The identification of mental health problems early in life can increase the well-being of children and youth. Several studies have reported that youth who experience mental health disorders are also at a greater risk of developing psychopathological conditions later in life, suggesting that the ability of researchers and clinicians to identify mental health problems early in life may help prevent adult psychopathology. Using large-scale administrative data, this study examined whether permanent settlement and within-province migration patterns may be linked to mental health diagnoses among adolescents (15 to 19 years old), young adults (20 to 30 years old), and adults (30 years old and older) who grew up in rural or urban communities or migrated between types of community .We conducted a nested case-control study of the impact of rural compared to urban residence and rural-urban provincial migration patterns on diagnosis of mental health. Conditional logistic regression models were run with the following International Classification of Diseases, 9th Revision (ICD-9) mental health diagnoses as the outcomes: neurotic disorders, personality disorder, acute reaction to stress, adjustment reaction, depression, alcohol dependence, and nondependent drug abuse. Analyses were conducted controlling for paternal mental health and sociodemographic characteristics.Mental health diagnoses were selectively associated with stability and migration patterns. Specifically, adolescents and young adults who were born in and grew up in the same rural community were at lower risk of being diagnosed with acute reaction to stress (OR = 0.740) and depression (OR = 0.881) compared to their matched controls who were not born in and did not grow up in the same rural community. Furthermore, adolescents and young adults migrating between rural communities were at lower risk of being diagnosed with adjustment reaction (OR = 0.571) than those not migrating between rural communities. No differences were found for diagnoses of neurotic disorders, personality disorder, alcohol dependence, and nondependent drug abuse.This study provides some compelling evidence of the protective role of rural environments in the development of specific mental health conditions  among the children of sawmill workers in Western Canada. Considerable theoretical debate has focused on the relationships between the development of mental health problems among youth and the role played by environmental stressors such as acute traumatic events, chronic strain and adversity, accumulation of stressful life events, and daily challenges -4. The mMuch evidence shows that several of these stressors may vary according to where individuals live. That is, the economy and social environment of the communities where youth live may be associated with the degree to which parents are able to find jobs, rely on the necessary networks of social support to cope with challenging times, and provide their children with opportunities for healthy development . SinResearch shows that youth and young adults often struggle with mental health problems such as depression, anxiety, and stress-related conditions. A recent World Health Report estimated that 10%-20% of youth worldwide experience one or more mental health disorders . Severalrural idyll - a notion that has been consistently influential since the 1960s  - th - thrura60s , while others migrate within urban communities or within rural communities only. For instance, census reports for 2006 indicate that approximately 14% of the Canadian population had migrated in the previous year, and 19% had migrated within the previous 5 years .The mobility of populations has been of interest to researchers attempting to uncover the impact of migration patterns on adolescent mental health. Studies have suggested that adolescents who change residence show higher rates of mental disorders. For example, McGee and colleagues  found thA study conducted by Mullick and Goodman  on 5-10 The purpose of the present study is to examine whether, in addition to permanent settlement in urban or rural communities, migration patterns within the province of British Columbia (Canada) may also be linked to mental health diagnoses among adolescents and young adults. We hope to contribute to the limited data and literature about rural mental health among youth, since few studies have investigated the effects of migration in conjunction with permanent settlement. To our knowledge, this is the first Canadian population-based study to investigate mental health diagnoses in adolescents and young adults by exploring the effects of rurality-urbanity and migration patterns through analysis of large-scale administrative data.This study is based on a cohort of male sawmill workers  on whom data was first gathered in the mid-1990s to study the effects of chlorophenol antisapstain exposure among British Columbian sawmill workers . RecentlMental health information of children of sawmill workers was gathered from the provincial administrative health data. The Canadian health system is public and universally accessible and it is regulated at the provincial level. In British Columbia, individuals experiencing mental health problems can be evaluated by mental health professionals at public hospitals or medical clinics. Every encounter that occurs between patients and health professionals is recorded on administrative forms that are sent and stored at the British Columbia Ministry of Health. The reason for medical visit or hospitalization (which can include a diagnosis if one is provided), and personal health information are recorded on such forms. This individual-level administrative health information is available to researchers who have obtained approval as the result of a stringent process of review of ethical standards and scientific rigor. Such data, which also include codes for mental health diagnoses in accordance with international code systems, are accessed at the British Columbia Linked Health Database (BCLHDB). Ethical approval was obtained from the University of British Columbia (UBC) and the British Columbia Ministry of Health to conduct a series of studies on the health of sawmill workers and their children.For the children of sawmill workers to be eligible for this study, the fathers must have worked at least one year in one of the study sawmills while their children were between the ages of 0 and 16 years. A total of 19,833 children of sawmill workers satisfied the eligibility criteria for inclusion. Our study focuses specifically on mental health diagnoses that were assigned to children of sawmill workers at different times from early childhood to young adulthood. Therefore, the sample for this study consists of a total of 8,508 participants: 2,127 cases and 6,381 controls (3 matched controls on age and gender for each case). Table International Classification of Diseases, 9th Revision (ICD-9) criteria and codes for children were used to diagnose mental health problems among individuals between the ages of 15 and 19, whereas adult ICD-9 criteria and codes were used to diagnose mental health problems among individuals 20 years of age and older.Mental health diagnoses for which there were less than 30 cases were not selected, because the ratio between participants and independent variables would have not been sufficient. The selected diagnoses were neurotic disorders , personality disorders, acute reaction to stress, adjustment reactions, depression, alcohol dependence, and nondependent drug abuse. Table Statistics Canada offers different definitions of rurality - based on population size, density or proximity to urban centres - and recommends that the selection of specific definitions of rurality be guided by the research question of any given study . In BritHealth information records were inspected for the periods between birth and time at diagnosis to identify migration patterns among the study participants. Definitions of migration patterns were based on changes to the participants' postal codes that were associated with records of health services utilization and provided by the local health authorities. Individuals could have been born in and stayed in rural or urban communities within the province of British Columbia, or moved from rural to urban communities within British Columbia, or vice versa. The following three migration patterns have therefore been identified to describe within province migration: urban to rural (0 = no and 1 = yes); rural to rural (0 = no and 1 = yes); and rural to urban (0 = no and 1 = yes). The following two additional migration patterns were identified to describe participants who had moved away from the province of British Columbia, and for whom we did not have information about the place of destination: urban (0 = stayed and 1 = moved); rural (0 = stayed and 1 = moved).It is worth noting that an 'urban to urban' migration pattern could not be included in the present study. The original cohort  was indentified among workers of sawmills located in British Columbia in the early 1980s. Urban communities in British Columbia, that is, those with population over 100,000 dwellings, are the cities of Vancouver, Victoria, and Kelowna. Of these, only Vancouver still has a sawmill, while Kelowna's sawmill closed in the late 1980s, and Victoria never had one. Therefore the likelihood of migration for work from an urban sawmill community to another urban sawmill community was largely non-existent among our study cohort.While the study focuses on the effect of rural-urban migration patterns on mental health of the children's cohort, there are some potential variables that need to be accounted for in the analysis. These variables are the sociodemographic characteristics, the mental health, and the employment history of the fathers.The following sociodemographic characteristics were obtained from the sawmill employment records: duration of employment (continuous variable); job mobility ; type of employment ; ethnicity ; and marital status of the fathers . ICD-9 mental health diagnosis ; suicidal behaviors ; and alcohol dependence  were obtained from the BCLHDB.Using survival-time to case-control on STATA 8.0, three controls were selected for each mental health case matched on age and gender. Controls were chosen randomly with replacement from the set at risk. The set at risk were all the offspring of the sawmill worker's cohort, born between 1952 and 2000, whose father had worked in a study sawmill for at least one year during the first 16 years of the child's life. These could be anyone at risk who also satisfied the matching criteria who had not been diagnosed with a mental health condition at the time of diagnosis of the case. Given this procedure, it is possible that a participant is a control in the analysis pertaining to a specific diagnosis, but a case in the analysis pertaining to another diagnosis. For example, a participant may be at risk for depression and be used as a control in such analysis, but also be used as a case for nondependent drug abuse if he/she was assigned such a diagnosis.Statistical analyses were conducted using conditional logistic regression on STATA 8.0. First, a series of seven univariate analyses (one for each diagnosis) were conducted to identify associations between the five migration patterns  and mental health outcomes. Second, we conducted a series of four separate multivariate analyses, one for each of the outcomes that yield significant associations with migration patterns. In these analyses we controlled for the following paternal characteristics: duration of employment, paternal ethnicity, marital status, paternal alcohol dependence, mental health of the father, suicidal behavior of the father, and type of employment.nondependent drug abuse, acute reaction to stress, adjustment reaction, and depression. Multivariate analyses were conducted for these diagnoses, as reported in Table Results of the univariate analyses are reported in Table acute reaction to stress and depression. Specifically, individuals who were born in and grew up in the same rural community were approximately 25% less likely to be diagnosed with acute reaction to stress  and approximately 10% less likely to be diagnosed with depression  than those who had not grown up in the same rural community in which they were born. Similarly, individuals who had migrated between rural communities were approximately 50% less likely to be diagnosed with adjustment reaction  than participants who stayed in the rural communities in which they were born. Interestingly, nondependent drug abuse was not significantly associated with rural stability  or migration between rural communities .Odds ratio (OR) analyses revealed that after controlling for important paternal characteristics, rural stability is significantly associated with The present findings show that growing up in a rural environment or migrating between rural communities may protect against some mental health conditions, namely, acute reaction to stress, adjustment reaction, and depression. More specifically, youth and adults who grew up in the same rural community were at lower risk of being diagnosed with depression and adjustment reaction than individuals who did not grow up in the same rural community in which they were born, and children migrating between rural communities were at lower risk of being diagnosed with acute reaction to stress than participants who did not migrate between rural communities.However, it is worth noting that for other mental health diagnoses we did not find a link with migration patterns. For example, we did not find significant differences between rural and urban environments or migration patterns between these two types of environments in the diagnosis of neurotic disorder, personality disorder, alcohol dependence, and nondependent drug abuse. Therefore we conclude that if rurality plays a protective role in the development of mental health, it does so only for specific conditions.We argue that clues to what might be protecting children living in rural communities from developing acute reactions to stress, adjustment reaction, or depression may be suggested by a null finding. We found that, after controlling for important paternal sociodemographic characteristics, adolescents and young adults living in rural places are as likely to become nondependent drug abusers as individuals growing up in urban communities. We qualify this null finding as important because it is indeed consistent with our interpretation of the protective role of rurality. However, it is contrary to a literature showing that leisure boredom is associated with substance abuse e.g., ,39-41], -41, 39-4It has been speculated that some of the alleged risk factors of rurality may be linked to the remoteness, isolation, and seclusion that generally are embedded in rural living and attract rural youth to large cities. Paradoxically, these features may relate to a perceived sense of status quo and lack of change. The underlying rationale is that the association between boredom and drug use in adolescents and young adults might be stronger in rural than in urban communities because living in rural communities might make individuals within these developmental periods more prone to boredom and, by implication, might make them experience less change or novelty than their counterparts living in urban communities.boredom may be confounded with uncontrolled socioeconomic and family variables, which instead reflect the typically greater availability of resources and access to services, facilities, and amenities enjoyed by urban populations.Our analyses clearly show that, when individuals are matched for a series of family and socioeconomic variables, differences relative to nondependent drug abuse among rural and urban groups disappear. Thus, we conclude that it is possible that the differences found in relation to nondependent drug abuse reported in the literature may be due to the fact that the latent variable Indeed, the pattern of results in our study suggests an alternative interpretation of the influence of rurality. That is, keeping constant the extent of access and resources varying with living contexts, rurality may well play a protective role for mental health of adolescents and young adults because it provides them with a needed sense of stability and control.This proposed interpretation evokes a host of interesting questions concerning what is the optimal level of "social environment stimulation" in critical periods such as adolescence and young adulthood. Research addressing such questions has almost exclusively focused on infancy and early childhood, but seems to have largely neglected other developmental periods in the life span, and to have underestimated the role played by the context in which individuals live. Clearly, given the potential important links with lifestyle, well-being, and health outcomes, this should be an area of priority for future research.While approaches to health policy tend to treat rural areas as uniform entities, mental health differences between rural areas may be as pronounced as those observed between urban and rural communities. There are an array of different and specific dimensions of rurality and urbanity that health researchers need to consider to better understand what community aspects may be associated with mental health outcomes . For exaThe present study has highlighted the important role played by stability, as opposed to migration, in contributing to the mental health of members of rural and urban communities. Our findings also suggest that important family characteristics such as sociodemographics, duration of employment, and a history of mental health may be possible confounders in previous studies in which differences between rural and urban communities have been identified.While in this study we treated paternal characteristics  as control variables, it is worth noting that these were consistently associated with increased risk of mental health diagnosis among the children. More specifically, paternal mental health diagnosis and Caucasian origins (compared to Chinese and Sikh) were associated with greater odds of mental health diagnosis among the children. These findings may explain in part some of the inconsistencies between rural and urban communities in drug use reported in the literature, as the inconsistent results could be confounded by factors such as ethnicity and familial history of mental health.There are a number of limitations to this study that are worth mentioning. First, because our outcome measures were derived from medical records, we were not able to address the link between mental health and urbanity-rurality that may exist at the subclinical level, nor could we explore the role of potentially important contextual factors . Second, while we controlled for important sociodemographic and mental health characteristics of the fathers, we did not have access to maternal characteristics and therefore could not include them in this study. Third, the participants in the study represent a very specific population - that is, the children of male sawmill workers in British Columbia, Canada - and therefore findings from this study cannot be generalized. Finally, rural health researchers may be critical of our definition of rurality, which was solely based on population size , and our classification of migration patterns is reductive in that it did not divide urban migrators into those who migrated to other urban places and those who migrated from urban to rural places.Because of the limitations of this study, further research on this topic needs to be conducted before recommendations for clinical practice can be extrapolated. Nonetheless, it is reasonable to advocate for a clinical practice that takes into consideration not only the individual histories of patients, but also the influence that broader social environments exert on the etiology of mental health conditions. This is a critical concept since it may have implications for treatment of the individual, but also for the identification of large-scale public mental health prevention programs.some mental health conditions  but not others .Thanks to the use of a relatively homogeneous sample, this study provides some compelling evidence of the protective role of rural environments in the development of BC: British Columbia; BCLHDB: British Columbia Linked Health Database; ICD: International Classification of Disease; OR: Odds Ratio; CI: 95% Confidence Interval.The authors declare that they have no competing interests.SM directed the analysis, and was the lead writer. AO was PI for purposes of obtaining funding for this research, and reviewed drafts. KC assisted with the literature review. RH conducted the analysis, and LC managed the database. AD contributed conceptually and reviewed drafts. CH conducted the research, helped direct the analysis, and read drafts of the paper. All authors read and approved the final manuscript.


Mexico is undergoing profound health reform, extending health insurance to previously uninsured populations and changing the way health care services are delivered. Legislation enacted in 2003 and implemented in 2004 mandated funding and infrastructure that will allow 52% of Mexico's population to access medical care at no cost by 2010. This ambitious social reform has not been without challenges, particularly financial sustainability. Health promotion, because of its potential to prevent or delay chronic diseases and injuries and their associated costs, is a key component of health care reform (In 2006, the Ministry of Health's General Directorate of Health Promotion developed the Health Promotion Operational Model. Based on Ottawa Charter functions, the model integrates health promotion activities within the overall health care system. The main goal of this model is to build strong human capital and to improve organizational capacity for health promotion starting at the local level by training health care personnel to implement health promotion activities. Organizational development workshops started in 2006, and implementation plans in all 32 Mexican states were in place by end of 2008 ( Departamento de Salubridad General) with federal jurisdiction and powers to mandate public health measures throughout the country.Before 1917, public health was in the hands of local authorities. The Board of Health of Mexico City had a limited scope, restricted to Federal District. Under the revolutionary principles in the Constitution of 1917, the old Council of Health was transformed into the new Department of General Health , founded in January 1943. By October of the same year the Ministry of Health was created and started providing health services to people who did not have access to IMSS, for a minimum fee. Finally, in 1959, the Institute of Security and Social Services for Federal Government Employees was created . Seguro Popular provides universal health insurance, subsidized by the federal and state governments, for the 52% of the Mexican population that is not covered by the other social security systems and is mostly marginalized. The main objective of Seguro Popular is to ensure that 50 million Mexicans .Health promotion in Mexico lacked the information systems and human resources to deliver health promotion services, according to a study done by the Pan American Health Organization in 2005 . To addrMOPS aims to take advantage of every contact that people have with health services to educate them about their health risk factors and train them to prevent or delay chronic disease. Health care visits are a key opportunity for health promotion interventions.MOPS contributes a conceptual framework for health promotion activities and then establishes the general guidelines to implement them at the local level, giving priority to the health care services but also focusing on schools, worksites, fields where migrants work, and other sites where promotion is critical. The model establishes the personnel structure that services have to have throughout the chain value, the collaborative communication between them, as well as the professional and technical profile, infrastructure, and responsibilities.The Ottawa Charter for Health Promotion, established in 1986, identifies 5 core functions: build healthy public policy, create supportive environments, strengthen community actions, develop personal skills, and reorient health services . MOPS tr1) Management of personal determinants. With health determinants tools people can identify the determinants that influence their health. This assessment can be developed according to age and sex, and biological, cultural, and employment status. People who know their health determinants profile are in a better position to make healthy choices. Mexico has a strategy called Prevention and Health Promotion at the Stages of Life that sets out the basic actions for preventive care during the life stages from birth until death. Health promotion activities are recommended according to the following age groups and sex:NewbornChildren younger than 5 yearsChildren aged 5 to 9 yearsChildren aged 10 to 19 yearsWomen aged 20 to 59 yearsMen aged 20 to 59 yearsWomen and men aged 60 and olderTo support this Stages of Life strategy, Mexico uses a system of national health cards. This system is designed to allow people to record on health cards their personal profile and their health promotion activities that they perform at each stage of life. Ideally, this card system will encourage the population to improve habits, customs, attitudes, and practices to protect and preserve their health throughout all stages of life.2) Health capacity building and competence development. This component promotes educating the population on values, attitudes, and skills to help them preserve their health and is built through individual health counseling and community workshops.3) Social participation for community action. This component drives organized and informed participation of the population and promotes the creation of social networks. The implementation of health promotion strategies from the social base has community empowerment as a main goal.4) Development of healthy environments. This component advocates the creation of physical and social spaces where people live, study, and work in hygienic, safe, and stimulating conditions to maintain health and improve quality of life. It promotes the protection and conservation of natural resources and the proper management of physical, chemical, and biological agents.5) Advocacy. This component refers to working both within and outside the health sector to promote cooperation with other sectors. Such efforts generate synergy between the various actors, fields, and levels that are or could be involved in providing health promotion services. Advocacy takes place at all levels of government, public and private health institutions, other public institutions, businesses, and nongovernmental organizations.6) Socialmarketing in health. This component seeks to promote healthy attitudes and behaviors. It involves the analysis, planning, execution, and evaluation of programs designed to influence the voluntary conduct of target audiences to improve their personal welfare and that of society. Social marketing uses a mixture of classical marketing techniques — product, place, price, and promotion — mixed with elements such as bonds to finance public and political alliances.7) Evidence in health promotion. Evidence refers to evaluation data on the effectiveness of health promotion interventions and other information that generates knowledge for decision making. The purpose of this component is to collect such data at the local, municipal, state, or national levels, for local decision making.The following is an example of how the components of MOPS could work together for health promotion:Fernando, 48, the father of 5 children, works for a computer company in Monterrey, Nuevo León. He gets up early every day, almost never eats breakfast, sits all day in front of the computer, and does not practice any kind of physical activity. At lunch, he frequently consumes fast food  with soda.Six months ago, he took his daughter Alejandra to a health center in response to an immunization campaign. The nurse who attended the child took the opportunity to present Fernando the National Health Card for men aged 20 to 59 years (which lists preventive screening recommendations) and performed a basic checkup. She created a personal risk profile for him and recommended that he attend an education program on healthy food and physical activity.Fernando started exercising every afternoon after work, eating more nutritious meals, and even motivated his wife and son to join him.Some weeks later, while walking with his wife, they were almost hit by a speeding truck on a street close to the community playground. Fernando organized his neighbors into a group that proposed an initiative for safer and healthier public spaces to local authorities. The authorities acknowledged the importance of the request, and together with some local companies started to create healthier environments by reorganizing public areas.Fernando's community improved. Because of the MOPS health marketing component, many people learned about these changes. Surveys collected evidence of the effectiveness of these activities.The MOPS implementation workshops represented a challenge because of the government structure, economic status, and cultural complexity of states. During the workshops, we focus on building the common language of health promotion throughout the managerial system at the states, including directors, program coordinators, and district health officers. The second part of the workshops analyzes the state conditions and develops a local and state light implementation plan, which is ultimately approved by the State Health Secretary. More than 2,000 state and local officers have participated in the workshops.The workshops motivated state public health authorities to embrace MOPS and work to implement it at all levels. A strong integrated health promotion service is seen as a basic necessity for the National Strategy on Health Promotion and Prevention for Better Health to function, and MOPS plays the main role in that.MOPS responds to the growing process of health care democratization and the challenge to sustain it. It demands trained professionals and evidence-based interventions; it is based on local experience but nevertheless is adaptable to all health system levels. MOPS can enable health care reform to be sustainable socially and financially.MOPS is a new tool that is has made it through a critical phase: the implementation process in each state of Mexico; this is a complex task that requires close monitoring by the state officers and the General Directorate of Health Promotion, which will advise and strengthen states' efforts to implement MOPS. Along the way, the relevance of the model will have to be evaluated and adjusted to the local and national changing realities. This is the next stage.


Despite gains in controlling mortality relating to diarrhoeal disease, the burden of disease remains unacceptably high. To refocus health research to target disease-burden reduction as the goal of research in child health, the Child Health and Nutrition Research Initiative developed a systematic strategy to rank health research options. This priority-setting exercise included listing of 46 competitive research options in diarrhoeal disease and their critical and quantitative appraisal by 10 experts based on five criteria for research that reflect the ability of the research to be translated into interventions and achieved disease-burden reduction. These criteria included the answerability of the research questions; the efficacy and effectiveness of the intervention resulting from the research; the maximal potential for disease-burden reduction of the interventions derived from the research; the affordability, deliverability, and sustainability of the intervention supported by the research; and the overall effect of the research-derived intervention on equity. Experts scored each research option independently to delineate the best investments for diarrhoeal disease control in the developing world to reduce the burden of disease by 2015. Priority scores obtained for health policy and systems research obtained eight of the top 10 rankings in overall scores, indicating that current investments in health research are significantly different from those estimated to be the most effective in reducing the global burden of diarrhoeal disease by 2015. Diarrhoeal disease causes an estimated 1.8 million deaths per year ,3, diarrAlthough there are numerous causes for the lack of greater progress in the control of diarrhoeal diseases, it is clear that our investments in related research over the last 20 years have not had the greatest attainable impact. It is now increasingly recognized that research priorities do not optimally address the needs of children in developing countries ,6. SettiAs part of a larger exercise of assessing research priorities for major child health conditions, the CHNRI decided that the exercise should consider research for burden of reduction of diarrhoeal disease by 2015 among children aged less than five years. Since the currently-accepted disease-burden measure is the disability-adjusted life-year (DALY), which incorporated both mortality and morbidity components of disease, our scoring exercise included both mortality and morbidity components. However, due to the current thinking on disease weighting, most burden of diarrhoeal disease is related to mortality rather than morbidity, and scorers were asked to respect this current thinking. The CHNRI Secretariat selected two group members (CL and MK). These two members defined the list of research options in communication with IR, based on a systematic framework for listing research options relating to a single disease developed by the CHNRI ,8. This A further 17 experts were invited to participate, of whom eight completed and returned priority scores for a total group of scorers comprising 10 individuals .These individuals were categorized as physicians with expertise in infectious diseases, gastroenterologists, public-health researchers specialized in programmatic issues, a health economist, and public-health researchers in areas other than programme development and evaluation. Each one scored the individual research options independently using a five-component structured model developed by the CHNRI to evaluate health research. The five components consist of the following: (a) likelihood that the research option can yield new knowledge in an ethical manner; (b) likelihood that the research findings will lead to efficacious and effective interventions; (c) likelihood that the intervention derived from the research would be affordable and deliverable to the population of interest; (d) most likely maximum burden of disease reduction that could be derived from interventions resulting from research within the option; and (e) likely impact that the derivates of the research will have on equity.Scores were computed as percentage of maximal obtainable points for each of the major five components being evaluated and then combined for an overall score. The scores outline both limitations and strengths of each research option. Each of the five intermediate scores reflect the likelihood that the research option will be answerable, that it will result in an effective intervention, that the resulting intervention will be deliverable, that the resulting intervention will increase equity, and an estimation of the maximal disease-burden impact an intervention resulting from the research is foreseen to have. When added together, this overall score becomes a quantitative measure of the collective optimism that research in that area can have substantial impact prior to 2015. Although this system easily accommodates weighting of these five options by donors or regional agencies or other stakeholders, we have presented the unweighted results. The process of scoring is presented in greater detail elsewhere -10.http://www.icddrb.org/jhpn).The listing of research options yielded 46 options. Twenty-one research options were designed as health policy and systems research to increase the efficiency of interventions already in place, 10 options addressed research to improve the affordability and deliverability of known interventions, and 15 options were primary research to develop new interventions. The complete list of the 46 research options is presented in Table Priority scores for research options evaluated solely on the criterion of their ability to generate new knowledge ranged from 57.0% to 95.8%. The top five research options that were predicted to encounter minimal obstacles in their realization are listed in Table Campylobacter, enteropathogenic Escherichia coli, Entamoeba histolytica, and norovirus all obtained scores for answerability ranging between 57% and 68%.Low scoring research options in this category were predominated by enteric vaccines that are currently in early stages of development as these are unlikely to yield clinical trials demonstrating efficacy prior to 2015. Scores for The priority scoring of research options based solely on their predicted potential to lead to (or improve) efficacious and effective interventions yielded scores ranging from 32.0% to 97.9% Table . The topResearch options that received low scores in this area were diverse and included research relating to fly control, the improved storage of weaning foods, and the development of interventions meant to curb bacterial contamination of crops.Priority scores for options evaluated based on sustainability and deliverability alone had the widest variation in obtained scores of the five criteria with scores ranging from 9% to 90%. The highest score in terms of sustainability and deliverability was given to effectiveness studies to increase the use of low-osmolarity ORS which obtained a priority score of 90% Table . The secE. histolytica and Camplylobacter.Research options scoring poorly in deliverability and sustainability included options to increase the use of refrigerators for the storage of weaning foods, cash-transfer programmes to improve the quality of diet and nutrition in poor areas, and vaccines for Priority scores to judge the maximum potential for disease-burden reduction ranged from 8% to 79% Table . The topLactobacillus GG.Low scores in maximal potential for disease-burden reduction were obtained by research options relating to fly-control interventions, effectiveness, and deliverability of cholera vaccine, and efficacy and effectiveness studies relating to use of probiotic The scores for equity were the highest of any of the criteria and ranged from 43.0% to 98.3%. All five top options received priority scores greater than 90% Table . The topLactobacillus GG, new antisecretory agents, and vaccines for E. histolytica, norovirus, and H. pylori.Low priority scores were obtained by research options to evaluate probiotic The overall priority scores that were assigned to research options by computing unweighted means of the five intermediate scores ranged from 35.0% to 85.2%  were, therefore, correspondingly low. While the aetiologic fractions may vary somewhat by region, few pathogens cause more than 10% of incident episodes globally, putting a practical ceiling on the overall diarrhoeal disease-burden reduction available by their control even with high efficacy and coverage. Further stifling the scoring were issues regarding to deliverability, and to a lesser extent, equity.It is somewhat surprising to see the predominantly intermediate ranks received by the research options that could broadly be categorized as dealing with water and sanitation, the theoretical mainstay to control the transmission of enteric diseases. Research options covered a broad range of issues, including those that deal with quality and quantity of water ; and a single research option addressing handwashing (research option 12). As a group, these obtained high scores in terms of equity and answerability and scores predominantly in the second quartile for maximum disease-burden reduction but lower scores in other categories, including deliverability and sustainability.Improving nutritional status has a key role in decreasing the burden of diarrhoeal disease. Two of the top 10 priority scores, overall, went to research options that included zinc, a micronutrient that has shown effects in decreasing the duration of diarrhoeal episodes and the risk of developing persistent diarrhoea. Increasing the coverage of vitamin A supplementation and increasing the energy-density of weaning foods in areas with food availability received priority scores of 71.2% and 67.5% respectively and were in the top quartile of rankings. Research to improve the quality of diet in areas with limited food availability obtained a more modest priority score of 61.0%. Cash-transfer programmes designed to improve diet in areas with restricted access were given a priority score of only 47.1% hampered in large part by the perceived problems in delivery and maintenance of the programmes.The research options that appear on the list are not comprehensive. These are rather meant to be a selection of the top research options representative of various strategies of diarrhoeal disease control. These include a balance between the development of new interventions with research that addresses improved implementation of interventions that have already been shown to be efficacious. We feel that the structured nature of the process of scoring research options leads to a significant improvement from previously-used methods involving expert consensus. The output is a list of ranking options developed by technical experts scoring independently to avoid problems associated with group dynamics in decision-making. The structure of the scoring process minimizes bias through its transparency and resulting accountability.The prioritization of research options has important implications for the assignment of available funds that are intended for the control of diarrhoeal disease and the improvement of child health. This approach to improve the decision-making process has steered away from informal meetings of experts that were classically used because of concerns of decision-making flaws resulting from both group dynamics (i.e. groupthink)  and vesthttp://www.icddrb.org/jhpn.One of the shortcomings of this scoring exercise done at this level and applied to a local level is related to problems of the context. When scoring is done, as was the case here, to be broadly applied to the majority of population of the developing world, assumptions are made that may not be truly representative of certain areas. A key example of this relates to issues of deliverability, cost, and sustainability. This criterion is the one most likely to vary between areas with different levels of political stability, public infrastructure, and economic resources. For these reasons, at the regional level, it is worth having a group of experts re-score research options for this particular criterion as this may optimize the overall evaluation of different research options in local contexts. An excel file that facilitates this process is available at A second shortcoming of this exercise was the limited availability of selected experts for the exercise. Although 19 experts were invited to participate, only 10 individuals contributed their priority scores. In the future, we would recommend linking the scoring activity to a meeting to facilitate higher participation rates among appropriate experts.Despite limitations of the CHNRI process, it has several advantages over existing priority-setting techniques. First, the transparency of the process in and of itself can be a roadmap to researchers and potential funding agencies in the area of interest. For example, if experts give a low scores for certain research option relating to issues surrounding deliverability and equity, researchers in the area will be stimulated to develop novel delivery strategies to deliver the intervention to those with the greatest need, and granting agencies can direct programme announcements to fund these proposals. Like the Delphi exercise, it controls the influence of group dynamics, although it does so to a greater extent because scorers are not ‘refocused’ or redirected by serial scoring exercises.It is clear that the domination of health policy and systems research among those obtaining the higher ranks is a consequence of results (effects on the burden of disease) being expected by 2015. A longer timeframe (e.g. 50 years) might allow more long-term strategic events to obtain higher scores. Furthermore, although the framework for scoring is transparent and systematic and it follows that rational answers to narrowly-formatted questions minimize personal biases, there is a possibility that a different group, composed of more policy-makers and programme officers rather than the group that preformed this exercise, may yield somewhat different results. Despite these limitations, we believe that this priority-setting exercise is a useful guide to investors in health research targeting diarrhoeal disease, who hope to observe measurable results prior to the end-date of the millennium development goals.This study was supported by the Child Health and Nutrition Research Initiative (CHNRI) of the Global Forum for Health Research, under support from the World Bank.


As a result of poor economic opportunities and an increasing shortage of affordable housing, much of the spatial growth in many of the world's fastest-growing cities is a result of the expansion of informal settlements where residents live without security of tenure and with limited access to basic infrastructure. Although inadequate water and sanitation facilities, crowding and other poor living conditions can have a significant impact on the spread of infectious diseases, analyses relating these diseases to ongoing global urbanization, especially at the neighborhood and household level in informal settlements, have been infrequent. To begin to address this deficiency, we analyzed urban environmental data and the burden of cholera in Dar es Salaam, Tanzania.2 in Dar es Salaam in 2006, and close to a fifty percent decrease in cholera incidence in wards where informal residents had minimally improved income levels, as measured by ownership of a radio or CD player on average, in comparison to wards where informal residents did not own any items about which they were asked. In this study, the range of access to improved sanitation and improved water sources was quite narrow at the ward level, limiting our ability to discern relationships between these variables and cholera incidence. Analysis at the individual household level for these variables would be of interest.Cholera incidence was examined in relation to the percentage of a ward's residents who were informal, the percentage of a ward's informal residents without an improved water source, the percentage of a ward's informal residents without improved sanitation, distance to the nearest cholera treatment facility, population density, median asset index score in informal areas, and presence or absence of major roads. We found that cholera incidence was most closely associated with informal housing, population density, and the income level of informal residents. Using data available in this study, our model would suggest nearly a one percent increase in cholera incidence for every percentage point increase in informal residents, approximately a two percent increase in cholera incidence for every increase in population density of 1000 people per kmOur results suggest that ongoing global urbanization coupled with urban poverty will be associated with increased risks for certain infectious diseases, such as cholera, underscoring the need for improved infrastructure and planning as the world's urban population continues to expand. In 2008, for the first time in human history, more than half of the world's population was living in urban areas, and this proportion is expected to increase. As a result of poor economic opportunities and an increasing shortage of affordable housing, much of the spatial growth in many of the world's fastest growing cities is a result of the expansion of informal settlements where residents live without security of tenure and with limited access to basic infrastructure. Although inadequate water and sanitation facilities, crowding, and other poor living conditions can have a significant impact on the spread of infectious diseases, analyses relating these diseases to ongoing global urbanization, especially at the neighborhood and household level in informal settlements, have been infrequent. To begin to address this deficiency, we analyzed urban environmental data and the burden of cholera in Dar es Salaam, Tanzania. We found that cholera incidence was most closely associated with informal housing, population density, and the income level of informal residents. Our analysis suggests that the current growth of many cities in developing countries and expansion of informal settlements will be associated with increased risks to human health, including cholera and other infectious diseases, and underscores the importance of urban planning, resource allocation, and infrastructure placement and management, as the rapidly progressive trend of global urbanization proceeds. In 2008, for the first time in human history, more than half of the world's population was living in urban areas, and this proportion is expected to increase. Much of the future growth in urban areas is expected to take place in developing countries, with Africa and Asia predicted to have nearly seven out of every ten urban inhabitants in the world by 2030 UN-HABITAT defines slums as urban areas where households lack one or more of the following conditions: access to an improved drinking water source, access to improved sanitation facilities, sufficient living area, durable housing in a non-hazardous location, and security of tenure 2 situated alongside the Indian Ocean. The city is comprised of three municipalities – Kinondoni, Ilala, and Temeke – which are divided into 73 wards  component of the outer membrane, and the strains that produce epidemic cholera belong to serogroup O1 or O139. V. cholerae O1 itself is classified into two biotypes, classical and El Tor, which differ clinically and biochemically. V. cholerae O1 biotype El Tor is responsible for the current seventh pandemic of cholera, and is the current cause of cholera in Dar es Salaam Though a cholera epidemic was first reported in East Africa in 1836, no cases were reported across Africa between 1870 and 1970 Cholera is most commonly caused by ingestion of water or food contaminated with fecal matter, and due to this mode of transmission, risk factors for cholera include lack of safe drinking water, poor sanitation, high population density, crowding, and lack of previous exposure, all of which are often common features in urban slum areas In order to gain a sense of the general pattern in cholera cases in Dar es Salaam and to identify a time period that might be particularly useful for analysis, weekly suspected cholera case reports from 2006 through June 2008 were gathered from the City Health Officer and analyzed over time and by municipality. Suspected cases included all those patients assessed at one of the city's three cholera camps (described in detail below) whose symptoms were deemed to meet the WHO case definition for cholera in endemic areas: “a patient older than 5 years who develops severe dehydration from acute watery diarrhea ; or any patient above the age of 2 years with acute watery diarrhea in areas where there is an outbreak of cholera” V. cholerae O1 during months when suspected cases were being reported. Rectal swabs were collected at the discretion of the attending health provider as part of routine diagnostic assessments and were not collected for research purposes. Cholera incidence was calculated by ward for each year, using the available cholera count data and population projections for each ward based on the 2002 Census Daily reports of suspected cases were collected from the District Medical Officer in each municipality, including information on the ward of residence, month and year. Where possible, information on the age and gender of suspected cases was also collected. Rectal swab results from those suspected cholera patients who were tested were also obtained from Amana Hospital in Ilala, from Temeke Hospital in Temeke, and from Mwananyamala Hospital in Kinondoni from 2006 through June 2008 in order to confirm the presence of In comparison to the year 2006, in which 8,753 cases of cholera were reported in Dar es Salaam, only 395 cases were reported in 2007 and only 216 cases had been reported by the end of June in 2008. Due to the high volume of cholera cases in 2006, we focused our analysis on this year alone. Though the number of cases by municipality was available for all months in 2006, the location of cases by ward for the months of June through September was unable to be retrieved. However, 89.2% of the year's cases occurred in other months, including the months with the highest number of cases. Therefore, our analysis focused on these eight months. In addition, by using data from the Unplanned Land Property Register Project, analysis was limited to the 45 of the city's 73 wards included in the project; included areas were predicted to contain 84% of the city's population  and 2. BAll potential cholera cases were sent to one of three cholera camps located in the city for further assessment and, if needed, treatment. These camps were located at Buguruni Health Center in Ilala, Mburahati Dispensary in Kinondoni, and at Temeke Hospital between Azimio and Tandika wards in Temeke. The geographic coordinates for these camps were obtained from the Tanzania Service Availability Mapping 2005–2006 Between 2004 and 2007, the Ministry of Lands and Human Settlements Development conducted a survey in informal settlements located in 45 wards as part of the Dar es Salaam Unplanned Land Property Register Project. The data were collected for administrative purposes. Data on 225,911 informal plots were gathered, mostly collected in 2005. Questionnaires were distributed to owners or close relatives, or, in the case of residences occupied by tenants only, tenants were questioned and the homeowner was notified in order to verify the information provided. Information was collected about plot use , the type and quantity of occupants, road access, source of water supply, type of sanitation, electricity, phone, building materials, length of time the occupants had lived in the area, ownership of household items and livestock, household income and type of employment, and garbage collection, among other characteristics.Of 207,085 plots whose use was known, 98.2% contained residences. Of 203,289 residential plots, 186,631 were occupied at the time of the survey, 23.9% of which were in Ilala, 37.4% of which were in Kinondoni, and 38.8% of which were in Temeke. Only records for occupied residential plots were included for analysis. Among these records, 97.5%  contained complete information about a water source, while 61.4%  contained complete information about sanitation.The number of informal residents in each ward was calculated by aggregating the number of occupants in each residential plot at the ward level. The percentage of informal residents in each ward was then calculated based on the 2006 population estimates. For three wards, estimates of the percent of the population that is informal were greater than 100. This is likely a result of rapid urban expansion that was underestimated by the population estimates. As a result, for these three wards, the maximum informal percentage obtained from other wards, which was 95.8%, was used. The percentage of informal residents in each ward was used as a proxy for the percent of residents in each area that would likely be living in areas with poorer environmental conditions.Access to improved drinking water and access to improved sanitation were assessed based on guidelines from the WHO Joint Monitoring Program for Water Supply and Sanitation Due to the lack of a reliable measure of income among informal residents, an asset index was constructed in order to serve as a proxy for long-term economic status and to provide a more sensitive means of differentiating between poor households Data analysis was conducted using only de-identified data, which were analyzed at the ward level. As a way to assess whether environmental conditions in informal settlements had an effect on the city's pattern of cholera incidence, correlations were first calculated between the natural log of cholera incidence in 2006 and the percentage of a ward's residents who were informal, the percentage of a ward's informal residents without an improved water source, the percentage of a ward's informal residents without improved sanitation, distance to the nearest cholera camp, population density, median asset index score in informal areas, and presence or absence of a major road.Including as predictors only those variables significantly correlated at the 95% confidence level with the natural log of cholera incidence, data on the number of cholera cases per ward in 2006 were used to estimate cholera incidence rate ratios associated with the percentage of a ward's residents who were informal, population density, the percentage of a ward's informal residents without improved sanitation, and median asset index score in informal areas. Since we sought to model the number of cholera cases, and considering that overdispersion was observed (i.e. the variance in the number of cholera cases exceeded the mean), a negative bionomial regression model was used for analysis, with the logarithm of a ward's population size included as an offset variable.V. cholerae O1 was identified by culture from rectal swabs taken from suspected cases in at least a third of those tested. The median incidence of cholera per 10,000 people in Dar es Salaam in 2006 was 15.8, with 25% percent of wards reporting an incidence of 7.8 cases or fewer per 10,000 people, and 25% of the wards reporting an incidence of 36.6 cases or higher per 10,000 people. The maximum incidence reported was 99.6, while one ward reported no cases  could possibly have significant impact on the burden of cholera in a slum area Individuals in densely populated urban slums characterized by poor sanitary conditions may be at particular risk of ingesting such hyperinfectious By suggesting that variations in the economic and physical conditions between and within informal settlements may translate into variations in disease patterns, this study validates previous findings that statistical analysis at the city level may mask important intra-urban differences. For example, infant and child mortality rates among Nairobi's slum populations were found to be three to four times higher than the city's average, and higher even than the average for rural areas in Kenya This pattern resembles the conditions resulting from rapid growth of European cities in the eighteenth and nineteenth centuries, which often led to a poorer health environment in urban areas V. cholerae infection, and that other actual cases of cholera were not captured in the municipal reporting system; however, all cases included in this analysis met WHO criteria, microbiologic data were highly supportive when performed, and reporting criteria did not change during the period of data collection. In addition, though the negative binomial model used in this analysis accounted for high variability in the number of cholera cases, it did not account for any spatial structure that might have been present in the data. Given that our model tended to underestimate the number of cholera cases in the center of the city while overestimating the number of cases farther from the center, a spatial model might have provided additional insight, but was not able to be used given the small number of wards for which data were available. By using an extant data set, we were also limited by incomplete survey information; however, we felt that the ability to analyze an urban environmental survey undertaken immediately prior to an urban cholera epidemic provided a unique opportunity for analysis and, at least in part, mitigated this limitation.Our study has a number of limitations. We analyzed cholera data collected during an epidemic, and patterns of endemic disease and factors involved in its transmission during endemic periods might be different than those we assessed. However, our use of data during the selected period allowed us to analyze a sufficient cholera case burden in the context of our measured environmental parameters. We used extant data sets reporting cholera burden that themselves were largely based on a syndromic classification system using WHO criteria. It is possible that cases classified as cholera where not caused by Similarly, while we may have obtained a more robust understanding of the risk of cholera had we analyzed data at the household or individual level (as opposed to the ward level), such data were not available. Such an analysis may have shown that access to specific water sources or certain types of sanitary conditions or behaviors may affect the risk for cholera within a household. For instance, in a randomized control trial in low-income squatter settlements with poor water and sanitation in urban Pakistan, children in households encouraged to wash their hands with soap had a 53% lower incidence of diarrhea than in control households It should also be mentioned that we made the assumption in this analysis that people who became ill with cholera did so due to conditions in their area of residence, while it may also be the case that where people work and the types of activities they engage in away from home may have an effect on their risk of diarrheal illness. For example, consumption of food prepared away from the home is increasing in many developing countries, and was found in Nairobi to be associated with the distance one worked from the home. Preparation of these foods often involves questionable hygienic practices, which may increase the risk of diarrheal disease for those who consume them In order to determine whether the relationship between environmental conditions and cholera in Dar es Salaam is unique or indicative of a more general relationship between environmental conditions and the risk for infectious disease, it would also be useful to compare the pattern of cholera incidence with patterns of other diseases across the city to see whether the nature and spatial pattern of risks are similar. For instance, one might predict that the risk for other enteric diseases such as shigellosis might similarly correlate with population density and sanitation, while tuberculosis and influenza might correlate with crowding, and vector-borne diseases such as arboviral infections and malaria might correlate more with water sources, vector biting habits, and human behavior.Equally important, as the municipalities have taken important steps in recent years to address conditions in informal areas, evaluating the impact of these efforts on the incidence of disease should be a crucial part of determining their effectiveness. For instance, in at least one example of informal settlement upgrading, improvements in health have already been noted. Specifically, the upgrading of an informal settlement in Hanna Nassif ward in Dar es Salaam from 1994 to 1998, which focused on the installation of water vending kiosks, the management of solid waste collectors, and construction of improved access roads and storm water drainage channels, led to a 39% reported decline in waterborne diseases from the start to the finish of the project In every developing region of the world excluding North Africa, slum growth is expected to closely match the rate of city growth


Plasmodium transmitted by female Anopheles species mosquitoes. Our understanding of the malaria parasites begins in 1880 with the discovery of the parasites in the blood of malaria patients by Alphonse Laveran. The sexual stages in the blood were discovered by William MacCallum in birds infected with a related haematozoan, Haemoproteus columbae, in 1897 and the whole of the transmission cycle in culicine mosquitoes and birds infected with Plasmodium relictum was elucidated by Ronald Ross in 1897. In 1898 the Italian malariologists, Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Camillo Golgi and Ettore Marchiafava demonstrated conclusively that human malaria was also transmitted by mosquitoes, in this case anophelines. The discovery that malaria parasites developed in the liver before entering the blood stream was made by Henry Shortt and Cyril Garnham in 1948 and the final stage in the life cycle, the presence of dormant stages in the liver, was conclusively demonstrated in 1982 by Wojciech Krotoski. This article traces the main events and stresses the importance of comparative studies in that, apart from the initial discovery of parasites in the blood, every subsequent discovery has been based on studies on non-human malaria parasites and related organisms.Malaria is caused by infection with protozoan parasites belonging to the genus  Malaria is an ancient disease and references to what was almost certainly malaria occur in a Chinese document from about 2700 BC, clay tablets from Mesopotamia from 2000 BC, Egyptian papyri from 1570 BC and Hindu texts as far back as the sixth century BC. Such historical records must be regarded with caution but moving into later centuries we are beginning to step onto firmer ground. The early Greeks, including Homer in about 850 BC, Empedocles of Agrigentum in about 550 BC and Hippocrates in about 400 BC, were well aware of the characteristic poor health, malarial fevers and enlarged spleens seen in people living in marshy places. For over 2500 years the idea that malaria fevers were caused by miasmas rising from swamps persisted and it is widely held that the word malaria comes from the Italian mal'aria meaning spoiled air although this has been disputed. With the discovery of bacteria by Antoni van Leeuwenhoek in 1676, and the incrimination of microorganisms as causes of infectious diseases and the development of the germ theory of infection by Louis Pasteur and Robert Koch in 1878-1879, the search for the cause of malaria intensified. Scientific studies only became possible after the discovery of the parasites themselves by Charles Louis Alphonse Laveran in 1880 and the incrimination of mosquitoes as the vectors, first for avian malaria by Ronald Ross in 1897 and then for human malaria by the Italian scientists Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Camillo Golgi and Ettore Marchiafava between 1898 and 1900. Excellent histories of this disease include those by Celli , RussellPlasmodium the life cycles of which are very similar  sporozoites, the infective stages, are injected by a mosquito and are carried around the body until they invade liver hepatocytes where (2) they undergo a phase of asexual multiplication (exoerythrocytic schizogony) resulting in the production of many uninucleate merozoites. These merozoites flood out into the blood and invade red blood cells where (3) they initiate a second phase of asexual multiplication (erythrocytic schizogony) resulting in the production of about 8-16 merozoites which invade new red blood cells. This process is repeated almost indefinitely and is responsible for the disease, malaria. As the infection progresses, some young merozoites develop into male and female gametocytes that circulate in the peripheral blood until they are (4) taken up by a female anopheline mosquito when it feeds. Within the mosquito (5) the gametocytes mature into male and female gametes, fertilization occurs and a motile zygote (ookinete) is formed within the lumen of the mosquito gut, the beginning of a process known as sporogony. The ookinete penetrates the gut wall and becomes a conspicuous oocyst within which another phase of multiplication occurs resulting in the formation of sporozoites that migrate to the salivary glands of a mosquito and are injected when the mosquito feeds on a new host.Bacillus malariae, which when isolated in culture and injected into rabbits caused febrile infections accompanied by enlarged spleens reminiscent of malaria [Oscillaria malariae. He presented his findings to the French Academy of Medical Sciences in December 1880 [Our understanding of the life cycle of the malaria parasites did not proceed in the logical order just outlined but more like a jigsaw in which the various pieces were painstakingly put into place and, like a jigsaw, often involved mistakes and false starts. The story begins with the discovery of the stages in the blood. Many textbooks merely state that 'in 1880 Laveran discovered the malaria parasite' words that do not give this discovery the credit it deserves. In order to understand the background of this discovery it is necessary to go back to the 1870s. The discoveries of Pasteur and Koch had precipitated a search for a bacterial cause for many diseases including malaria. By 1879 the miasma theory was going out of favour and the two theories vying for contention were whether the microorganisms responsible were transmitted (1) by air and inhalation or (2) by water and ingestion. The leading theory was that proposed by the Italian Corrado Tommasi-Crudeli and the German, Theodor Albrecht Edwin Klebs, an eminent microbiologist who had been the first person to see the bacteria responsible for typhoid and diphtheria. Tommasi-Crudeli and Klebs claimed that they had isolated from the waters of the Pontine Marshes, where malaria was prevalent, a bacterium,  malaria . It was ber 1880  but failber 1880 . His bigber 1880 . , malignant tertian  and quartan  malaria now respectively Plasmodium vivax, P. falciparum and P. malariae. The situation as it existed in 1900 is beautifully summarised by Grassi in his monograph, Studi di uno Zoologo Sulla Malaria [P. vivax which he described as P. ovale in 1922 [By this time it had also become clear that the paroxsms characteristic of malaria coincided with the bursting of infected red blood cells and the release of the products of multiplication something that Laveran, who had also realised that in the case of malignant tertian malaria the brain was involved, had proposed . Thus by Malaria  and, alt in 1922 .Haemoproteus columbae, a haematozoan closely related to the malaria parasites, observed flagellated structures which they described in detail and also recorded how the flagellated bodies fused with non-motile bodies to form a vermicule  [Halteridium; if it is correct, it is of the greatest importance' [The action now moves to Canada in 1897 and to the United States a year later where a medical student, William MacCallum, and his colleague, Eugene Opie, while examining the blood of crows infected with okinete) . MacCallokinete) ,29) and okinete) . The sigokinete)  but was ortance' ,32. HereDespite all their accumulated knowledge and skills no malariologists could explain how the parasite spread from one human to another. The clues were, however, in place. Over the centuries, circumstantial evidence had accumulated that suggested that mosquitoes might somehow be connected with malaria and by 1883 the American physician, Albert King, had assembled the mass of evidence that was to become known as the mosquito-malaria doctrine . BetweenBy 1894 Manson, who had spent much of his working life in Taiwan and was then in his 50s and in an established medical practice in London, turned his attention to the possibility of mosquito transmission of malaria but, as he was unable to go to malarious countries himself, he needed someone to carry out the necessary investigations and experiments for him. His colleague-to-be was an unlikely choice, Ronald Ross Figure .Plasmodium relictum and suggested that human malaria parasites might also be transmitted by mosquitoes. Later, when working in Sierra Leone in 1899, he demonstrated that the human malaria parasites were indeed transmitted by anopheline mosquitoes. In the meantime, however, several Italian scientists had already shown that this was the case.Ronald Ross 1857-1932. In 1897 Ronald Ross working in India discovered that culicine mosquitoes transmitted the avian malaria parasite Ross then aged 37 was an established army surgeon working in India who did not believe that malaria was caused by a blood parasite but thought that it was an intestinal infection. Throughout the second half of 1894, Manson worked on Ross, showed him blood slides containing malaria parasites and convinced him that incriminating a mosquito vector of malaria was a goal worth aiming for. Ross returned to India and over the next four years Manson directed operations at a distance and we are fortunate to have an almost complete collection of the letters that passed between the two men . This waProteosoma relictum , common in many species of birds including crows and sparrows. This parasite, he discovered, was transmitted by his 'grey' (culicine) mosquitoes, probably Culex fatigans. Of 242 'grey' mosquitoes fed on infected birds, 178 developed pigmented spores. Ross concluded that mosquitoes fed on infected birds took up male and female gametocytes which fertilized in the mosquito gut and developed into spores on the surface of the mosquito's gut within which rod-like structures were produced that invaded the mosquito's salivary glands and were injected into a new host when the infected mosquito fed. His results were made public in 1898 [Manson, who had access to malaria patients in London, had observed that it was only when blood taken from such patients began to cool that the flagellated forms and subsequent fertilization, as described by MacCallum, appeared and concluded that further development must occur outside the human body in another host, probably a mosquito. Ross, having returned to India, examined several thousand mosquitoes from endemic areas without any success but, remembering Laveran's dictum 'follow the pigment' and Manson's advice to 'follow the flagellum', a reference to the flagella of the male gamete, he eventually found pigmented bodies, which he called spores, on the stomach wall of a mosquito experimentally fed on an infected patient. Ross was no entomologist (in fact the only book he had on entomology was one written for anglers) so he classified the mosquitoes he was studying as grey or barred-back (A), brindled (B), and dappled-winged (C). We now know that the grey mosquitoes were culicines and that the dappled-winged mosquitoes were anophelines. Grey mosquitoes were very common but never contained the pigmented spores. On the other hand the rarer 'dapple-winged' mosquitoes, after being fed on a malaria patient, were found to contain pigmented bodies that ruptured releasing 'rods' that invaded the mosquito's salivary glands. Ross had now made the crucial break-through and had found developmental stages of human malaria parasites in anopheline mosquitoes and, in his letters, he calls August 20th 1897 'Mosquito day' ,32. Ross in 1898 ,36. Ross in 1898 . These e in 1898 .Plasmodium relictum in culicine mosquitoes and had come tantalizingly close to completing the mosquito stages of the human malaria parasites the actual proof of the transmission of human malaria by anopheline mosquitoes still remained unresolved. Ross recorded that one single experiment could bring about the life cycle of human malaria [Although Ross had elucidated the whole of life cycle of  malaria  but his Anopheles claviger mosquitoes on infected patients and subsequently transmitted the infection to uninfected individuals via the bite of these mosquitoes [Anopheles mosquitoes could transmit malaria and methodically consolidated their findings and described the whole blood-mosquito life cycles of P. vivax, P. falciparum and P. malariae . Ross,  Ascenzi , Dobson  Ascenzi  and Fant Ascenzi  which weThe discovery of the role of mosquitoes in the transmission of malaria provided malariologists with a new weapon against this ancient disease. In a classical experiment, Grassi dispatched 112 volunteers to the Capaccio Plains, a malarious area in Italy, protected them from mosquito bites between dusk and dawn and found that only five succumbed to the disease compared with 415 unprotected volunteers who all contracted malaria . Thus thBabesia bigemina, an intraerythrocytic protozoan resembling a malaria parasite, could infect susceptible animals and this was confirmed in a series of meticulously controlled experiments over the next two years [One surprising aspect of this whole story is that some of the clues about arthropod-transmission of blood-inhabiting protozoa were available several years before Ross and the Italian scientists began their investigations. In 1890 the American microbiologists Theobald Smith and Frederick Kilborne had observed that young ticks taken from cattle infected with the piroplasm wo years . It is sP. vivax [P. relictum in the liver and spleen of infected birds [P. gallinaceum infections in chickens there was phase of multiplication between the injection of sporozoites and the appearance of parasites in the blood and that this occurred in cells of the reticuloendothelial system [The life cycle in humans, however, remained incompletely understood and nobody knew where the parasites developed during the first 10 days or so after infection during which they could not be seen in the blood. Grassi was the first to suggest that there must be some developmental stage in cells other than red blood cells, possibly white blood cells . This thP. vivax . No one ed birds  and thered birds ,44. In 1l system .Plasmodium and Haemoproteus species, differing only in detail particularly relating to the types of cells involved which varied from species to species, had been worked out. What happened in primates was not so clear and during the 1930s and 1940s there were sporadic reports of parasites in the tissues, particularly in the brain and nervous system, of animals infected with primate and bat malarias. After the end of the Second World War in 1945 malaria research throughout the world intensified and a number of workers became convinced that that there must be an exoerythrocytic stage in the life cycle of the primate malarias but what form this took was not known. This question was not resolved until 1947 when Henry Shortt and Cyril Garnham, working in London, showed that a phase of division in the liver preceded the development of parasites in the blood [Hepatocystis kochi, another parasite of monkeys first identified by Laveran as Haemamoeba kochi. Hepatocystis spp. are related to malaria parasites but do not have an erythrocytic stage in their life cycles so these parasites must have only an exoerythrocytic stage which in H. kochi is in the parenchyma cells of the liver [P. cynomolgi in rhesus monkeys for their investigations. Previous attempts by other workers had failed to find any liver forms so Shortt and Garnham decided to use 500 infected A. maculipennis atroparvus, a massive dose of sporozoites, and found exoerythrocytic stages seven days later [P. vivax in human volunteers [P. falciparum in 1949 [P. ovale in 1954 [P. inui, a quartan form of primate malaria. The exoerythrocytic stages of P. malariae were more elusive and it was not until 1960 that Robert (Bill) Bray demonstrated their presence in experimentally infected chimpanzees [By the late 1930s there was no doubt that in all the avian malaria parasites studied there was a phase of multiplication in various nucleated cells before (and after) parasites appeared in the blood and over the next decade the complete life cycles of a number of avian he blood . The cruys later . Shortlylunteers  and subs in 1954 . In the mpanzees . The stompanzees  and updaP. vivax? This led to the discovery of dormant exoerythrocytic stages, hypnozoites, by Wojciech Krotoski, working with Garnham's team, in 1982 [The story of the life cycle of the human malaria parasites was almost complete and had taken nearly 70 years to elucidate. There remained, however, one further question; what caused the long prepatent period between infection and the appearance and reappearance of parasites in the blood seen in some temperate strains of  in 1982 .Hepatocystis in non-human primates were first recognised by Laveran in1899 but true malaria parasites, Plasmodium spp., were not identified with certainty until 1907 with the independent discoveries of P. cynomolgi, P. inui, and P. pitheci in monkeys imported into Germany from Java [P. knowlesi in 1932 [P cynomolgi, P. inui and P. knowlesi in humans suggesting that some primates might act as reservoirs for human malaria but it appeared that the chances of such naturally acquired infections were very remote. However it is now known that humans are at risk from infection with P. knowlesi, a malaria parasite with a 24 hour erythrocytic cycle, in Southeast Asia where its natural hosts are macaque and leaf monkeys. Until 1971 there had only been two authenticated cases of naturally acquired human infections with P. knowlesi both in peninsular Malaysia. No other cases were recorded until 2004 when a focus of human infections was identified in Sarawak, Malaysian Borneo [P. knowlesi is a zoonosis involving macaque (Macaca spp.) and leaf (Presbytis spp.) monkeys as reservoir hosts with mosquitoes belonging to the Leucosphyrus group of Anopheles mosquitoes as the vectors in Malaysia and elsewhere in Southeast Asia [P. malariae in Malaysia were misidentified and that they were in all probability due to P. knowlesi [It has already been noted that malaria-like parasites are commonly found in birds, mammals and reptiles and studies on many of these have contributed to our overall understanding of human malaria. Malaria-like parasites belonging to the genus rom Java . Through in 1932 ,54. Durin Borneo . Since tast Asia . Retrospknowlesi .P. relictum, which has contributed most to our understanding of the transmission of human malaria parasites, and P. gallinaceum which not only contributed to our understanding of the exoerythrocytic phases of the malaria life cycle but also, because it could easily be maintained and mosquito-transmitted in chickens, served at the main model for chemotherapeutic studies until the discovery of rodent malarias.The first avian malaria parasites were discovered at about the same time as the human species and there are now about 24 species including P. berghei, was identified and isolated from wild rodents in Central Africa by Ignace Vincke and Marcel Lips in 1948 and subsequently adapted to mice, rats, hamsters and gerbils and easily maintained laboratory-bred mosquitoes such as A. stephensi [P. yoelii, P. vinckei and P. chabaudi, of which there are a number of subspecies and strains, have been identified, isolated and adapted to laboratory rodents and have become the mainstay of studies on chemotherapy and have served as surrogate models of human malaria in the fields of immunology, genetics, molecular biology and biochemistry [The first rodent malaria parasite, tephensi . Since themistry .P. falciparum, thus reducing their dependence on laboratory animals and blood taken from humans. The ease with which the erythrocytic stages could be grown in bulk made it possible not only to test the effects of drugs directly but also to isolate and purify parasite components in order to identify biochemical pathways and molecules of potential use in the development of vaccines and chemotherapy. The cultivation of sexual stages provided insights into the genetics of human malaria parasites and the development of drug resistance. The cultivation of liver stages, although more difficult to achieve, made it possible to develop and test drugs against these stages and provided vital information about the immune responses in the liver. Finally, the cultivation of sporogonic stages has enabled scientists to discover what happens to the parasite in its mosquito vector.One of the most important breakthroughs in malaria research was the development of techniques that enabled scientists to grow the erythrocytic stages of malaria parasites in continuous culture pioneered by William Trager and J.B. Jensen  thus frePlasmodium falciparum [The final stage in the story of our understanding of the malaria parasites that began when an unknown French scientist, working by himself in Algeria with a crude microscope, noticed that the blood of patients suffering from malaria contained organisms that he identified as parasitic protozoa culminated 122 years later when a massive team of investigators determined the compete genome of lciparum  since whlciparum .Haemoproteus columbae, in birds in 1897, Ross was the first to show that any malaria parasite, in this case the avian Plasmodium relictum, was transmitted by the bite of infected mosquitoes in 1897 and, by implication, that this would be the case for human malarias and in 1898 Grassi, Bignami and Bastienelli were the first to demonstrate that human malaria parasites were actually transmitted in this way. The most far-reaching discovery made by Ross, and one that is frequently ignored, was that a blood-sucking insect could not only take up infective organisms from an infected individual but could also transmit them some time later when it fed on an uninfected host something that was completely contrary to the received opinion of the time. It took a long time before other investigators realised the universal importance of this discovery and it was not until the first decades of the twentieth century that diseases such as African trypanosomiasis, leishmaniasis, filariasis and loaiasis were discovered to be transmitted by the bites of infected insects. This discovery was not missed by virologists who, after the discovery of viruses, soon established the concept of arthropod-borne or arboviruses or by bacteriologists looking for the mode of transmission of the plague bacillus. The tissues stages in the blood were discovered half a century later, in 1947, by Shortt and Garnham and the final mystery, the persistence of liver stages was established by Krotoski in 1962. The story of the elucidation of the complex life cycle of the malaria parasites was only possible because the various scientists involved were able to transfer knowledge gleaned from non-human malarias in birds and primates to the problem of human malaria thus emphasising the importance of comparative studies in the investigation of human diseases.Over a century later it seems appropriate to attribute the various discoveries concerning the malaria parasites and their transmission as follows. Laveran was the first person to find parasites in the blood of patients infected with malaria in 1880, MacCullum was the first to observe the sexual stages of a malaria-like parasite, The author declares that they have no competing interests.