This study examines potential challenges facing Lyme disease patients in Canada’s Maritime provinces—New Brunswick, Nova Scotia, Prince Edward Island—and considers how issues could be addressed. Reviews of both the academic and grey literature are complemented by surveys targeting both medical professionals and decision makers in government. Combined, the literature reviews and surveys demonstrate that there is considerable debate surrounding the effectiveness of testing, treatment options, and the existence of chronic Lyme disease. As the focus on the Maritimes demonstrates, these debates often pit the medical community against patients and patient advocates and, thus far, governments have been unable to produce policy that entirely pleases either side. Moving forward, this study recommends the creation of a discussion forum via a federal Commission of inquiry to review best practise guidelines for Lyme disease. The key is to foster an unbiased probe of central issues surrounding treatment and diagnosis without alienating stakeholders. This course of action will not necessarily solve the issue of Lyme disease, but would foster a greater understanding through dialogue that includes and validates the experiences of stakeholders, which is something that is currently missing. Borrelia burgdorferi infected Ixodes scapularis, commonly known as black-legged ticks. These ticks have expanded into Canada, in particular Canada’s Maritime provinces of New Brunswick (NB), Nova Scotia (NS) and Prince Edward Island (PEI), largely due to climate change. The result has been a dramatic rise in Lyme disease [Lyme disease has increased in prevalence in Canada in recent years. As a vector borne disease, Lyme disease is transmitted to humans via the bite of  disease . Early d disease . For exa disease . It is tWe approach the questions in three ways. First, a review of the literature, both academic and grey, is conducted to illustrate the current scholarship surrounding Lyme disease in order to better understand why Lyme disease has become such a polarizing issue. The key debates revealed include the current testing procedures for diagnosis and the length and efficacy of antibiotic prescriptions. Combined, these issues contribute to a contentious discussion, which often pits the majority of the medical community against patients and Lyme disease advocacy groups. Moving forward under such conditions is challenging. Second, surveys of family physicians, politicians and government health officials within the Maritime provinces were conducted to better understand how Lyme disease is processed and perceived. This allowed us to situate the regional context in the broader literature to reveal potential blockages. Third, we propose policy options in the analysis section that follows. These options were informed through the lens of multiple streams theory, which looks to explain the necessary circumstances for policy change to be achieved via the coming together of problems, solutions and politics by policy entrepreneurs within a favourable window of opportunity. We conclude that an unbiased yet guided discussion forum to investigate best practise options, a Commission of inquiry that includes all stakeholders, may be a good means of bridging the gap between advocacy groups, governments and the medical community before innovations in the realm of diagnosis and treatment options can be realized. Increased scholarship over the past twenty years has been dedicated to the study of Lyme disease in North America. This scholarship has centred on the expansion of ticks in Canada, diagnosis issues, treatment options and chronic Lyme disease. Borrelia burgdorferi. This bacterium is transmitted to humans via the bite of infected ticks, most commonly Ixodes scapularis, better known as the black-legged or deer tick [I. scapularis expands, more areas are at risk for Lyme disease.At the heart of understanding tick expansion is recognizing the nature of the disease itself. The main cause (though not the only one) of Lyme disease in North America is the bacterium eer tick . These teer tick . Lyme dieer tick ,6. HowevI. scapularis has been expanding due to climate change, as warmer weather has allowed their range to gradually expand north. Previously established tick populations thrived in two regions of the U.S.: The Northeast, particularly in the states of Maine, New Hampshire, New York, and Massachusetts; and, the Midwest, particularly in Minnesota and Wisconsin [Agreement in the literature exists on the fact that isconsin . As the isconsin . This isisconsin . Model pisconsin . A similar convergence, however, does not exist surrounding the diagnosis of Lyme disease. There are two means by which an individual can be diagnosed with Lyme disease, either clinically or via serological testing. A clinical diagnosis can take place if an individual shows erythema migrans and has plausible exposure. That is, exposure to known areas with high tick populations instead of the clinical condition of the patient . Some, sIf the patient does not have erythema migrans then they must receive positive serological tests for evidence of antibodies against the Lyme disease bacteria (in most cases even if they have been exposed to areas of high tick populations). Canada follows the Centers for Disease Control and Prevention (CDC) protocol for serological testing by first, the Enzyme Immunoassay (ELISA) test, and, if positive, verification via a Western blot test. These tests look for antibodies the body produces in response to infection . As a reCurrent and former patients are unhappy with diagnosis procedures with many seeking treatment outside of the conventional Canadian health care system. Issues abound including perceived misdiagnosis, failure to obtain a diagnosis, or persistence of symptoms often after years of seeing specialists . Some scComplicating matters is the minimal knowledge of Lyme disease by medical professionals. For example, in examining the experiences of individuals who sought treatment for Lyme disease outside of the conventional Canadian health care system, Boudreau et al. reported many individuals struggling to get treatment in Canada or be successfully diagnosed with Lyme disease while others were denied conventional antibiotics and belittled for insisting that they had Lyme disease . This frB. burgdoferi only rely on this test, which on its own has a high false positive rate [Seeking medical treatment outside the Canadian health care system, and specifically in the United States, remains controversial. Much of the controversy surrounds the current two-tier serological testing procedure where it is argued that it is no more effective in the U.S. than that found in Canada given similarly high false negative rates in the U.S.  . Canadiaive rate . Furtherive rate . A complive rate ,15. The ive rate .Canadian physicians generally agree that seeking Lyme disease testing in the United States is a mistake as misdiagnosis and or treatment could lead to lasting economic, psychological, and physically adverse outcomes . IronicaDebate is not limited to the diagnosis of Lyme disease, but extends to treatment options. Lyme disease is currently treated through a variety of short-term (10–28 days) antibiotics which are widely accepted within the academic and medical communities ,18. HoweChallenges surrounding diagnosis and the debate over the existence chronic Lyme disease, and by extension the use of long-term antibiotics, has driven many Canadian patients into seeking treatment outside of the conventional health care system. Surprisingly, Boudreau, Lloyd, and Gould found that patients were “pushed” to seek out-of-country treatment given specialists in Canada, particularly infectious disease experts and neurologists, were the most unhelpful within the Canadian health care system. Changes are required including an effective treatment protocol, effective diagnostic tests, more knowledgeable physicians, financial coverage for alternative treatments, as well as increased respect towards patients, including acknowledgment of the disease itself and the suffering state of the patient . This stCurrent challenges and debates have also renewed interest in Lyme disease vaccines. Two vaccines, approved in the 1990s, were voluntarily withdrawn from the market under the threat of a class action lawsuit due to adverse events to the vaccines  . OvercomB. burgdorferi and is transmitted to humans via ticks (most often black-legged or deer ticks). Second, increasing temperatures due to climate change are facilitating the expansion of tick populations into Canada, giving rise to more cases of Lyme disease. How to address this disease remains a topic of heated debate. While the medical community generally agrees on the diagnosis process and short-term antibiotic treatment, much criticism exists from some scholars and, particularly, patients and patient advocates. The main issue at the root of these debates is the accuracy of serological testing to determine Lyme disease [Overall, the divergence within the academic community regarding Lyme disease is shrinking with increasing research. The facts are that, first, Lyme disease is an infectious disease that infects humans via  disease ,12. Many disease ,31. Media coverage surrounding Lyme disease in Canada generally covers similar topics—the expansion of tick populations and by extension Lyme disease, government initiatives, as well as cases of mistreatment. The media is also largely sympathetic towards Lyme advocacy groups and those suffering from Lyme disease, a position that is not held in the majority of the academic scholarship .Canadian news articles typically report an increase in tick populations and by extension cases of Lyme disease. Within the Maritimes specifically, the rise of Lyme disease in Nova Scotia draws much attention due to the rapid increase of infections—from 7 confirmed cases in 2007 to 326 in 2016 . It is aTelegraph Journal covered the case of Mitch Thibodeau whose doctor had retired, forcing him to travel the country in search of another physician who would consider the possibility of antibiotic treatment until symptoms resolved [Chronicle Herald echoed these two stories, with the patient, Jana Young from Nova Scotia, being forced to search for a doctor willing to consider treating her for Lyme disease [Some of the most common media stories concerning Lyme disease in New Brunswick, Nova Scotia and PEI surround individuals who have struggled to find treatment for symptoms they attribute to Lyme disease . The comresolved . An arti disease . All of Media reports also illustrate the significant divide that exists between the majority of the medical community, patients and patient advocates. Ubelacker illustrates this debate concerning the number of Lyme disease cases in Canada quoting Harvey Artsob, the Director of zoonotic diseases at the Public Health Agency of Canada, that, annually, there are between 20 and 60 cases of disseminated Lyme disease every year. The Canadian Lyme Disease Foundation has argued that, in reality, the infection rate was between 2000 and 20,000 cases, demonstrating the vast gap between the two positions . An Act respecting a Federal Framework on Lyme Disease, introduced in 2011 and entered into law in December 2014, illustrating the potential shortcomings of patient advocacy [Anne Kingston also focuses on this tension, in particular how patients increasingly attempt to have a say in their own treatment . She notadvocacy . OverallIncreased media and public attention and academic scholarship has resulted in some government action. The Canadian federal government and the Maritime provinces, except PEI, have released similar policy statements and developed broad frameworks to address Lyme disease. Provincial efforts are at times limited and refer individuals back to federal initiatives such as in New Brunswick’s case. These frameworks typically note that Lyme disease is on the rise and projected to continue expanding and, in the federal government’s case, that Lyme disease became a nationally notifiable disease in 2009 ,43. To sFederal Framework on Lyme Disease consists of surveillance, education and awareness, as well as guidelines and best practises [Tick Borne Response Plan 2018, the Nova Scotia Department of Health and Wellness is charged with surveying and reporting on areas with tick populations [New Brunswick Lyme Disease Strategy 2017 has the same core aspects concerning surveillance and public education, while referencing a medical practitioner survey in creating an informational document to reinforce best practises [Canada’s ractises . The govulations . It is aulations . The Newractises . The outractises . PEI is Statement for Managing Lyme Disease in Nova Scotia which illustrates how NS favours conventional approaches supporting the current CDC-endorsed two-tier testing method and the current treatment of antibiotics, stating that 95% of Lyme disease cases are cured via short-term antibiotics [Government efforts have not been well received by patient advocacy groups. Tension surrounds the current testing protocol and guidelines regarding Lyme disease diagnosis and treatment (use of short-term antibiotics). Government action plans seem to reinforce practises that advocacy groups contest. This is exemplified in the ibiotics . It alsoibiotics . Such anibiotics . Strang’ibiotics .New Brunswick Lyme Disease Strategy acknowledges that Lyme disease has become a political issue with advocacy groups working to have patient experiences heard and advocating for better diagnosis and treatment [Overall, the grey literature illustrates some of the shortcomings of the current approach to Lyme disease. Governments have accepted the wide range of scholarship, which indicates a dramatic rise in ticks and Lyme disease that is projected to continue. Frameworks and action plans have been created and, in the case of the federal government, funds have been allocated for Lyme disease research. However, governments have also strongly sided with the majority of the Canadian medical community, reinforcing the current approach to Lyme disease. Even so, some do recognize the tension between patients and the medical community. For example, the reatment . Yet, goOur study focused on Canada’s Maritime Provinces—New Brunswick, Nova Scotia, Prince Edward Island—and relied on two surveys see  designedFor the purposes of this research, the conventional  Canadian health care system refers to Canada’s publicly funded health care system. Treatment outside of this system, such as unauthorized medical visits to the United States, is considered as an alternative to Canada’s conventional health care system.Two electronic surveys were designed for distribution using Survey Monkey, a web-based survey company located in the USA. Survey Monkey was used due to its minimal cost and ease of use. The surveys combined questions offering a range of answers for participants to answer using a Likert scale, questions that asked them to rank a series of choices, and questions to select a particular choice . The first survey focused on family physicians and nurse practitioners given they are the first point of contact for patients. Questions probed their perceptions of Lyme disease, general knowledge, professional approach to the disease, and how to improve services. The second survey was sent to provincial politicians and government health officials such as public health officers, deputy ministers, directors and policy analysts. Questions for these individuals also probed their general knowledge and perceptions of Lyme disease, and also probed a political party’s stance on Lyme disease and existing government policy. Questions regarding diagnosis and treatment options were only present in the family physicians and nurse practitioners’ survey. Lastly, the survey was translated in French by the co-author, Mario Levesque, a native Francophone, for administration. This is important given the sizable population of Francophones in New Brunswick at 31.6% 232,450 people) with smaller populations in Nova Scotia  and PEI   people w. Once doThe identification of survey participants and, in particular, obtaining contact information (e-mail addresses) was challenging. This was especially the case for family physicians because while their telephone and facsimile numbers were listed on provincial health websites, e-mail addresses were not. To address this, a multipronged approach was used. First, a facsimile campaign was used for family physicians who were targeted based on their area of practise in relation to tick populations. Hence, for New Brunswick, the contact information for all family physicians was gathered for Health Regions 1 (Moncton/Southeast area), 2 (Saint John/South-West), and 6 (Bathurst/Northeast). The contact information for Region 4 (Edmundston/Northwest area) was also gathered as a potential control region, as tick populations are comparatively low in this region. Nova Scotia’s health system is not based on a regional system so certain geographic areas were selected to act in a similar fashion given known high tick populations. The first area included Halifax, Dartmouth, and Bedford; the second included Yarmouth, Shelburne, and Liverpool in the province’s southwest; and the third area included Pictou, Trenton, New Glasgow, and Antigonish (Northeast). Finally, for PEI, due to its smaller population  and geoAdmittedly, a fax campaign is not the best approach given current technology with e-mail communication being the norm. We surmised that few family physicians would respond to a facsimile and were proven correct as only four (4) responses were received. Initially, we had tried to directly call the offices of family physicians to obtain their e-mail address, so we could forward them our information directly, but these efforts were futile as the vast majority of doctors’ offices claimed to either be uninterested or to rely primarily on fax as opposed to e-mail. We questioned this yet decided to proceed with the fax campaign, which had its own challenges. It was time consuming and more problematic was the fact that individuals were not able to simply click a hyperlink for the survey but would instead receive the fax and, to complete the survey, had to manually type in the survey URL from the fax. No doubt this had a negative effect on the response rate from family physicians.To increase the response rate, provincial medical associations were contacted via e-mail and asked if they could forward the information letter and survey link to their members. This included all three nurse practitioners’ associations in the Maritimes, Doctors Nova Scotia and all three provincial Colleges of Family Physicians. All three nurse practitioners’ associations agreed to forward our materials to its members as did the New Brunswick and Nova Scotia Colleges of Family Physicians. Doctors Nova Scotia declined to do so while there was no response from the PEI College of Family Physicians. In addition, the survey was broadened to include the rest of Canada and was forwarded to various health professional associations for distribution to its members. For example, the Registered Nurses Association of Ontario endorsed our survey and distributed it to its members.For provincial politicians and government health officials, obtaining their contact information was straightforward via government websites. In terms of government officials, individuals were largely selected from within the provinces’ Departments of Health based on their role including public health officers, deputy ministers, directors and policy analysts. This worked well for New Brunswick and PEI, but Nova Scotia’s website was less user friendly, which in turn resulted in less contact information for Nova Scotian government officials and therefore less officials selected for the province as shown in In total, the provincial politicians and government health officials survey was sent to 152 individuals across the Maritimes with nine (9) completed surveys for a response rate of 5.92% which is considered low. Of the nine completed surveys, 4 were from NB, 4 from NS, and 1 from PEI. The family physicians and nurse practitioners survey was distributed to 1833 family physicians  via facsimile or through their associations. It is unknown if it was distributed to family physicians in PEI (102) by its College of Family Physicians as noted above but it was faxed to half of them. In addition, it was distributed to 286 nurse practitioners via their provincial associations . All told the survey was distributed to 2171 family physicians and nurse practitioners with 40 surveys completed (4 in response to the fax campaign), and all 40 completed surveys were from family physicians . This represents a response rate of 1.84% which is very low. This brings up a host of questions related to the response rate. First, a fax campaign is not a good method for survey administration given the state of technology as previously discussed. Second, the medical professions are a closed network making it very difficult to access and gain participation, especially for social science researchers. Still, two of the three Colleges of Family Physicians  did agree to distribute our survey as did the nurse practitioners’ associations, which helped especially since the fax campaign led to poor results. Even so, soliciting participation via association newsletters is not the same as directly contacting someone. A third issue was the time of year the survey was administered—late June and July 2018, summer months—with July especially being a time of the year when many people typically take holidays. This was hard to avoid since the project began 1 May 2018 and had to be completed by 31 August 2018. Time was required to draft the ethics proposal and to obtain research ethics approval (granted at the end of May 2018). No doubt the time of year contributed to the lower response rate. Lastly, the Office of the Chief Medical Officer of Health for New Brunswick in conjunction with the New Brunswick Medical Society completed a survey on Lyme disease exploring physicians’ clinical experience and management of the disease in 2016 . While tThree key points emerged for the surveys concerning the prevalence and knowledge of Lyme disease and government action. First, in terms of prevalence and shown in However, knowledge of Lyme disease’s prevalence did not translate into a significant topic of discussion for respondents. As shown in Second, in terms of knowledge about Lyme disease, 92.7% of family physicians and 88.9% of political leaders and government health officials claim to have ‘moderate’ to ‘a lot of knowledge’ on Lyme disease . When asLastly, questions arise on the effectiveness of government actions to date, which is important in the context of this research. When asked to rank options provided in response to the question, “Which of the following could politicians do to improve how Lyme disease is addressed?”, the top three responses by family physicians were to ‘defer to medical experts’, ‘fund Lyme disease education among health care providers’ and ‘increase public awareness’ as shown in Federal Framework on Lyme Disease had resulted in either ‘no changes’ or had not played a role in any change to approaching Lyme disease. Furthermore, 58.6% of family physicians feel that increased federal funding to Lyme research had not affected their approach to Lyme disease, while 77.8% of provincial political leaders and government health officials had also felt no affect. This ultimately brings into question the value of current federal and provincial government approaches to Lyme disease as some of their key priorities included educating and implementing best practise guidelines among physicians who many had felt were not properly educated in terms of Lyme disease. However, the majority of responding family physicians in New Brunswick, Nova Scotia and PEI have not been affected by these government efforts. While identified policy options have been established as priorities by governments, most family physicians do not feel these efforts have influenced their approach to Lyme disease. For example, 82.9% of medical professionals and 100% of political leaders and government health officials felt that the The survey findings demonstrate debates prevalent in the literature are also prevalent within the Maritimes: Many are unhappy with the current medical practises, the media is critical of the health care system, and a significant portion of family physicians feel their patients are misinformed . FurtherThe survey results also identified the minimal effectiveness of government policies and action plans. For example, political leaders and government health officials noticed no change in how the disease is approached, meaning there could not have been noticeable changes in the realm of education, surveillance or public awareness. This is important because it is patients and patient advocates that argue that family physicians are poorly educated about Lyme disease. The fact survey results highlight family physicians have not changed their approach to Lyme disease given government actions is concerning. We question whether this is ineffective government action or whether there is a time lag effect at play. That is, government Lyme disease frameworks, policies and action plans are relatively new, most within the last decade, and more time is needed for their effects to be realized. One of the biggest blockages remains current best practise guidelines for the diagnosis and treatment of Lyme disease. The much-debated guidelines dictate the diagnosis process stating that an individual can only be diagnosed clinically if the patient shows a bull’s eye rash and had plausible exposure to an area with known tick populations. If they are showing specific symptoms and do not have a rash then the two-tiered serological testing is undertaken . This prSimilarly, the debate surrounding chronic Lyme disease and the length of antibiotic treatment is linked to the guidelines, as antibiotics are to be kept under a month . These gUnderstanding the relationships between problems, policies and politics (decision-making) remains crucial and is at the heart of John Kingdon’s multiple streams framework of policy making, which is used below to assess the politics of Lyme disease ,59. KingThree processes are at the heart of the multiple streams framework. Problems are issues in need of attention. They come into focus based on indicators that measure conditions, due to focusing events, or through the study of issues. The increased spread of ticks and cases of Lyme disease along with more people seeking treatment outside of the Canadian health care system are problems in need of attention. Policies are ideas for how to address identified problems. Ideas are plentiful and vary depending on the stakeholder, with few seriously considered by decision makers because of time and institutional constraints, among other things. Lastly, politics refers not only to the individuals involved in the policy process (and their turnover), but also to the broader set of groups  exerting pressure for change as well as to the political climate within which they operate .The key to policy making in the multiple streams process is the coupling of problems, policies and politics. All three need to come together for an issue to be addressed, and this is where much of the randomness occurs. For example, problems and policies coming together in an inhospitable political climate will go nowhere. For the three streams to come together, a window of opportunity must open for coupling to occur. These can be random opportunities, such as a favourable minister or deputy minister entering the decision-making process or a change in attitudes of family physicians for the diagnosis and treatment of patients. Alternatively, windows of opportunity can be regular, such as through yearly budget consultation processes or regular elections. The coupling of the streams also needs to be facilitated by policy entrepreneurs. These are highly skilled individuals attuned to the political climate and cognizant of existing problems and policies. With their substantial resources, they can bring the streams together by crafting an acceptable framework for stakeholders to support.The multiple streams framework is useful for assessing decision making by considering the randomness and ambiguity involved in the process . It is uOne of the main issues is defining the problem itself. There has been little convergence between the medical community, patients and patient advocates on how to address outstanding issues. The medical community generally does not see Lyme disease as anything other than an emerging disease. Defining the problem in this manner places an emphasis on tracking tick populations and keeping track of endemic regions. However, much of the discontent that has been cited in the media, as well as some scholarship , surrounDiffering perspectives on the problem of Lyme disease is also evident in the current policy on Lyme disease. These policies seem to be addressing the fact that tick populations, and by extension Lyme disease, are on the rise and are predicted to continue. This reflects government policy aligning with public health researchers, who emphasize endemic regions and the expansion of tick populations. This is reflected in the focus on tick surveillance and minimal policy addressing the main concerns of diagnosis and treatment. Furthermore, most experts who inform policy stand by the current protocol as being the safest option for Lyme disease, making it even less likely that policy would touch on the concerns of patients and patient advocates. Even as the politics stream may be slightly in favour of patients and patient advocates at the moment, the problem remains unsettled thereby undercutting needed policy actions from emerging. In short, the three streams are out of alignment.There are some factors that could affect this gridlock as multiple streams theory claims that events may bring a problem to the forefront of the policy agenda or change how the issue is perceived. In terms of a potential crisis, Eastern Canadian tick populations may expand to 80% of human inhabited areas by 2020 . Such ciFor a policy entrepreneur looking to push policy that addresses the current clinical guidelines concerning Lyme disease, one of the first actions would be to change the perception of this issue within the medical community. Admittedly, this may have to happen internally given the resistance of the medical community to outsiders, yet we note the gradual increase of patient voices in research and meetings as a positive trend to that end. Policy entrepreneurs can also seek to address the source of the Canadian guidelines given they were not created domestically but by the Infectious Diseases Society of America (IDSA) and Centers for Disease Control (CDC) . We noteWhile a critical focus on the CDC may help change the perception of Lyme disease among experts, there would still need to be general agreement in terms of a policy option. These options often must adhere to the general norm and tendencies of the government to help in it being perceived as reasonable . ConsideThis project examined the current state of Lyme disease within Canada’s Maritime provinces  from a political perspective, a subfield that is still relatively new to the study of Lyme disease. It identified the ongoing debates concerning Lyme disease in the literature and, through surveys, revealed their prevalence in the Maritime provinces. Given the study’s low response rate, the findings should be considered exploratory and not conclusive. They are nonetheless valuable given it is one of the first attempts to think critically about Lyme disease policy in the region. Ultimately, Lyme disease is a Pandora’s Box of debates and ambiguity. Both the medical community and patient advocates do not seem poised to make any concessions soon. However, a considerable amount of scholarship is projecting the dramatic spread of tick populations to continue, suggesting that cases of Lyme disease will only continue to grow. Whether you agree with Lyme disease patients and patient advocates or not, when over half of the family physicians responding in our survey were aware that they have patients seeking treatment in the U.S., something must be wrong with the current diagnosis and treatment options in Canada. As advancements in diagnostic and or treatment technology still seem to be years away, action is needed to address the concerns of patients, patient advocates and former Lyme patients as their numbers are only projected to grow. Our recommendation of an independent Commission of inquiry that brings together government officials, medical professionals, patients and patient advocates is a reasonable way of fostering understanding and exploring policy options.


Before a test can be used in the target population, it is necessary to demonstrate that there is measurement equivalence. One way to do this is by studying differential item functioning (DIF).In this study, we used the Mantel–Haenszel procedure and logistic regression to analyze DIF in the Spanish version of the Verbal Selective Reminding Test between Spaniards, Mexicans, and Hispanics in the United States.n = 211), Mexico (n = 201), and the United States (n = 205)]. A six-trial version of the Spanish version of the Verbal Selective Reminding Test was administered and scored according to standard procedures.Three balanced samples, matched by age, education, and sex, were studied: Spaniards, Mexicans, and Hispanics [616 healthy participants from Spain (pollo showed DIF: the Mexicans and Hispanics outperformed the Spaniards, holding a total score constant. The item oído also showed DIF and was remembered in greater measure by the Spaniards.Statistical analysis showed some DIF between the samples of Spaniards, Mexicans, and Hispanics. A bootstrap validation of results confirmed that the item The Spanish version of the Verbal Selective Reminding Test can be used with Hispanic populations. In recent years the Hispanic/Latino population has been increasing, both in absolute terms and as a percentage of the total population of the United States. The most recent census data indicate that the figure is already over 59 million, which is more than 18% of the United States population . This percentage is even higher if we include those who are unregistered, a population that has been estimated at 11.2 million . Most ofThe neuropsychological assessment of this population in the United States poses a challenge for professionals as special training that takes multicultural aspects into account is necessary before the assessments can be successfully carried out . For a lMost of the tests available for the English-speaking population in the United States cannot be considered suitable for the assessment of the Hispanic groups who live there . The samVarious studies have revealed the differences found in the adaptation of the Mini Mental State Examination (MMSE) test. It has been found that the “no ifs, ands, or buts” item is usually easier for some Spanish-speaking populations , althougStudies on DIF in neuropsychology with Spanish–American populations are extremely rare or non-existent. Only the MMSE has been studied in any depth, comparing Hispanic and English-speaking populations . DIF wasThere are several methods for assessing DIF . The maiThe present study applied methods that allow comparisons to be made between more than two groups and do not require excessively large sample sizes, namely the generalized Mantel–Haenszel (GMH) procedure and generalized logistic regression (GRL). The Mantel–Haenszel (MH) procedure is one of the most popular techniques for studying DIF because of its computational simplicity and its capacity for detecting DIF with small samples .Mexicans) and Mexicans who are resident in the United States (Hispanics). The hypothesis to be tested was that there was no DIF between the different populations.There are currently no studies indicating whether the Spanish version of the VSRT can be used with Hispanic populations. The objective of this study, therefore, was to examine whether DIF was present in the Spanish version of VSRT when applied to two Hispanic populations: Mexicans living in Mexico  = 0.33, p = 0.84]. There were no significant differences in age  or educational level  = 0.526, p = 0.591]. Subjects were excluded if they fulfilled any of the following criteria: (1) history of neuropathology; (2) hospitalization due to psychopathological disorders ; (3) history of abnormal psychomotor development; (4) history of drug or alcohol abuse; (5) taking psychotropic medication that affects attention and concentration or causes sleepiness; (6) mother tongue was not Spanish. The three samples included some students. Researchers made an effort to obtain data from both rural and urban areas. The raw data are available upon request from the corresponding author.Three balanced samples, matched by age, education, and sex, were studied: Spaniards, Mexicans, and Hispanics  consisted of a total 201 adult and adolescent volunteers, selected in the city of H. Matamoros, Tamaulipas. The type of sample used was intentional, selecting those subjects who agreed to participate in the study and who met the same inclusion criteria as the sample of Spaniards but had Mexican nationality. The selection of the subjects was carried out by searching for the same percentage of men and women of similar ages and educational levels as the Hispanic sample.The sample of the second focal group consisted of 205 adult and adolescent volunteers, selected in Brownsville, Texas. The sampling was intentional, selecting those subjects who agreed to participate in the study and who met the same inclusion criteria as in the previous samples. They also had to be of Mexican origin, live permanently in the United States, and have Spanish as their mother tongue. The Spanish version of VSRT form 1 was used to carry out this research . A questThe VSRT is one of the most widely used to assess verbal learning and memory . It has A Spanish version of the VSRT has been developed and there is some evidence of its reliability and validity , with siDado (Dice), Cinta (Ribbon), Norte (North), Jarro (Jug/Pitcher), Pollo (Chicken), Frente (Forehead), Llave (Key), Cruz (Cross), Fuego (Fire), Pena (Pity), Modelo (Model), Oído (Ear). After administering the six learning trials, multiple choice recognition trials were conducted. Twelve separate white index cards were presented to the subjects. Each card consisted of a list word and three foils . The participants were asked to identify the list word.Spanish Form 1 consisted of 12 unrelated words: A single delayed-recall trial was given without prior warning 30 min after completion of the multiple-choice recognition trial. The interval was filled with other neuropsychological tests that did not involve memory. After the free delayed-recall trial, the multiple-choice recognition trial was conducted again. The six-trial version of the test was administered according to the procedure described by The tests were administered in private rooms with the least possible noise to distract individuals. The tests were performed individually with each subject and took 50–60 min on average to complete. The first activity in the evaluation process was to obtain the participants’ informed consent. A written form was devised that explained the general study objectives, procedures, implications for participants, and so on. The same consent form was given to each subject of the study to read carefully and, once concluded, any doubts that may have arisen during reading were clarified. Once read and signed, both the examiner and the assessed proceeded to the evaluation. For subjects under the age of 18, the informed consent of the parents or guardians was required. The ethics committee of the University approved the study.difR library was used for DIF analysis  method was chosen]. Lastly, model validation was performed using the boot and boot.ci function to calculate the confidence intervals for the statistical estimates. The Nagelkerke function of the fmsb library was used to calculate the R2 statistic for the logistic regression models.Statistical analyses were performed with the R program v. 3.3.0 . The difanalysis . The genanalysis . The difp adjusted < 0.05) was present in the items dado, pollo, cruz, pena, modelo, and oído.pollo showed significant DIF when only p-values were considered. However, using ETS criteria based on effect size, two items appeared with a high DIF score: dado and pollo.pollo.pollo and modelo displayed significant DIF, which also showed fairly large DIF using the ETS criteria. It is interesting to note that the item pollo was used more frequently by the Hispanic population than by Spaniards.After comparing Spaniards with Hispanics, the items modelo showed moderate DIF using ETS criteria.When the results of the Mexican and Hispanic samples were compared, significant DIF was not present in any item. Only the item dado, pollo, cruz, pena, modelo, and oído also displayed DIF. Nevertheless, when the effect size criterion (Nagelkerke’s R2) proposed by oído) presented moderate DIF. This criterion is the one recommended in the literature  and the degree of DIF according to the effect size criterion  were recorded. DIF was considered to occur when there were significant differences (p < 0.05) and an effect size of B or C.In order to try and resolve the discrepancy between the MH and GLR procedures, we decided to validate them using the pollo and oído. Nevertheless, neither of the two methods showed DIF for the item modelo (only 3.9% of simulations found significant differences and DIF B using the MH technique and 0.4% using GLR).The results obtained confirmed that the methods showed discrepancies for the occurrence of DIF in two items: Neuropsychological assessments in different countries generally makes use of tests that have been standardized for other populations. It is common practice, therefore, to use neuropsychological tests devised for native English speakers and translated into other languages in order to evaluate populations of Hispanic origin . This isIn the present study, we evaluated the possibility of using form 1 of the Spanish version of the VSRT on Mexican and Hispanic populations, since we already have normative and validation studies of the test on Spaniards. The results show that there were very few differences between the responses of the Mexican and Hispanic populations. This can be interpreted as the Hispanic populations of Mexican origin maintaining their cultural references in spite of being immersed in a different culture. The first conclusion that can be drawn from our study, therefore, is that the normative data of Mexican populations may be valid for the neuropsychological evaluation of Hispanics resident in the United States, at least for the verbal memory test used here and for Hispanic populations of Mexican origin. In future studies, it would be interesting to determine whether these conclusions can be extrapolated to other Hispanic American populations resident in the United States and in their countries of origin. It should be pointed out that, at least for the evaluation of verbal memory, there is a test available that allows the neuropsychologist to evaluate clients of Hispanic origin with greater reliability and increased diagnostic sensitivity. Using tests that do not meet these requirements implies obtaining measurements that do not represent the true ability of the individual.pollo and for pollo/modelo when the samples of Spaniards and Hispanics were compared. For the item pollo, the percentage of responses was favorable for the Mexican and Hispanic populations. This could be explained as a greater presence of this item at the cultural level in these populations and is consistent with the result indicated earlier that the two populations share the same cultural referents. Nevertheless, the same results were not found using the LR test or in the validation study. Various authors have pointed out that the MH technique tends to increase the percentage of false positives  for which the validation study did not present conclusive results. In the case of the MH technique, the most plausible conclusion is the presence of DIF . If the results obtained with the LR method are taken into consideration, the conclusion would favor the absence of large DIF for these items. Nonetheless, considering the worst case (presence of DIF), the test remains valid for studying Mexican and/or Hispanic populations since the two items that display DIF have a compensatory effect. In one case it benefits the population of Spaniards, and in the other the Mexican or Hispanic populations. Some authors have contemplated the possibility of keeping items that present DIF in the test when there may be a compensatory effect between the groups, as in this case (Likewise, for the item his case .It may be concluded, therefore, that the evidence of a high degree of DIF when comparing populations of Spaniards, Mexicans, and Hispanic Americans is inconclusive and that any possible DIF has a compensatory effect. The normative data obtained for the population of Spaniards  can be cNevertheless, these conclusions should be interpreted with caution since the sample sizes used make it impossible to detect items that display low or moderate DIF when the MH technique is used. Future research should be directed at studying further the existence of DIF between these and other Latin-American populations by increasing the size of the samples. Similarly, it would be interesting to expand the range of populations to include individuals from other South American countries.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by the University of Seville. Written informed consent to participate in this study was provided by the participants’ and their legal guardian/next of kin where appropriate.MM-O contributed to the conception and design of the study, performed the statistical analysis, and wrote the first draft of the manuscript. FP-C collected data, organized the database, contributed to the manuscript revision, and read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The emergence of new technologies for genetic modification has broadened the range of possible new products. The regulations of many countries that could benefit from these new products may not be prepared to assess risks and enable science-based decision-making. This is especially acute in the case of genetically modified insects with potential use in public health and agriculture. Modifications of the regulatory framework, sometimes necessary to allow a proper risk assessment of products from new technologies, are strongly influenced by political decisions derived from the balance of power and interest among stakeholders. This article discusses the genesis of the Brazilian regulatory framework, its applicability for the risk assessment of genetically modified insects and the scenarios that have shaped the two biosafety laws that established the basis for the use of modern biotechnology in the country. It is concluded that, for the adoption of the new technologies, it is important to carefully navigate the political tensions by seeking the engagement and empowerment of stakeholders supporting science-based decision-making in order to gather the necessary support for adoption of risk assessment as the basis for final decisions, allowing the use of new technologies. Its main responsibilities are outlined in Table Like many other countries, Brazil has adopted a technology-based approach to regulate GMOs . In 1995http://www.planalto.gov.br/ccivil_03/decreto/1995/D1520.htm) and its decisions, primarily based on risk assessment, cannot be overturned by any other instance or legislative body except the National Biosafety Council (CNBS), composed of 11 State Ministers. Even this Council may only argue based on social or economic issues directly linked to the intended commercial use of the new GM product. However, if new hazards or damages are identified by any third party, they can be reported to CTNBio, which must reassess the product and, if non-negligible risks are identified, act accordingly.CTNBio is an entity composed of representatives from all five relevant ministries (Both the Council (CNBS) and the Committee (CTNBio) integrate a network including regulation/enforcement agencies and local institutional Internal Biosafety Committees – CIBio Fig. . MoreoveBrazil was one of the first countries to embrace agricultural biotechnology. Following a then prevailing international trend of regulating the technology, instead of the product, in 1995 the country produced a new specific law on the use of transgenic organisms and adapted the existing legal framework to assess GMO risks and pave the road for the adoption of agricultural biotechnology.http://www.planalto.gov.br/ccivil_03/leis/L8974.htm). This, in turn, created unsurmountable conflicts of authority [Regulators and scientists then faced the difficult task of weaving the first GMO regulatory framework in a complex scenario, with very vocal stakeholders against biotechnology, a populist government and a general lack of experience in dealing with GMOs . The Brade facto moratorium, disqualifying CTNBio’s decisions and requiring an overly complex and onerous process for the approval of commercial releases of new GMOs [By exploring the existing legal conflicts in the regulatory framework, the GMO opposition was able to halt the release of the sole GMO approved for commercial release by CTNBio in 1998, a genetically modified soybean variety, and establish a new GMOs , 4.A new strong stakeholder was decisive in reversing the moratorium: the soybean growers of Southern Brazil. As depicted in the stakeholder maps from Fig. https://bch.cbd.int/about/countryprofile.shtml?country=br). The progressively larger adoption of GM plants, the lack of any evidence of negative environmental impact or health damage due to the planting and consumption of GM plants and a wider and more influential participation of the scientific society in the debates around GMOs and stem cells [By 2004, the legal conflicts in the regulatory framework were considered to be unsurmountable [em cells  contribuAedes aegypti was considered safe by CTNBio in 2014 [The adoption of both agro- and industrial biotechnology has progressed immensely ever since in Brazil, with the adoption of GM products for many different applications, such as cellulose production, second-generation ethanolic fermentation, vaccines, diagnostics and recently, vector control. Indeed, the transgenic OX513A  in 2014  and is cThe step-by-step approach to GMO risk assessment was developed in the last 20 years, building on the experience of many specialists, and is largely accepted –10. The http://ctnbio.mcti.gov.br/resolucoes-normativas) regulates the unconfined commercial release of GMOs and is structured as a primary general part, followed by a set of annexes with specific questions needed to assess food and feed safety (Annex III) and environmental risks (Annex IV). This last annex has specific questions aimed towards organisms used for biological control (item E) and invertebrates (item I). The use of question lists, while providing some legal certainty to the applicant and helping in the identification of possible hazards, rigidifies the risk assessment. Aware of this limitation, CTNBio exercises its right to add appropriate questions for each new risk assessment and, likewise, exempts the applicant from responding to questions that do not apply to the GMO being evaluated.Although transgenic plants were the main subjects of the first risk assessments, animals, bacteria, protozoa, fungi and viruses were also regarded as potential organisms to be assessed, and this allowed the accommodation of specific questions relative to different taxa in the broad risk assessment procedure. In the Brazilian regulatory framework, Normative Resolution nr. 5  regulating confined releases were of little help with this concern. However, as the genetic construct inserted in this GM mosquito determines its death and that of its offspring, the commission considered the dispersion to be very limited due to the short life span of the insects. Although a few insects escape the lethal mechanism in the first generation, they are very unlikely to do so in the next generation and the chances of dispersion are very low, even in the absence of any physical barrier. A similar approach may be used to any self-limiting GM insect, both for vector or for pest control.When assessing OX513A Aedes in the unconfined release risk assessment phase, but most plausible hazards came from the regular assessment of the context, as determined by the application of the same risk assessment guidelines used for other GMOs. Similarly, plausible hazards from other GM insects will possibly derive in a straightforward way from the application of the regular risk assessment guidelines.Specific questions from Annex IV were of some help to derive possible hazards associated with the transgenic Aedes, it is likely that non-biosafety issues will be brought to the forefront by stakeholders opposed to other GM insects . This is a common strategy in many fora and a well-delineated regulatory framework can avoid mixing issues relevant to risk assessment with those important in other contexts . Brazilian legislation requires that the risk assessment of GMOs be the exclusive attribution of CTNBio, while economic and social issues must be addressed by the various ministries that will register and supervise the use of the new product or by the National Biosafety Council (CNBS). This strategic separation prevents CTNBio from having to discuss and take into account aspects that are not directly related to biosafety in its technical decision. On the other hand, the separation leaves the market, the regulatory agencies or the CNBS with the economic, social, political or religious decisions.As with the discussion surrounding the approval of planned releases and the commercial release of the GM Transparency and other issues of risk communication must be thoroughly assessed and the success of a commercial application for a new GM insect will strongly depend on how the different stakeholders will access the information. Reeves, et al.  suggest A. aegypti field releases back in 2011–2012 and is currently unfolding as a successful strategy in the mass releases for A. aegypti control in Piracicaba, Brazil [Moreover, the technology developer must act accordingly and should bring to the public the largest possible set of useful information in accessible language to gather the public cooperation and reduce mistrust. This was effectively done in Brazil during the GM The recent discovery of new ways to efficiently edit genomes of many organisms, including insects, coupled with the insertion of gene drives in the newly edited genomes, opened a whole new field of applications for both genome editing and gene drives –15. VectGene drives, however, are such powerful tools that they immediately raised concerns among a wide range of stakeholders, including scientists, activists, politicians and health managers –21. The Anopheles gambiae in an African environment, do not pose important risks either to the environment or to human health [For risk assessors, however, gene drives can be considered as genes having an increased non-Mendelian transmission rate, usually approaching 100%. All other aspects are similar to regular genes. Indeed, using the regular approach for GMO risk assessment commented above, a group of scientists and regulators came recently to the conclusion that gene drives for population substitution or population reduction, when applied to n health . A similThe 2005 Brazilian Biosafety law defines what qualifies as a GMO. As many other former legislations, the Brazilian law and its decree regulate genetic engineering (GE) products, which should contain a transgenic DNA either in its genome or in extrachromosomal plasmid or in an organelle. Although the GE definition is rather ample, encompassing most new techniques, the constraint imposed by the presence of a new transgenic DNA could exclude certain products from CTNBio’s assessment, such as those created by genome editing, potentially generating a limbo for many new products. In fact, there seems to be a consensus among Brazilian scientists that not all products derived from the new breeding technologies (NBTs) should be regulated and assessed before being released, especially if they do not contain “foreign” DNA or RNA. CTNBio can, by law, decide how to resolve omissions in its normative resolutions - and has often acted accordingly - in the assessment of genetically modified organisms. Therefore, it has the necessary tools to reach and apply its internal consensus to NBTs in a consistently science-oriented manner.In conclusion, the authors would like to emphasize that the genesis of an efficient regulatory system naturally depends on a balance of forces between those interested in modern biotechnology and those opposed to it. If pro-biotech players are the determinants of the regulatory process, it will probably be based on risk assessment recommendations. If, on the other hand, the opinion of the opposition group prevails, socio-economic issues will be placed side-by-side in the risk assessment process, which confuses the risk assessor and leads to frequent deadlocks. However, irrespective of the many methodological approaches to GMO risk analysis, at the end of the day it is often political will that determines GMO regulatory processes .


Background: Evidence-informed deliberative processes (EDPs) were recently introduced to guide health technology assessment (HTA) agencies to improve their processes towards more legitimate decision-making. The EDP framework provides guidance that covers the HTA process, ie, contextual factors, installation of an appraisal committee, selecting health technologies and criteria, assessment, appraisal, and communication and appeal. The aims of this study were to identify the level of use of EDPs by HTA agencies, identify their needs for guidance, and to learn about best practices.Methods: A questionnaire for an online survey was developed based on the EDP framework, consisting of elements that reflect each part of the framework. The survey was sent to members of the International Network of Agencies for Health Technology Assessment (INAHTA). Two weeks following the invitation, a reminder was sent. The data collection took place between September-December 2018. Results: Contact persons from 27 member agencies filled out the survey (response rate: 54%), of which 25 completed all questions. We found that contextual factors to support HTA development and the critical elements regarding conducting and reporting on HTA are overall in place. Respondents indicated that guidance was needed for specific elements related to selecting technologies and criteria, appraisal, and communication and appeal. With regard to best practices, the Canadian Agency for Drugs and Technologies and the National Institute for Health and Care Excellence  were most often mentioned. Conclusion: This is the first survey among HTA agencies regarding the use of EDPs and provides useful information for further developing a practical guide for HTA agencies around the globe. The results could support HTA agencies in improving their processes towards more legitimate decision-making, as they could serve as a baseline measurement for future monitoring and evaluation. Ethical issues in particular are left unaddressed, thereby compromising the legitimacy of eventual decisions. The call for a more integrative perspective on HTA aligns with evidence-informed deliberative processes (EDPs) that were recently introduced to support HTA agencies in organizing legitimate processes.3 Although the use of EDPs is relatively new, deliberative methods have been developed and used to some extent in the field of HTA since the 2000s.9Health technology assessment (HTA) is used to inform decision-making, such as coverage-decision making, and is described as a process that includes governance and structure, scoping, assessment, appraisal and implementation and monitoring.11 EDPs are based on rational decision-making through evidence-informed evaluation of identified relevant values  as well as fair decision-making (as reflected in the accountability for reasonableness approach – A4R). The underlying premises of the EDP framework are: (1) that involvement of relevant stakeholders to identify, reflect, and learn about the meaning and importance of relevant values and questions, and (2) an evidence-informed evaluation of the identified values (criteria), can contribute to the legitimacy of recommendations and/or decisions by improving the quality, consistency and transparency of the HTA process.EDPs draw on this earlier work and provide a structured process in which stakeholders participate throughout the HTA processto identify criteria for the selection of health technologies and assessment, to interpret forthcoming evidence, and to deliberate on recommendations and decisions.11 Several approaches undertaken by these agencies rely on deliberative processes, for example regarding identifying topics for HTA and how to appraise health technologies. These agencies may serve as inspiration for others, especially those who have recently formally set-up their HTA practice , but they can also improve regarding certain components.3Some HTA agencies already have several of these components in place .12 In this practical guide, we describe the EDP framework that consists of 5 steps and contextual factors for HTA development .13 The way in which these steps can be applied in a specific country or region depends on the context, and therefore is not meant as a blueprint.We defined the core elements of each step on the basis of our previous work in this field,To identify the level of use of EDPs by HTA agencies, and to further develop the guide to support HTA agencies, we felt it was important to collect views and experiences from HTA agencies around the globe. We therefore conducted a survey among INAHTA member agencies to identify the current level of use of EDPs, identify the need for guidance regarding elements of the framework, and to learn about best practices. In this article, we present the main findings from the survey.A questionnaire for a semi-structured online survey was developed based on the EDP framework, consisting of elements that reflect each step of the framework and the contextual factors for HTA development. We also asked respondents to list any element that they felt was missing and for best practices regarding each part of the framework. The questionnaire is provided as We contacted the INAHTA secretariat for supporting us in contacting their members. INAHTA is a network of 50 HTA agencies that support health system decision-making in 31 countries around the globe (2018 figures). The INAHTA secretariat provided consent and agreed to send an invitation to participate in the survey to their members through email. Two weeks following the initial invitation, a reminder was sent by the research team, targeting the contact persons as listed on the INAHTA website, which is publicly available. A second reminder was sent 2 weeks after the first reminder. The data collection took place, using the online tool CheckMarket, between September-December 2018.In the introduction to the survey, we made clear that all answers were treated confidential, ie, no attribution would be made to specific persons. Two survey respondents explicitly wished not to disclose their affiliation. Therefore, we provide the results anonymously, presenting the main results and highlighting specific areas that were felt to be in need of guidance. We used basic descriptive statistics , derived from the CheckMarket tool, to summarize the findings.15 In addition, the distribution of HTA agencies providing responses, per region can be considered a representative reflection of the INAHTA membership. From the 50 member agencies, 64% is located in Europe, 14% in the Asia-Pacific region, 10% in Latin-America as well as in North-America, and 2% in South-Africa; http://www.inahta.org.Twenty-five completed survey forms were received from 15 European HTA agencies, 4 HTA agencies were located in the Asia-Pacific region (15%), 3 HTA agencies in Latin-America (11%), 2 came from North-America (7%) and 1 was situated in South-Africa (4%). We received incomplete survey responses from 5 other HTA agencies, of which we included the survey responses from 2 European HTA agencies that provided meaningful responses to some of the questions (63%). As the number of member agencies was 50 in 2018, the overall response rate was 54%. This is comparable with other studies that surveyed INAHTA members.All agencies were asked about the presence of factors that are supportive of HTA development and whether these were in need of guidance in their specific context, ie, factors reflecting the linkage between HTA practice and policy; the level of institutionalization of HTA and the ability to networking and capacity building. Overall, the respondents mentioned that the contextual factors were present in their contexts, and up to 30% of the respondents felt that guidance was needed for specific factors . There wNineteen respondents (70%) answered the question about which HTA practice serves as best practice. Of these respondents, 21% mentioned CADTH, followed by NICE (16%).With regard to the existence of an appraisal committee/stakeholder panel and related guidance it became clear that 62% of the respondents mentioned to have such a committee installed in their country. Two respondents questioned the need for one central committee, and mentioned that it could be beneficial to have several specialised committees  with overlapping functions and responsibilities. A publicly available guideline or document that describes the roles and responsibilities of the committee/panel (remit and scope), and the procedures followed was present according to slightly more than half of the respondents . A document that describes the composition, terms, and selection of members, as well as the roles and responsibilities of stakeholders involved in the process was felt to be less often present (46%). The respondents expressed the need for guidance with respect to various elements of an appraisal committee/stakeholder panel, ranging from 38%–46% for the different elements . Two resWe also asked the respondents if they were aware of any HTA practice that could serve as best practice. Of the 19 respondents that answered this question (73%), both CADTH and NICE were mentioned each by 21%.The elements in relation to selecting technologies and criteria  were most often not present or present to some extent, according to the majority of the respondents. Also, more than half of the respondents felt that guidance was needed for almost all specific elements; with regard to the methods used for horizon scanning 46% of the respondents had the opinion that guidance was needed .16 and EuroScan, a non-for-profit network and scientific association of public HTA agencies, scientific organizations and individuals for sharing and collecting information and development of methods for the early identification, appropriate use and awareness of health technologies.17 CADTH was specifically mentioned as a best practice in relation to scoping by several respondents.Fourteen respondents (54%) answered the question regarding best practices for horizon scanning. Of these respondents, 14% mentioned the UK National Institute for Health Research Innovation Observatory, CADTH was also mentioned by 14%, as well as the Spanish cross-regional collaboration between HTA agencies in the field of non-pharmaceuticals,18 and methodological guidelines)was mentioned as a best practice example by 35%, followed by the Cochrane Handbook for Systematic Reviews of Interventions (12%).19The findings show that 2 out of the 3 elements related to conducting and reporting assessments are present in most of the HTA practices surveyed. The element that was mainly present to some extent concerns stakeholder consultation to review the plausibility of the evidence reports. However, the respondents overall felt that there was less need for guidance regarding the elements linked to the assessment phase, ranging from 12%–32% for the different elements . By thosWith regard to the appraisal phase it became clear that all the surveyed elements  are present in less than half of the responding HTA agencies. More than half of the respondents mentioned that there was a need for guidance; only with regard to the process less than half (44%) of the respondents felt that guidance was needed . Three rAlmost all respondents (92%) indicated that decisions and the underlying reasons are made public or made public to some extent, and 60% indicated that there is no need for guidance in this respect. However, guidelines or documents describing the mechanism(s) for appeal, how to propose revisions, and to receive a reasoned response, as well as addressing monitoring and evaluation of the process were less present. Not surprisingly, more than half of the respondents felt that there is a need for guidance  . With re12 using these insights. Specifically, we have added guidance on stakeholder participation20 as well as guidance on how to use MCDA for HTA agencies, based on a recent consensus statement among more than 20 experts in the field.21This semi-structured survey intended to collect views and experiences from HTA agencies around the globe in order to identify the level of use of EDPs by HTA agencies, and to further develop the EDP guide to support HTA agencies. The level of use of EDPs was measured by asking respondents about the extent to which elements of the EDP framework were present and whether there was a need for further guidance. We found that contextual factors to support HTA development and the critical elements regarding conducting and reporting on HTA are in place. This is reflecting current HTA practice of the respondents, as most INAHTA members are already well-established HTA agencies. However, respondents indicated that guidance was needed for specific elements related to selecting technologies and criteria, appraisal, and communication and appeal. Guidance was especially felt in terms of the practical organization of meaningful stakeholder participation and the methods to include deliberation during the appraisal step. As a result, we have updated the practical guideIt is important to highlight the limitations of this study. First, the response rate (54%) might suggest that some selection bias might be present. However, the survey respondents reflect the INAHTA membership (in 2018) in terms of geographical representation. As such we feel confident that some conclusions can be drawn from this study, even though we acknowledge that reports by single persons from an INAHTA member agency are not representing the overall HTA practice in a particular jurisdiction. In addition, bias might be that the responses came from HTA agencies that are already doing quite well, while the survey might not have captured responses from less well-established HTA agencies. This might have led to an underestimation of the percentage of HTA agencies that actually are in need of guidance. We are aiming to broadening the survey towards HTA organizations from low- and middle-income countries. Second, reporting on any set of elements implies that they are equally important, but this is not true. Depending on the contextual factors, certain steps and/or elements can be more important than others. Therefore the findings should be mainly viewed as indicative for the level of EDP use by HTA agencies.1 From this report it becomes clear that many good practices have been developed in the areas of assessment (Step 3), and several with regard to priority setting, scoping (Step 2), only a few with regard to structure, governance, organizational aspects (Step 1), deliberative processes (Step 4), and measuring the impact (Step 5). The findings are also in line with previous work on priority setting23 and reported needs of HTA agencies in specific regions. For example, in Latin America, the need for transparency in the production of HTA, involvement of relevant stakeholders in the process, mechanisms to appeal decisions, clear priority-setting processes, and a clear link between HTA and decision-making have recently been emphasized.25 In addition, HTA agencies in Asia recently expressed their need to improve transparency and accountability throughout the process. For example, it was recommended by the HTAi Asia Policy Forum members that a standardized, transparent methodology for priority-setting regarding coverage decision-making needs to be developed.26 Furthermore, some respondents explicitly mentioned particular best practices per step, such as the CADTH for scoping, and NICE for having clear procedures in place for appeal. Also, Brazil was mentioned as best practice for the Latin American region. These findings are in line with previous studies in this area.27 As such, we feel empowered to further optimize the guide on EDPs to support HTA agencies.The findings suggest that contextual factors to support HTA development and the critical elements regarding conducting and reporting on HTA are currently overall present, mainly in countries with well-established HTA practices. Furthermore, respondents indicated that specific guidance was needed for elements related to selecting technologies and criteria, including scoping, appraisal, and communication and appeal. These results are in line with the findings of the ISPOR HTA Council that recently presented a report on good practices in HTA.This is the first survey among HTA agencies regarding the use of EDPs and provides useful information for further developing a practical guide for HTA agencies around the globe. Based on the results from the survey, we conclude that – as expected – several HTA agencies have already certain (elements of) EDPs in place and can serve as inspiration for others. The results could also serve as a baseline measurement for HTA agencies for future monitoring and evaluation of the level of EDP use and to study the effectiveness of EDPs in practice. This could support them in improving their processes and enhancing legitimate decision-making.We thank Agnes Toll for supporting us in developing the online survey. We thank the INAHTA secretariat for their support in distributing the invitation to participate in the survey, and we are grateful to the survey respondents for providing their views on the needs of HTA agencies regarding optimizing their processes and listing best practices.Not Applicable. We contacted the secretariat of the INAHTA for supporting us in contacting their members. The secretariat provided consent and sent an invitation to participate in the survey to their members through e-mail. Reminders were sent by WO, targeting the contact persons as listed on the INAHTA website, which is publicly available. In the introduction to the survey, we made clear that all answers were treated confidential: no attribution would be made to specific persons. Two survey respondents explicitly wished not to disclose their affiliation, we therefore provide their results anonymously.None. The work described in the manuscript is conducted as part of a research program that rethinks the theory and tools to value interventions for priority setting in healthcare (REVISE2020), and is supported by a grant from the Netherlands Organisation for Scientific Research (NWO).All authors were involved in the conception of the study. WO and MJ were involved in the design of the study and data collection. WO analysed the data and drafted the manuscript. All the authors read and approved the final version of the manuscript.Supplementary file 1 contains the questionnaire.Click here for additional data file. The evidence-informed deliberative processes (EDPs) framework can support the decision-making process of health technology assessment (HTA)-agencies but is also relevant for countries that have not (yet) established such an agency. It takes the current decision-making context as the starting point, and offers specific advice depending on the level of HTA development.Using EDPs can contribute to the legitimacy of recommendations and/or decisions, eg, by improving the quality, consistency and transparency of the HTA process.The results provide an overview of the level of use of EDPs by HTA agencies around the globe. It includes best practices for the different parts of the EDP framework, and as such the results are practice-oriented and meant to be inspirational to improve HTA practices.(a) how HTA agencies ideally should organise their processes in line with EDPs, which could include the involvement of citizens and their views; and (b) to what extent this is currently being implemented by members of the International Network of Agencies for Health Technology Assessment (INAHTA).Health technology assessment (HTA) is intended to inform decision-making, including decisions regarding which health technologies  should be reimbursed or not (anymore). There is a need for structured, explicit and transparent approaches with regard to how such decisions are made to facilitate legitimate decision-making. Current HTA methodologies and decision-making informed by HTA only partly respond to these requirements. Using evidence-informed deliberative processes (EDPs) can support this; by enhancing stakeholder deliberation throughout the HTA process it contributes to the legitimacy of recommendations and/or decisions. This manuscript provides insight in


Chlamydia trachomatis, remains a significant cause of blindness worldwide. While mass treatments with azithromycin decreases disease and infection, re-emergence occurs, indicating that elimination may require other sustainable interventions. Environmental changes largely focus on facial hygiene and latrines, but further work to identify other possible transmission targets are needed. We sought to determine, in a cross-sectional survey of households of children with active trachoma, if we could detect the presence of Chlamydia trachomatis on household objects and on family members based on sleeping and caretaking patterns.Trachoma, a conjunctivitis caused by repeated infections with C. trachomatis DNA.In five villages in Kongwa, Tanzania, children <five years were randomly chosen for examination for trachoma, and households of all children with active trachoma (n = 90) were eligible for this study. We administered structured questionnaires of sleeping and caretaking habits. Based on the responses, environmental swabs of bedding, furniture, clothing, and hands were taken and processed using Amplicor for detecting C. trachomatis DNA. A positive environmental swab was associated with the presence of ocular infection in the index child , the presence of an infant <1 year of age in the household, and whether the children’s clothing had not been recently washed.Of 80 visited households, 13 (16%) had at least one swab from environmental sources positive for C. trachomatis DNA is present in the environment of children with active trachoma, especially in households with an ocular infection. Specific findings also suggest that washing hands, clothing, and bedding may be important. Chlamydia trachomatis, spread from person to person by contact with infected ocular/nasal secretions. While mass treatment with azithromycin decreases infection, re-emergence occurs, indicating that elimination may require other sustainable interventions. Environmental changes largely focus on facial hygiene and latrines, but further work to identify other possible transmission targets is needed. In this cross-sectional study of households where at least one child has trachoma, we found evidence of C. trachomatis DNA on several environmental sources including clothing, bedsheets, furniture, and hands. Besides the presence of infection with C. trachomatis in the index child, chlamydial DNA in the environment was also associated with the presence of an infant in the household. Washing clothes within the past three days was associated with not having C. trachomatis DNA in the environment. Our study provides suggestive evidence that in high prevalence villages, C. trachomatis may be contaminating environmental objects, including hands and clothing. These findings suggest that behavior change communication around hygiene may need to be enlarged to focus on keeping ocular and nasal secretions off faces and hands, and promoting washing of clothing as well.Trachoma is the leading infectious cause of blindness world-wide. It is a conjunctivitis caused by repeated infections with  Chlamydia trachomatis, is the world’s leading cause of infectious blindness [C. trachomatis infections, leading to inflammation and follicles on the upper tarsal conjunctiva. Over years of re-infection, these initial changes may proceed to scarring, trichiasis , and ultimately, corneal opacity and blindness.Trachoma, a disease caused by repeated infection with ocular serovars of lindness . It is tlindness . The patIn response to this large public health problem, the World Health Organization has recommended the SAFE strategy for trachoma elimination. This approach consists of surgery for trichiasis, antibiotics for treatment of infection, facial cleanliness, and environmental interventions to for sustained reduction of transmission . Alone, C. trachomatis is present in the ocular and nasal secretions of infected persons, and is the only route for the spread of infection as there is no animal or insect reservoir. Re-emergence of trachoma following mass treatment occurs in spatial clusters, suggesting that household and other close contacts contribute to disease spread [C. trachomatis. Maintaining facial hygiene and environmental improvements, largely focused on reduction of flies through latrine construction, have been promoted to reduce access to infected secretions [e spread . Personae spread , facilitcretions –15. HoweC. trachomatis DNA on household objects, clothing and hands of family members, in order to understand potential environmental sources of disease transmission.In this study, we identified children with active trachoma and went to their households to find evidence of the presence of The current study was part of a larger two year study of trachoma prevalence performed in several districts in Tanzania that was evaluating the effects of multiple rounds of mass drug administration . In thatOcular exams to identify the presence of trachoma were conducted for all sentinel children within a village on a single day. An experienced trachoma grader, with 2.5x loupes, assessed the presence of clinical trachoma using the WHO simplified grading system . In thisC. trachomatis infection was taken of the index children in the home. For this, a sterile Dacron swab was rubbed across the upper left conjunctiva three times and placed in a sterile, dry vial. A standard protocol was used in the field to avoid contamination. The individual who swabbed the eyelid was the only person to touch the swab at any point and never touched the children or any other individual during the procedure. A separate individual flipped the eyelids of the children, switching gloves between each child. “Air” swabs were taken at random, about 1 per 50 examinations and tested masked to the status as control swabs. The swab-containing vials were frozen and stored in a -20 degree freezer until shipped to the International Chlamydia Laboratory at the Johns Hopkins Hospital in Baltimore, MD. They were tested for the presence of C. trachomatis DNA using a, qualitative polymerase chain reaction assay, Amplicor  according to the manufacturer’s directions. Samples were considered negative if they had an optical density of <0.2 A450 and positive if ≥0.8 A450. Samples with optical densities ≥0.2 and <0.8, were considered equivocal and retested; no sample had equivocal results upon retesting. All “air” swab controls were negative, indicating no contamination.An ocular swab for detection of In order to guide the collection of environmental samples to test for the presence of chlamydia DNA, we developed a questionnaire on the sleeping and caretaking arrangements of all children age five and under in a household. Questions included where each child slept and with whom, who took care of each child during the day, how ocular and nasal secretions were cleaned or each child, and frequency of washing of bedding and clothing . Questions were directed to the individual caretakers. The houses of the index children were visited the day after the survey. All questions were asked by a local Tanzanian interviewer, fluent in the local dialect. Questionnaire information was also supplemented by observation. For example, if any child was observed touching a household object, we added that potential site for swabbing. Observations were only made during three time points: the greetings as the staff came to the house, during the conduct of the questionnaire, and while swabbing sites identified from the questionnaire. Relevance and comprehension of the questions were tested during a pilot study on women with children from a village not included in this study.We attempted to visit the household of each index child for interviewer administration of the questionnaire. Each household in which the inhabitants were absent was visited at least twice on two separate days in an attempt to collect information.C. trachomatis DNA for environmental swab collection. These areas were sprayed with sterile water, and a sterile Dacron swab was rubbed against the damp material and then placed into sterile, dry vials. Samples were collected as follows: samples from where the child slept were collected from an area of one foot by one foot, at the location of where the child’s head rested while sleeping; for bedding, the area of collection was approximately one foot by six inches near the head of the bed; furniture  samples were obtained from a one foot by six inch area in which ocular and nasal secretions were said to be wiped; clothing samples were collected from a smaller area of six inches by two inches at the location of the child’s head when carried or where secretions were said to be wiped; those from the hand were collected from the entire palmar surface and in between the fingers. The extent of the area to be swabbed was arbitrary but standardized by use as there are no published data on collecting environmental samples. All vials were frozen and shipped to Johns Hopkins for PCR analysis, as described for the ocular exam vials.Based on the answers obtained from the questionnaire, one person (AN) determined where to target areas of the household  as potential sources of C. trachomatis DNA in the environment, defined as having one or more PCR-positive environment samples from the household. Data collected on potential risk factors for environmental exposure was summed across each household. .The primary outcome was presence of Data was analyzed using STATA version 10.0. Frequency of washing clothes was categorized as <3 days ago versus more than 3 days. The last washing of bedding was asked as less than a week, or a week or more ago. Unadjusted analyses of association between household risk factors and the outcome were done using the Fisher’s exact test. A multivariate model was created using logistic regression and backwards elimination employed to remove factors if shown to be statistically insignificant, using a pre-specified criterion p-value of 0.1.Ethical approval for this study was obtained from the Johns Hopkins University Institutional Review Board and the National Institute for Medical Research in Tanzania. Written informed consent for study participation was obtained from the child’s guardian, and oral consent was re-obtained for conducting swabbing of surfaces at the home, as approved by the National Institute for Medical Research. All consents were obtained following the tenets of the Declaration of Helsinki.A total of 669 children age ≤5 years in the five villages received an ocular examination. Active trachoma was identified in 90 of these children. Prevalence of trachoma in those ≤5 years of age varied by village  from morOf the 90 households in which an index child with active trachoma was present, we were able to collect questionnaire information from 80 . In the Overall, the group was 47.5% male and 20% were age ≤ 1 years . ApproxiAlmost all of the index children slept with at least one other person, and 46% of the children slept with at least one other child, predominantly between ages 0–5 years. More than 90% of children slept on an actual bed, rather than on animal skin, mat, or clothes on the floor.Three-quarters of the children were carried by their caretakers except for older children ages 4–5 years who were not carried. Children were carried in multiple ways, with carriage on the hip being the most common, but followed closely by carriage on the caretaker’s back. Eighty-six percent of children, regardless of where they were carried by the caretaker, were carried using a kanga, a large rectangular cloth.Ocular and nasal secretions were cleaned by both caretakers and the children themselves in a variety of ways. For all but one index child, one of the methods used involved use of hands, either the child’s or caretaker’s to wipe away secretions. In the majority of cases (88%), either the child or caretaker’s clothing was also used for cleaning. Secretions were rarely wiped using a separate cloth (5%) or washed with water (2.5%).C. trachomatis DNA was present on household objects, children, and adults . The average number of samples taken per household was 7.9 and every household had at least 4 samples taken. Samples of the household environment showed that d adults . LocatioThe 23 positive environmental swabs were obtained from 13 households . Twenty-Obtaining at least one positive environmental swab from the household was associated with village of residence  and presence of ocular infection in the index child  . AlthougWhen we included presence of ocular infection in the index child in the model , model AC. trachomatis DNA is present in the household environment of children with active trachoma, especially those that currently had ocular infections. These positive environmental samples were found both on household objects and on the hands and clothing of children and their caretakers. The findings do not mean that the environmental source contained live organisms capable of transmission, as we did not test for replicating organisms or load. However, it does suggest the presence at one point of a possible environmental source of infection, and these may have the potential to contribute to disease transmission.Our study found that Chlamydia, which in turn may be contributing to the high levels of trachoma. In studies of the contribution of flies to transmission of trachoma and infection, flies seem to play a larger role in transmission in areas of low prevalence, like The Gambia, but not in areas of high prevalence [The majority of our positive environment swabs came from the one village, Njoge, with the highest prevalence of trachoma. In all villages, households were only visited if the child had active trachoma and therefore, while we expected to visit fewer households in lower prevalence villages, we expected all households with a child with trachoma to have an equal proportion of positive environmental specimens. However, this was not the case, and in two villages we had no positive environmental specimens in the household. In fact, these two villages had the lowest rates of infection in the index children. The other villages had fewer environmental positive swabs compared to Njoge, although the rates of infection in their index children were similar to the children in Njoge. This difference suggests that the practices of children and caretakers in Njoge may contribute to diverse environmental presence of evalence , 18. Thievalence . Our stuNot surprisingly, positive environmental swabs were associated with the presence of ocular infection in the index child, which no doubt increased the likelihood that we would find contaminated surfaces. Since the sign of TF can persist long after infection clears, it is possible that degradation of Chlamydial DNA in the environment precluded finding even more positive environmental samples. It is also possible that we missed a fomite in the household if it did not turn up in our questionnaire.C. trachomatis, and included sites like door handles and locks, washbasin taps and wash basin edges. That study was able to show that such sources were also capable of contaminating clean urine samples, as proof of principle. A similar study of clinic surfaces suggested the load of infection was low, but the time of infection was unknown and the load could have declined with time [The study of potential sources of environmental contamination of urine samples for diagnosing sexually transmitted chlamydia provides further insight into our findings. Andersson et al swabbed a variety of environmental locations in STI clinic bathrooms, including door handles, locks, doors, walls, toilet flush buttons, and wash basins and taps for evidence of contamination using Aptima 2 Combo Assay (Gen Probe) . They foith time . In studith time . NeverthWe were less likely to find a positive environmental swab in households with increased clothes washing practices. Current hygiene education focuses on face washing to decrease transmission of infected ocular and nasal secretions. Our study suggests that ocular and nasal secretions were wiped using clothing, suggesting that washing clothes and bedding may also be important.We recognize that this study is limited in its ability to assess associations because of the small number of positive environmental samples obtained. This small number is likely a result of several factors: 1) The low prevalence of trachoma in some of the studied villages, and with fewer index children, we visited fewer households, decreasing the likelihood of finding positive samples; 2) use of active trachoma as a surrogate for infection at the time we scheduled a visit to the house. Ideally, we would have had a rapid test of infection to decide which households to visit, but there was not one available at the time of the study. We have shown the correlation of trachoma and infection even in low prevalence settings which justified the use of this purposeful sampling approach ; 3) imprA second limitation is the absence of diversity in a few of the responses; for example, almost all children who were carried, were carried on the caretakers hip. Thus, any association of an environmental positive sample due to that practice is diluted by the commonality of the practice.C. trachomatis may be contaminating environmental objects, including hands and clothing. These findings suggest that behavior change communication around hygiene may need to be enlarged to focus on keeping ocular and nasal secretions off faces and hands, and promoting washing of clothing as well.Our study provides suggestive evidence that in high prevalence villages, S1 checklist(DOCX)Click here for additional data file.