diagnostic methods of qPCR for parasite DNA detection in stool for their sensitivity, specificity and feasibility for elimination; (viii) develop and validate mathematical models for the prediction of STH and schistosomiasis prevalence after MDA and/or WaSH interventions.(i)Expanded MDA, improved WaSH and BCC in five districts (Wolaita Zone). “Expanded MDA” will be conducted at several levels. First, PCT will be extended to all the community, including adults and pre-SAC in the MDA eligible population (ALB ≥ 1 year and PZQ ≥ 5 years). Secondly, MDA coverage will be scaled up to reach 90% verified coverage, with 10% confidence interval, in all target age groups. “Improved WaSH” will incorporate clean water provision, sanitation and hygiene. Increased access to clean water supply will be achieved through building both deep and shallow water wells, as well as public taps. Sanitation improvement will be addressed through mobilisation of people to build and use latrines, with a reduction of open defecation through community led total sanitation (CLTS). All WaSH interventions are led by World Vision Ethiopia (WVE). Health education will be aimed at encouraging healthy behaviours and reducing contamination of soil and water by promoting the use of latrines and hygienic behaviour through BCC. This is also led by WVE.(ii)Expanded MDA and “One WaSH National Programme” (OWNP): ten districts (Wolaita Zone). Community-wide deworming of everyone in ten districts (over the age of one-year-old) with ALB  and PZQ . This will be coupled with the Ethiopian government’s “One WaSH National Programme”. Since 2013, Ethiopia has established a WaSH sector-wide approach under the umbrella of the OWNP, which brings together ministries, development partners, and civil society organisations to a common goal of one plan, one report and one budget. The aims of OWNP are to harmonise and align approaches to WaSH improvement, ensure equity in WaSH provision, and avoid varying financial and procurement procedures by donors.(iii)Annual school-based MDA and OWNP (Control): outside of Wolaita zone. Standard annual school-based deworming of pre-SAC and SAC (2–14 years-old), with ALB, will be maintained through the government nutritional programme of under-fives and the National STH/schistosomiasis Control Programme, respectively. Annual treatment of SAC with PZQ will be carried out in the STH and schistosomiasis school-based treatment programme. Again, this will be combined with the government’s “One WaSH National Programme”.The Geshiyaro Project has three intervention arms Fig. . The thrThe project will last seven years and consists of three phases. Phase 1 (2018/2019) is the pilot year in which Arm 1 study activities will take place in one district, Bolosso Sore. Phase 2 (2019–2023) will scale-up activities to all 15 districts of the Wolaita Zone. Phase 3 is two years of observation (2024/2025) where, providing transmission has been interrupted in the community, the regular national control programme MDA will continue in Arms 1, 2 and 3 as per the National Control Programme guidelines. At the end of Phase 3 progress in achieving the final aims and objectives of the project will be evaluated.Schistosoma mansoni are endemic in Wolaita, with hookworm as the dominant infection in most districts. Ascaris lumbricodes and Trichuris trichiura are both present in Wolaita at low prevalence. The national deworming programme has been active in the zone since 2013, treating SAC annually, apart from one district which is treated biannually, as per the WHO treatment guidelines. There is thought to be negligible presence of S. haematobium.The study will be conducted in the Wolaita zone (population 1.9 million), in the SNNPR region of south-western Ethiopia. The Wolaita zone consists of 15 districts or ‘woredas’. A woreda is the smallest functional unit of the health care system covering a population of at least 100,000. Ethiopia conducted a STH and schistosomiasis nationwide mapping survey in all regions of the country between 2013 and 2015 , 34. TheAll communities in Wolaita (Arms 1 and 2) will receive expanded MDA organised and overseen by the Federal Ministry of Health (FMoH) and implemented at community-level by the Health Extension Workers (HEWs). All community members ≥ 1 year of age will receive ALB against STH, while those ≥ 5 years of age will receive PZQ for schistosomiasis infections . All comArm 3 will continue to receive annual school-based deworming through the National Programme in accordance with the WHO guidelines for STH and schistosomiasis control. All deworming (community-wide and school-based) will be administered by HEWs who are responsible for all community-level health interventions, including deworming, immunisations and nutrition support.In Arm 1, improved WaSH interventions targeting risk behaviour and barriers to access will be implemented through WVE. In Year 1, the aim is for 40% of the communities to be declared open defecation free (ODF) through CLTS, whereby communities work together to build household level, institutional, and community improved pit latrines. CLTS is an approach to addressing open defecation that triggers emotions such as shame and disgust to generate a collective demand for sanitation within a community. In Ethiopia, evidence has shown that HEW-facilitated CLTS can be effective and is currently the strategy promoted by the national OneWASH programme . In addiBCC materials will include counselling cards for the HEW and posters, both of which will be designed to promote good hygiene practices to minimise risk of acquiring STH and schistosomiasis infection. Specifically, STH targeted messages will include (i) handwashing with water and soap; (ii) latrine use and reduction of open defecation; (iii) proper household waste management including disposal of infant faeces; (iii) practising safe household water handling, storage and treatment; and (iv) shoe wearing. Messages to reduce acquiring and transmitting schistosomiasis infection will comprise of (i) safe water storage; (ii) avoiding freshwater contact either through bathing or washing clothes; (iii) latrine use as above. In addition, messages to increase participation in the MDA will be delivered, including biometrics and study ID card registration in census districts.A sales catalogue for the WaSH business centre will also be published advertising products, services and associated costs (including loans).Prevalence and intensity of both STH and schistosomiasis will be evaluated cross-sectionally through baseline, endline 1 (end of Year 5 after four years of study activities) and endline 2 (end of year 7) mapping. In addition, longitudinal sentinel site monitoring of prevalence and intensity of infection in defined cohorts with a sample of 150 individuals stratified by age  will be conducted in each arm from Year 1 to Year 5. The primary outcome of the project is that transmission interruption is achieved as a community-level prevalence ≤ 2% of schistosomiasis and the dominant STH species (primary outcome) and any detectable STH species (secondary outcome) at the end of Phase 2, as determined by qPCR. If prevalence has been reduced to an acceptable level (< 2% by any detectable STH) in a defined primary health care unit , two years of observation will begin where the study population received the national control programme (school-based) MDA. Another assessment will take place at the end of Year 7 (end of Phase 3), two years after the cessation of study activities, to evaluate whether STH/schistosomiasis prevalence has remained low or “bounced back” in the intervening years. Transmission models suggest that reaching a 2% prevalence of STH , 24 months after stopping MDA reliably predicts transmission interruption with a positive predictive value of > 90% , 38. ThiWithin the context of elimination, the current WHO guidelines for mapping both STH and schistosomiasis recommend sampling approximately five schools per “health district” , which iBased on these calculations, baseline Geshiyaro mapping survey took place in 137 kebeles (approximately 40% within Wolaita) in December 2018 with a total of 100 individuals sampled per community stratified for equal sample size  by age grouping (pre-SAC (1–4 years), SAC (5–14 years), 15–20 years, 21–35 years, 36+ years) and sex. The overall prevalence across Wolaita showed the prevalence of STH at 11.3% and schistosomiasis at 0.27% by Kato–Katz. Between 26% and 75% of kebeles will be surveyed within each Woreda, with a higher proportion of kebeles being surveyed in small woredas. Communities were randomly selected for sampling. A sample size of 137 communities is sufficient to detect, in children and adults separately, a true reduction in prevalence from 15% at baseline to 0% at the end of the project.(i)Provide robust estimates of prevalence and intensity of infection within each woreda, and the degree of parasite aggregation within the population and age groupings within each setting; and(ii)Identify 30 communities within Wolaita (approximately 15% of those surveyed) to purposively select for more intensive impact monitoring, plus compliance to treatment, through sentinel sites.The aims of the mapping are to:The sentinel site longitudinal cohort allows for annual monitoring of a subsample of the population and will explore the association between infection and treatment coverage/compliance , and between infection and access to WaSH facilities. These sites are crucial to understanding impact of compliance to treatment, data obtained from individual barcoded ID cards or fingerprints scanned at MDA, on parasitology (changes in intensity of infection post-treatment). The Geshiyaro Project defines a protocol to sample 150 individuals per site, with 45 sites in total (15 in each arm). Arm 3 will be evaluated in 15 sentinel communities within Southern Nations and Nationalities People’s Region (SNNPR), which are currently being assessed longitudinally through the national monitoring and evaluation sentinel site programme. This figure was determined to allow for anticipated drop out of 10% from the cohort sample. Sample size calculations suggest that, with 95% significance and 80% power, and assuming an intra-class correlation of 0.05, will allow a detection of change in prevalence of at least 10% from an initial prevalence of 11.3%. The study design effect is estimated at 2.5 and is accounted for in the sample size estimation. This sample size equates to one site per 67,000 individuals in the intervention area, which is substantially higher than the WHO recommendation of one site per every 200,000–300,000 individuals. In addition, the design includes monitoring of not just school-aged children, but a broader range of age classes including adults and pre-SAC. Consequently, 30 communities in Wolaita and 15 communities from Arm 3 sites outside of Wolaita were chosen as sentinel sites. An age- and sex-stratified random sample of 150 individuals will be followed in each community selected, totalling 6750 individuals.A. lumbricoides, T. trichiura and hookworm, which tend to be less focal in the magnitude of the prevalence of infection. Additionally, the ability to detect true prevalence is more sensitive both to the diagnostic used and to the number of sites, than to the number of individuals sampled per site [Following baseline mapping conducted in December 2018, a list of all communities was categorised as low, medium or high prevalence for both STH and schistosomiasis based on the current WHO guidelines. Each community was then stratified by co-endemicity whereby the number of sites for schistosome infection in each STH category was tabulated. The sentinel sites were randomly selected from each category to ensure a balance of sites across the different infection categories. Due to the focal distribution of schistosomiasis, the ability to capture accurate prevalence data in a defined region will be more sensitive to the number and location of sites compared, for example, to per site . At midlA population census will take place for the Geshiyaro Project prior to any intervention in a total five districts in Wolaita. Three will take place in districts within Arm 1  and two in districts assigned to Arm 2 . The purpose of the census is to determine an accurate denominator for the MDA using fingerprints and study ID cards, identify  non-compliers to the MDA, and assess baseline sociodemographic and WaSH coverage prior to the start of the intervention. The Ethiopian government is planning to conduct a full census throughout SNNPR in the late part of 2019, which will be used as a denominator for the remaining districts. Between October and December 2018, a pilot census was carried out in one district (Bolosso Sore) to test acceptance of communities to census activities, specifically the fingerprinting technology. The remaining four districts will carry out their census between October and December 2019.Door-to-door visits will be conducted by enumerators selected by the zonal health bureau and accompanied by a local guide, who is selected by each village, to enrol (consenting) households who will provide the name, age, sex, and relationship to the household head for all individuals residing within the household. Questions regarding household possessions and access to electricity, in addition to the materials used for the household structures  will be asked to obtain a measure of socioeconomic status. Household surveys to determine access to water and sanitation services  will be supplemented by community-wide sanitary surveys. Observational data will be collected on the type of toilet, household structure materials and shoe wearing will be recorded. The GPS coordinates of each household will be recorded.All individuals within consenting households will be registered with a pre-printed barcoded Geshiyaro study ID card and asked to provide a biometric fingerprint. The accuracy of how many fingers need to be scanned was assessed in the pilot using one, two and four fingers. The result of the pilot analysis showed that taking four fingers yielded the highest accuracy. The barcoded study ID card was not only an additional method of identification, but also to mitigate the limitation of the biometric technology in accurately identifying pre-SAC. For any individuals from the household that were not present, the data collectors will return at another time (in the evening or weekend) to ask for a fingerprint, with a limit of re-visiting an unsuccessful household three times. All individuals, regardless of whether they consented to fingerprint registration or not, will be given a study identification card with a unique study QR code. Every household will also have a unique household study QR code which will be on the back of the household head’s study ID card. The biometrics and study ID cards will be used in all data collection rounds for anonymous data linkage. At each school and health facility within the zone, a WaSH survey will be performed. The total number of students enrolled in each school, and the catchment population and number of households served by each health facility will be documented.The Geshiyaro Project will use fingerprinting technology to link individuals over multiple data collection activities. Simprints, a technology company, will provide the biometric fingerprint identification system used in this project. Fingerprint characteristics are unique to each individual and will be used therefore to identify individuals reducing the risk of identification errors, such as ID cards being swapped or lost, which can lead to data being linked to the incorrect individual. However, the use of biometric fingerprinting comes with challenges of its own including its reliability in accurately identifying children under the age of five, the number of fingers captured in order to balance data collection burdens with maximizing accuracy, acceptability among community members, and feasibility of using the technology at scale.Parasitological data collection will take place in randomly selected communities at baseline (Year 1), midline (Year 3), endline 1 (Year 5) and endline 2 (Year 7). There will also be annual parasitological data collection in the assigned longitudinal sentinel sites.Recruitment for the parasitological mapping and sentinel sites will be through door-to-door and school visits with the aid of the HEWs. Individual (≥ 16 years-old) or parental consent (< 16 years-old) for study participation will be obtained. All individuals approached to be registered in sentinel sites will be asked about any plans to move household over the study years.Duplicate Kato–Katz slides will be prepared from a single (mapping) or two stools over two days (sentinel sites) from all individuals and the number of parasite eggs found in each slide recorded. A single urine sample from each individual will be tested using a POC-CCA test and haemastix. If the latter is positive for blood in urine, then two filtrations on 10 ml of urine will be carried out for each individual and microscopically examined; the number of eggs found in each slide and the corresponding volume of urine filtered will then be recorded. A subset of samples from the sentinel sites in the first year will be stored for subsequent qPCR analysis. At endline all mapping site samples will be analysed by qPCR , 42.Independent treatment validation surveys are household-based surveys which can verify routinely reported treatment coverage. The findings are used to carry out any necessary mop-up activities to achieve higher coverage, as well as providing additional information on disaggregated coverage by factors such as age, gender and school attendance. During these surveys, conducted by the Ethiopian Public Health Institute (EPHI), data will be collected on where individuals took the drugs, where they heard about treatment, and reasons for not taking the tablets . These coverage surveys will be conducted within three months of each MDA to identify challenges related to achieving MDA coverage targets and to evaluate reported coverage. The WHO method, adapted from the Expanded Programme on Immunization (EPI) coverage surveys, will be used . ApproxiEliminating open defecation is a key health outcome of the Geshiyaro Project, given the links to reduced stunting, improved educational and positive health outcomes for children. The Geshiyaro Project has a goal of 40% ODF in Year 1 and 100% from Year 2, to be achieved through CLTS. The approach focuses on community mobilisation to motivate all individuals in a community to understand the health risks associated with open defecation through knowledge, disgust, shame and fear as “triggers” to promote action which ultimately lead to construction and use of household latrines. The FMoH national CLTS protocol used to define and verify ODF .The specific ODF objectives are ambitious and include (i) total elimination of open defecation practices; (ii) 100% coverage of latrine use; (iii) improved personal, household and environmental hygiene; (iv) increased ownership and sustainability of hygiene and sanitation activities; (v) contribution to reduction in sanitation related diseases.(i)Verification at the community level by the community administrative team;(ii)Verification at the district level of each community declaring ODF status;(iii)Verification by the stakeholder, WVE;(iv)Review reports: provided by the community, district and WVE records of ODF;Observations: transect walks to observe households in 30% of each community;Interviews: a sample of households will corroborate a visual inspection of the community through interviews with family members; interviews at health centres and schools; community consultations; and key informant semi-structured questionnaires.Independent verification by the Geshiyaro evaluation team. This will include:Verification validates the submissions of communities about progress to achieve the stated goals and builds on the key indicators of ODF, i.e. that there is no evidence of open defecation, that households have access to and use latrines. Within each community, verification will occur at various levels (in order):When trying to develop specific interventions aiming at improving communities’ knowledge, attitudes and practices (KAP), pre-existing capacities must be considered . Qualita(i)In-depth observations (formative assessment): a walkthrough of common areas, observing the environment for issues of relevance to schistosomiasis and STH transmission cycles. Household observations involving researchers spending periods of time observing daily routines including sanitation and hygiene behaviours, water contact site observations with visits throughout the day and in different seasons to capture different user groups and risk behaviour;(ii)Household observations: household members including children will be observed for risk exposure behaviours;(iii)Key-informant interviews: observations will be supplemented by key-informant interviews and focus group discussions (FGD) with community members who are knowledgeable about community norms, perceptions and beliefs, social structure, sanitation and health care services, and drivers of STH/schistosomiasis risk behaviours will be triangulated using key informant interviews with HEWs. Qualitative research will be conducted in Year 1, at mid-point, and endline (Year 5). The endline research will also be performed to measure success in behaviour change strategies and determine lessons learned from the interventions. Appropriate statistical methods will be employed to evaluate changes in both qualitative and quantitative measures from baseline to endline.The formative research will include:The formative research will be carried out by two HEWs from each kebele. In total approximately 15 to 20 kebeles in each arm will be randomly selected to be surveyed each year. This qualitative data triangulated with quantitative WaSH assessment data on hardware coverage to explore core topics that help to understand risk behaviours for acquiring infection and engagement with the interventions (both MDA and WaSH).There are two major outcomes of the WaSH implementation; total elimination of open defecation through BCC and CLTS, and ultimately the provision of safe water supply and improved latrines.(i)Project and service monitoring: school and household level observations of the interventions or activities planned for implementation, evidence of use, cleanliness, photos and GPS coordinates of facilities used both at home and school;(ii)External evaluation of WaSH will be explored using: (a) the longitudinal parasitological data collection and correlation with WaSH uptake to track programme impact; (b) qualitative assessment of hygiene and sanitation behaviours at baseline, midline and end of the investment to understand whether behaviour has changed in areas that reached transmission interruption; (c) scoring of exposure to infection as determined by WaSH facilities ; and (d)The WaSH intervention will be assessed through:In order to assess the scalability of the Geshiyaro Project, the economic costs and benefits of the intervention will be assessed. We will analyse costs as a management tool to understand where to spend resources and where to reduce costs. A combination of prospective and retrospective data will be collected at central, zonal and community levels for analysis . Annual Data from each survey are collected in the field using Samsung J5 smartphones. Questionnaires are coded in SurveyCTO and uploaded from the phones onto the SurveyCTO server. After each year of data collection is complete, the data will be stored on a secure server at EPHI in Addis Ababa, Ethiopia and removed from SurveyCTO. Laboratory parasitological results will be written on paper forms by the laboratory technicians and transferred to SurveyCTO forms at the end of each day.Standardised approaches to data cleaning and creation of data sets for analysis will be used. Data will be cleaned in-country based on a series of checks provided by the Monitoring and Evaluation (M&E) team (comprising of staff from EPHI and LCNTDR). “Clean” data will be decided upon by both EPHI and LCNTDR prior to assessment, and issues identified with the data  to be corrected where possible. Nonsense values (out of known ranges) will be re-coded as missing. Primary data analysis will include the estimation of the prevalence of infection, the intensity of infection and parasite aggregation measures  counts across age classes) within and between intervention arms. To evaluate the primary outcome, data from baseline, midline and endline will be analysed to determine differences between the arms and to assess what fraction of communities have reached the 2% prevalence threshold for the compilation of positive predictive values for reaching the defined prevalence goal employing data from the end of Phase 2 and the end of Phase 3. To assess overall population-level programmatic impact on the prevalence of STH and schistosomiasis between intervention arms, Generalised Linear Mixed Models (GLMM) will be used in statistical analyses to estimate the differences between arms. Prevalence will be modelled using a binomial (positive and negative) GLMM with logit link function. Unadjusted results will use community and study arm only as covariates. Adjusted results will incorporate pre-determined covariates captured during census, such as urban/rural classification, household sanitation infrastructure, community ODF status, access to adequate water and household socioeconomic status.Baseline characteristics (captured during census) will be analysed to assess any systematic differences between communities, both within and between intervention arms. This would include number of communities, number of participants, and age, sex, prevalence, and intensity by age classes assessed both by including all individuals and including only egg-positive individuals. Measures of dispersion will be included, for example, interquartile measures of intensity and the negative binomial k value for epg distribution within age groupings. Secondary outcome analysis will include quantifying longitudinal compliance to treatment in conjunction with parasitology data, stratified by age and sex, to determine whether any demographic groups are consistently missing treatment and whether this is associated with infection levels over multiple rounds of MDA. Other secondary analyses will include assessing the change in the intensity of infection and uptake of improved WaSH.The main objective of the Geshiyaro study is to develop a scalable model for STH/ schistosomiasis transmission interruption which can be feasibly rolled out by the health ministries in endemic counties and leads to MDA no longer being required for infection control. The collection and analysis of process monitoring data will ensure intervention facilitators and barriers to implementation are identified. This monitoring of system capacity will be verified through pre-developed tools for preventative chemotherapy such as the NTD Data Quality Assessment Tool  and the WHO Quality Standards Assessment Tool .Community engagement (sensitisation) is a vital part of all disease intervention studies. It will be performed before each data collection round, specifically covering the activities for that stage of the project. This will comprise of a top-down information dissemination strategy, utilising meetings with community officials prior to the start of data collection. Community official support will be obtained, and the officials will relay the information about the study and how their fingerprints will be used in the study to their respective communities. Secondly, there will be “town-hall” style meetings in the communities presenting the study activities to the population and answering any questions they may have. Sensitisation will cover the aims and outcomes of the project, consent, data capture, MDA and fingerprinting technology. Sensitisation for census, mapping and sentinel sites will be performed by EPHI. Sensitisation for MDA will be performed by FMoH.Experience in many settings suggest that chemotherapy has the greatest impact in rapidly reducing the burden and morbidity of helminth infections. However, to accelerate reaching morbidity control and transmission elimination targets, and to sustain improvements, additional measures are ideally needed including WaSH and community public health education. These include a safe water supply, appropriately constructed and maintained sanitation infrastructure that ensures safe disposal of human excreta, the promotion of hygiene such as handwashing plus bathing, and the management of water in the home. Studies have shown that the provision of additional interventions should allow the suppression of the prevalence of STH and schistosomiasis infection to very low levels, achieved through MDA, to be sustained once transmission has deemed to be broken in defined settings such that MDA can cease in these settings –51. The


We report a case of monkeypox in a man who returned from Nigeria to Israel in 2018. Virus was detected in pustule swabs by transmission electron microscopy and PCR and confirmed by immunofluorescence assay, tissue culture, and ELISA. The West Africa monkeypox outbreak calls for increased awareness by public health authorities worldwide. Monkeypox is a zoonotic disease caused by monkeypox virus, an orthopoxvirus closely related to variola virus, the causative agent of smallpox. Human cases were first described in 1970; in subsequent decades, sporadic outbreaks were reported in Africa. Mortality rates are 1%–10%  and chills and started self-medicating with nonsteroidal antiinflammatories and oral penicillin. On October 1, an erythematous rash appeared first on his face and later on his trunk and extremities. Examination at Shaare-Zedek Medical Center on October 4 revealed that the patient was febrile and had a nonblanching maculopapular rash on his face , panel ARickettsia conori, Rickettsia typhi, Brucella spp., Treponema pallidum, and antigen/antibody combination for HIV. Pustular samples were negative for herpes simplex virus by PCR. Because of the rash characteristics and the patient’s travel history, monkeypox was suspected.At a follow-up visit 2 days later (October 7), he was afebrile. The rash was locally synchronous and had progressed from maculopapular to vesicular and pustular; some lesions displayed black umbilication and crusting (https://www.beckman.com) before negative staining with phosphotungstic acid. Samples were sent to the Israel Institute for Biological Research, Ness-Ziona, Israel, and processed in Biosafety Level 3 laboratories. The pustule sample was processed for PCR analysis and transmission electron microscopy. Vero cells were infected for immunofluorescence assay and monitored for cytopathic effect. For transmission electron microscopy, particles were enriched by using a Beckman Airfuge  embedded in skin tissue and as single virions (PCR diagnosis was based on specific primers to discriminate between the West African (581 bp) and the Congo-Basin (832 bp) clades by product size  and were shed (All of the patient’s contacts in Israel (5 household members and 11 HCWs) were offered smallpox vaccination, but only 1 HCW agreed. All contacts were followed up for 21 days; no virus transmission was detected.Since the first documented case of human monkeypox in 1970, sporadic outbreaks have been reported, especially in the Congo Basin and West Africa. Contributing to the increased frequency of such occurrences were discontinued vaccination against smallpox, increased interaction with wildlife because of deforestation and population movement, consumption of bushmeat, and increased population density  have involved the West African clade of the virus (For this study, we used multiple diagnostic approaches. The virus was detected in pustule swab specimens by transmission electron microscopy and PCR within 3 hours of sample arrival and confirmed by immunofluorescence assay, tissue culture, and ELISA for orthopoxvirus antigens.The very high virus titers contained by pustules and scabs, as demonstrated in this case, increase the risk for human-to-human transmission and environmental spread. To prevent further transmission, HCWs should implement safety practices and local authorities should map contacts and consider use of smallpox vaccines or antiviral drugs (


The past few decades have seen substantial improvements in cancer survival, but concerns exist about long-term cardiovascular disease risk in survivors. Evidence is scarce on the risks of specific cardiovascular diseases in survivors of a wide range of cancers to inform prevention and management. In this study, we used large-scale electronic health records data from multiple linked UK databases to address these evidence gaps.For this population-based cohort study, we used linked primary care, hospital, and cancer registry data from the UK Clinical Practice Research Datalink to identify cohorts of survivors of the 20 most common cancers who were 18 years or older and alive 12 months after diagnosis and controls without history of cancer, matched for age, sex, and general practice. We compared risks for a range of cardiovascular disease outcomes using crude and adjusted Cox models. We fitted interactions to investigate effect modification, and flexible parametric survival models to estimate absolute excess risks over time.Between Jan 1, 1990, and Dec 31, 2015, 126 120 individuals with a diagnosis of a cancer of interest still being followed up at least 1 year later were identified and matched to 630 144 controls. After exclusions, 108 215 cancer survivors and 523 541 controls were included in the main analyses. Venous thromboembolism risk was elevated in survivors of 18 of 20 site-specific cancers compared with that of controls; adjusted hazard ratios (HRs) ranged from 1·72 (95% CI 1·57–1·89) in patients after prostate cancer to 9·72 (5·50–17·18) after pancreatic cancer. HRs decreased over time, but remained elevated more than 5 years after diagnosis. We observed increased risks of heart failure or cardiomyopathy in patients after ten of 20 cancers, including haematological , oesophageal , lung  kidney  and ovarian . Elevated risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease were also observed for multiple cancers, including haematological malignancies. HRs for heart failure or cardiomyopathy and venous thromboembolism were greater in patients without previous cardiovascular disease and in younger patients. However, absolute excess risks were generally greater with increasing age. Increased risks of these outcomes seemed most pronounced in patients who had received chemotherapy.Survivors of most site-specific cancers had increased medium-term to long-term risk for one or more cardiovascular diseases compared with that for the general population, with substantial variations between cancer sites.Wellcome Trust and Royal Society. Improvements in cancer survival in the past few decades have resulted in a large and growing population of long-term cancer survivors; about half of patients diagnosed with cancer in high-income settings are now expected to survive for 10 years or longer.8Although randomised trials have shown short-term to medium-term adverse cardiovascular effects of some specific cancer treatments, such studies cannot quantify the broader differences in risk between cancer survivors and individuals with no history of cancer.Evidence before this studyWe searched PubMed and OVID MEDLINE for epidemiological studies, reviews, and guidelines published in English from Jan 1, 2008, to Dec 31, 2018, using search terms for cardiovascular outcomes and cancer  and the Independent Scientific Advisory Committee for the Medicines and Healthcare products Regulatory Agency database research (16_274). The study protocol is available in the Cancer survivors entered the study 1 year after diagnosis (index date) and were matched on age (±3 years), sex, and general practice with up to five controls with no history of cancer and at least 24 months of continuous preceding follow-up on the index date of the matched cancer survivor (mirroring the requirement on cancer survivors to have 1 year of follow-up before and after cancer diagnosis to enter the study on the index date). If a control went on to receive an incident cancer diagnosis during follow-up, they were no longer available as a control at that time but could then contribute as a site-specific cancer survivor (if the cancer was at one of the 20 sites of interest) with their own set of matched controls.The outcomes of the study were fatal or non-fatal coronary artery disease , stroke (haemorrhagic and ischaemic stroke), arrhythmia, venous thromboembolism (deep vein thrombosis and pulmonary embolism), heart failure and cardiomyopathy combined, pericarditis, valvular heart disease, and peripheral vascular disease. Component outcomes within coronary artery disease, venous thromboembolism, and heart failure or cardiomyopathy were also analysed separately. We identified outcomes using Read codes within CPRD GOLD, ICD-10 codes within HES APC, and ICD-9–10 codes within the ONS mortality database.Code lists for all study variables are available online.Demographics and shared risk factors, including smoking, BMI, and comorbidities, were identified at the cancer diagnosis date for the cancer survivor group and at 1 year before the index date for the matched cohort. Full covariate definitions are provided in the For all analyses of each outcome, patients were followed up from the index date  until the earliest occurrence of: death, end of research-quality follow-up, end of study period, or first occurrence of an outcome. Patients with a record of an outcome of interest before the index date were excluded from the analysis of that outcome. We calculated crude incidences for each cardiovascular disease outcome in cancer survivors and matched controls, with separate models for each cancer site. To relate site-specific cancer history to risk of each cardiovascular disease outcome, we then fitted Cox proportional hazards models with time since index date as the timescale, initially accounting only for matching factors  through stratification by matched set and then additionally adjusting for shared risk factors and demographics listed in vs control) included as a time-dependent effect and adjustment for all covariates included in our Cox models, and then predicting incidence over time at both levels of exposure, with all other covariates fixed at the mean values in the cancer survivor group.We investigated the modification of the effect of cancer survival on cardiovascular disease risk by the following variables by fitting interaction terms and doing likelihood ratio tests for interaction: age group, sex, smoking status, BMI, other pre-existing cardiovascular disease at index date, hypertension at index, Index of Multiple Deprivation, and calendar period. Proportional hazards were checked by fitting interactions with time since index date. Definitions of interaction terms are provided in the We did sensitivity analyses based on our primary Cox models. First, we repeated the analysis using only unlinked data from CPRD GOLD, which allowed a larger UK-wide population to be drawn (because only a proportion of CPRD has linkage available). This extended the analysis to the whole of the UK and to the period January, 1987, to June, 2017, but at the expense of a probably higher misclassification of cancer diagnoses and cardiovascular disease outcomes. Second, we repeated the analysis excluding people without at least two blood pressure measures before the index date, rather than classifying these individuals as normotensive . Lastly,The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Between Jan 1, 1990, and Dec 31, 2015, 126 120 individuals with an incident diagnosis of a site-specific cancer of interest, still being followed up at least 1 year later were identified and matched to 630 144 controls with no history of cancer. 17 905 (14·2%) cancer survivors and 106 603 (16·9%) controls were then excluded because of missing smoking or BMI data, leaving 631 756 individuals in the final analysis cohort . 115 886We calculated incidences and cause-specific HRs adjusted for age and sex alone and then additionally for shared risk factors . AdjustmFor the coronary artery disease and stroke outcomes, we found little statistical evidence of effect modification by any of the factors assessed . We founAbsolute venous thromboembolism incidence was highest closer to the time of cancer diagnosis and reduced over time, as did incidence of arrhythmia after lung cancer, whereas heart failure or cardiomyopathy incidence increased with time after diagnosis . AbsolutIn exploratory analyses in which cancer survivors were grouped according to treatment methods recorded in the registry data, we found evidence of a substantially elevated risk of venous thromboembolism in all cancer survivor groups compared with that of the general population, regardless of treatment. This risk was most pronounced in patients receiving chemotherapy. Chemotherapy use also seemed to be the key driver of heart failure or cardiomyopathy risk after breast cancer . In sensIn this comprehensive assessment of the risk of cardiovascular disease in cancer survivors compared with that of general population controls, we found increased risks of cardiovascular diseases in the years after diagnosis of most site-specific cancers. We observed large increases in the risk of venous thromboembolism in survivors of 18 of 20 cancer types. This risk attenuated over time but remained elevated for at least 5 years after diagnosis for most cancer types. We also observed increased risks of heart failure or cardiomyopathy in survivors of ten of 20 site-specific cancer types, including greater than 50% increases in risk after haematological, oesophageal, lung, kidney, and ovarian cancers and increased risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease for multiple cancer sites. Survivors of haematological malignancies had increased risks across all these outcomes, but the pattern of risks varied for other cancer sites. Adjustment for shared risk factors for cancer and cardiovascular disease had little effect on associations. Relative risks for heart failure or cardiomyopathy and venous thromboembolism associated with cancer survival were most pronounced in younger ages and in individuals with no previous cardiovascular disease or hypertension ; however, higher absolute effects were often observed in older individuals.Our finding of substantial variability by cancer site of associations between cancer survival and subsequent cardiovascular disease is consistent with a US studyMost previous studies have focused on survivors of a single, site-specific cancer, most commonly breast cancer . AlthougA major strength of our study was that the size and breadth of the linked data sources enabled us to investigate associations in granular detail. The importance of this is evident in the observed heterogeneity in the associations by cancer site and specific cardiovascular disease outcomes, showing that analyses of composite outcomes and all-cancer exposures can mask important variation. We had the data and statistical power to do a comprehensive analysis of medium-term and long-term cardiovascular disease risks for survivors of 20 site-specific cancers and to investigate effect modifications for the nine most common cancers and key cardiovascular disease outcomes. The use of consistent methodology across a wide range of cancers and outcomes gives confidence that the observed patterns of risk reflect real phenomena, rather than methodological artefacts. Multiple validation studiesNonetheless, our study has important limitations. Although we could broadly categorise some groups of cancer survivors according to key treatment methods recorded, and thus begin to explore the role of treatment in driving cardiovascular disease risks, we had no information on specific chemotherapy drugs or doses received and no details on fields or doses of radiotherapy exposure. For several cancer sites, cancer registration data were too incomplete to be used at all. Where data were available, power was insufficient to assess whether the time course of cardiovascular disease in cancer survivors differed according to the initial treatments received. Cancer registry treatment data are most complete for treatments received during the first 6 months after diagnosis, with less information after this, and we had no reliable information on cancer recurrence, which could have been an important predictor of further cardiotoxic treatment and subsequent increased cardiovascular disease risk. Stage and grade data were not sufficiently complete across the study period to assess differences by severity of cancer at diagnosis. Our prescription data came from primary care alone and thus, we could not assess trends over time in hospital prescribing of drugs that might be given to mitigate chemotherapy-induced cardiotoxicities, such as anti-hypertensive drugs or dexrazoxane, in the context of increasing awareness of the cardiovascular risks in patients after cancer. The greater use of such cardioprotective drugs in patients with pre-existing cardiovascular disease might explain the lower HRs observed in that group for some outcomes. We did not have sufficiently detailed data to classify the stroke outcome as ischaemic or haemorrhagic, which could have been important given the observed heterogeneity of associations between cancer survival and different cardiovascular disease outcomes. Some individuals had missing BMI and smoking data; our complete-case analysis assumed that associations between cancer and cardiovascular disease, conditional on covariates, do not differ between included and excluded individuals,The causes of increased cardiovascular disease risks in these patient groups are likely to be varied, but our analyses suggest that cancer treatments, particularly chemotherapy, are likely to play a more prominent role than shared risk factors such as smoking and excess weight. Surgery-associated phenomena and mechanisms directly related to cancer biology might also play a part, for example in the increased risk of stroke in survivors of central nervous system cancers. The best-known cardiotoxicity related to cancer treatment is that of anthracycline chemotherapy drugs, which have been found to substantially increase risk of reduced left ventricular ejection fraction and subsequent clinical heart failure.Our findings might have several implications for patient management to improve outcomes. The relevance of traditional cardiovascular disease risk prediction and risk minimisation for patients living after a cancer diagnosis is unclear. Prediction models of cardiovascular disease risk used in general practice typically do not include outcomes such as heart failure and venous thromboembolism and do not include cancer as a predictor. Additionally, these models generally ignore competing risks,In conclusion, survivors of most site-specific cancers had higher risks of cardiovascular disease compared with those of people without diagnosed cancer, with patterns of risk varying by cancer site and by specific cardiovascular disease outcome. Strategies to minimise and manage cardiovascular risk are needed for the growing population of cancer survivors.