N = 22], explanatory factors for mental health [N = 25], or both [N = 5] were identified. Consistent across cohorts, higher prevalence rates of internalizing disorders were found for women and more externalizing disorders for men. Risk and protective factors for mental health included social factors, lifestyle, physical health, body mass index (BMI), diabetes, genetic and biological factors. In all areas, differences and similarities were found between women and men. The most evident were the sex-specific risk profiles for depression with mostly external risk factors for men and internal risk factors for women. Gender was not assessed directly, therefore we examined whether socioeconomic and family-related factors reflecting gender roles or institutionalized gender could be used as a proxy for gender. Overall, this systematic review shows differences and similarities in prevalence rates and determinants of mental health indicators between women and men. They underline the importance of focussing on sex specific approaches in mental health research and in the development of prevention measures. Current research on mental health still lacks focus on gender aspects. Therefore, an increased focus on sex and gender in mental health research is of great importance.In Germany, large, population-based cohort studies have been implemented in order to identify risk and protective factors for maintaining health across the life span. The purpose of this systematic review is to analyse findings from three large ongoing cohorts and to identify sex-specific prevalence rates, risk and protective factors for mental health. Published studies from the Cooperative Health Research in the Region Augsburg (KORA), the Study of Health in Pomerania (SHIP) and the Gutenberg Health Study (GHS)), representing the southern, north-eastern and middle parts of Germany, were identified through searches of the databases PubMed and Web of Science. A total of 52 articles was identified from the start of each cohort until June 2019. Articles reporting prevalence rates of mental health [ Mental disorders have become major public health concerns affecting quality of life, work productivity and life expectancy  of a larMental health differences between women and men have been attributed to sex and gender differences. Rooted in genetics, anatomy, and physiology , sex repSex and gender differences vary across countries and regions . In a stN = 15 010 respondents, 35–74 years; KORA: N = 18 079 respondents, 25–74 years; SHIP: N = 12 324 respondents, 20–79 years). The three German regions differ regarding socioeconomic and economic parameters: Unemployment rates are highest, discretionary incomes, and life expectancy lowest in Greifswald (SHIP). As the eastern and western states of Germany have evolved in different political and economical systems following the 2nd World War, these regions show pronounced differences regarding full-time employment rates among mothers resulting in different gender pay gaps  [formerly Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA)], the Study of Health in Pomerania (SHIP) and the Gutenberg Health Study (GHS), representing different German regions, respectively, the southern, north-eastern and middle part of Germany. KORA focusses on the fields of epidemiology, health economics, and health care research , SHIP copay gaps .These three cohorts also include mental health variables and are therefore particularly suitable to derive knowledge on sex, mental health and their relationships to physical health. The GESA consortium  has recently been established to enable future conjoint analyses . The purKORA,” “Cooperative Health Research in the Augsburg Region,” “SHIP,” “Study of Health in Pomerania,” “GHS” or “Gutenberg Health Study” combined with “mental health,” “sex,” or “gender.” English and German publications were considered. Unpublished papers, abstracts, dissertations and book chapters were not included. The search took place from April until June 2019.Published studies were identified through searches of the databases PubMed and Web of Science. We included studies from initiation of each cohort until June 2019. KORA started in 1996  followinTo decide whether an article fulfilled the criteria, the first rough selection was made by inspecting the title and abstract of the article. To identify relevant studies, the following inclusion criteria were used:1) studies using KORA, SHIP or GHS data;2) cross-sectional and longitudinal/prospective studies addressing mental health;3) studies containing sex, respectively gender.Furthermore, it was required that the articles either (1) contained descriptive statistics on mental health variables including statistical tests that probed for differences between women and men, or (2) tested factors related to mental health with separate analyses for women and men, respectively analyses with an interaction term for sex. We only selected papers that included mental health as a dependent variable. This first group of articles was used to describe prevalence rates of mental health for women and men. The second group of articles was analyzed to describe explanatory factors for mental health between women and men. Of the selected articles the literature list was meticulously examined and further relevant articles were selected. Articles including analyses with mental health as dependent variable, but only including sex as a control factor, were not taken into account. Articles containing descriptive statistics for mental health aspects, but without differences between women and men  were excluded. Lastly, we excluded methodological papers. The selection procedure is displayed in detail in Mental health is a broad concept. In this article, we were guided by the definition of WHO including mental, physical and social well-being, not just the absence of mental disorders . SimilarN = 22], explanatory factors for mental health [N = 25] and articles reporting both [N = 5].Our search strategy has identified 52 articles reporting GHS, KORA or SHIP data on mental health and sex differences. We found articles reporting prevalence rates of mental health [Articles assessing gender differences based on gender identity and gender relations were not found, but some articles included variables indicating gender aspects related to gender roles and institutionalized gender. Previous research indicated gender differences in power, responsibilities and in dimensions of the self , contribThe articles reported a broad range of prevalence rates of mental health indicators for women and men. The articles are consistent in their findings, but most prevalence rates were only reported in one or two of the three cohorts, based on specific diagnostic instruments. The results are listed in In general, women reported more mental health problems than men , 39. RegWomen reported more somatic complaints compared to men , 57. ThiA broad range of factors was associated with mental health. We categorized the results in five categories: (1) social and gender-related factors, (2) lifestyle, (3) interplay of physical and mental health, (4) body mass index (BMI) and diabetes and (5) genetic and biological factors. An overview of the results can be found in The three cohorts have been drawn as local representative samples of the general population, stratified for sex, age, and urban-rural residence. In all cohorts, women had a lower income than men. Furthermore, men were more often married or living with a partner, whereas more elderly women were living alone. In addition, life expectancy differed between the regions; life expectancy was highest in the middle of Germany and lowest in the northeast of Germany. The demographic and socioeconomic differences between the cohorts influenced associations with mental health.Social support and social isolation were often associated with mental health. Lack of social support was a strong predictor for somatic symptoms for both women and men . For oldWith regard to gender-related factors, findings for women and men were similar. Social economic status predicted somatic symptoms for women and men . Low incSmoking and physical inactivity are known factors to negatively influence physical and mental health. Smoking was a risk factor for new onset of depression, but only in men . BesidesThe interplay between physical and mental health has been examined in many studies included in the current review. For both women and men chronic diseases were associated with worse mental and physical well-being . For womObesity and diabetes are significant health threats in an aging population. When comparing women and men in the association between BMI and HRQL , women with a higher BMI reported lower physical HRQL later in life than men with a higher BMI . Anothers/s-genotype and the s/l-genotype on the serotonin transporter gene in combination with unemployment or chronic diseases was related to higher mental and physical distress for women  should be further examined . Mental Overall, this systematic review shows the differences and similarities in prevalence rates and determinants of mental health indicators between women and men, from genetic and biological factors to indicators of the social environment. While our picture is far from complete, gender gaps regarding income, education, or living in a relationship underline the need to differentiate mental health outcomes according to sex-related determinants of mental health. Differing risk and protective factors for mental health require a sex sensitive prevention approach. However, this review shows that current research on mental health still lacks a clear focus on gender roles and identities, which have recently been included in the Gutenberg Health Study. Future research should therefore illuminate sex differences and broader sex and gender diversity . TherefoThis review was written as part of the GESA Project. All authors contributed to the development and refinement of the GESA consort. MB, EB, HB, HG, JK, K-HL, GS, and PW were grant holders. The idea for this paper came from DO and MB. DO performed the literature search, selection of paper and drafted, together with MB, the first version of the review, which was substantially revised by GS, AT, and EB. Improvements of HB, JK, K-HL, PW, and HG lead to the current version of this review.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.


Anopheles mosquitoes and Plasmodium parasite development. Thus, as climate changes, shifts in geographic locations suitable for transmission, and differing lengths of seasons of suitability will occur, which will require changes in the types and amounts of resources.Malaria continues to be a disease of massive burden in Africa, and the public health resources targeted at surveillance, prevention, control, and intervention comprise large outlays of expense. Malaria transmission is largely constrained by the suitability of the climate for The shifting geographic risk of malaria transmission was mapped, in context of changing seasonality , and the number of people affected. A published temperature-dependent model of malaria transmission suitability was applied to continental gridded climate data for multiple future AR5 climate model projections. The resulting outcomes were aligned with programmatic needs to provide summaries at national and regional scales for the African continent. Model outcomes were combined with population projections to estimate the population at risk at three points in the future, 2030, 2050, and 2080, under two scenarios of greenhouse gas emissions (RCP4.5 and RCP8.5).Estimated geographic shifts in endemic and seasonal suitability for malaria transmission were observed across all future scenarios of climate change. The worst-case regional scenario (RCP8.5) of climate change predicted an additional 75.9 million people at risk from endemic (10-12 months) exposure to malaria transmission in Eastern and Southern Africa by the year 2080, with the greatest population at risk in Eastern Africa. Despite a predominance of reduction in season length, a net gain of 51.3 million additional people is predicted be put at some level of risk in Western Africa by midcentury.This study provides an updated view of potential malaria geographic shifts in Africa under climate change for the more recent climate model projections (AR5), and a tool for aligning findings with programmatic needs at key scales for decision-makers. In describing shifting seasonality, it was possible to capture transitions between endemic and epidemic risk areas, to facilitate the planning for interventions aimed at year-round risk versus anticipatory surveillance and rapid response to potential outbreak locations. Malaria causes an estimated 435,000 deaths per year, with the majority of cases occurring in sub-Saharan Africa, affecting children under 5 disproportionately . Recent R0 curve, was found to best capture spatial and seasonal risk for Africa, from independent models of malaria risk prediction, based on statistical models of spatial case data from the Mapping Malaria Risk in Africa (MARA) and Malaria Atlas Project (MAP) projects [Geospatial modelling approaches provide a flexible framework in which to explore possible future scenarios of malaria risk as a function of changing climate . Mordecaprojects , 6–8.Climate change threatens to the alter the nature of future malaria exposure across Sub-Saharan Africa , 6, 7. MThe goals of this study were to (1) identify new areas that will emerge as suitable for malaria transmission under different scenarios of change; (2) identify areas that may experience reductions in transmission suitability season length; and (3) provide an estimate of the human population at risk under each scenario. These are presented in the language of malaria seasonality risk, to align with surveillance and intervention targeting goals, and summarized as regional scale outcomes, broadly aligned with USAID’s planning scales, as the parent aid organization of much of the US investment in the global malaria strategy.R0, the basic reproductive rate of the disease, in order to account for the fitting of these rates to laboratory measurements:The model for temperature-dependent malaria transmission presented in Mordecai et al.  used thiThe temperature-dependent parameters are the mosquito biting rate (a), vector competence (b*c), mosquito density (m), the mosquito survival rate (p), and the parasite’s extrinsic incubation period (T), all of which are measurable empirical parameters.Anopheles gambiae and the malaria pathogen Plasmodium falciparum, with additional information used for related Anopheles and Plasmodium species. Transmission, R0 was scaled from 0 to 1, to describe relative transmission suitability across the range of temperature. In the paper by Ryan et al. [The model incorporated temperature response curves fit for the mosquito species n et al. , the topn et al. ; this isCurrent temperature data is represented by globally gridded 5 arc-minute WorldClim (version 1) monthly mean temperature data . This re2). For strategic planning in malaria prevention and control, information is required on a much more local scale than GCMs can provide. Here, a statistically downscaled multi-model ensemble product is used for this analysis, compiled at a resolution of 5 arc-minutes (~ 10 km2) from 6 downscaled GCMs. The climate projection data used in this study consisted of the median value for the multimodel ensemble representing future climate, compiled from the Coupled Model Intercomparison Project (CMIP5) archive, downscaled using a Change Factor (CF) approach and sourced from Navarro-Racines et al. [General Circulation Models (GCMs) are the primary source of information about potential future climate. GCMs comprise simplified but systematically rigorous mathematical descriptions of physical and chemical processes governing climate, including the role of the atmosphere, land, oceans, and biological processes. They allow for modelling the expected climate response to increasing greenhouse gas concentrations. The direct application of GCM output to adaptation decision making, however, has been relatively limited due to GCMs’ coarse spatial resolution  require an appropriate level of moisture in their environment to provide breeding habitat with which to complete their lifecycle. Humidity or moisture is thus another component in the climate–transmission relationship. While several models use rainfall as a predictor for malaria occurrence, it is complicated to generalize how precipitation measures, such as monthly rainfall totals, cumulative rainfall, or relative humidity, actually manifest as breeding habitat for mosquitoes at large scales [e scales –15.Anopheles breeding. The threshold of “too dry” is based on prior work conducted by Suzuki et al. [Precipitation may not be a good indicator of standing water, and in a world of increasingly extreme precipitation events, the difference between a month’s rainfall occurring in a single day versus gradual accumulation over that month becomes more relevant. Mosquito habitat can wash away, “flushing” away eggs and disrupting the lifecycle, meaning that more rain does not necessarily translate into more habitat . In addii et al.  to exclui et al. . A modifi et al.  was usedi et al.  and monti et al. . That is2) resolution were downloaded. Population data for Africa used as input for calculating population at risk (PAR) under the various transmission scenarios were derived from the Gridded Population of the World, Version 4 (GPWv4) [Global gridded population products, the Gridded Population of the World (GPW), at a 30 arc-second (~ 1 km (GPWv4) , with baThe gridded temperature data  were constrained to the temperature range of the optimal quantile of transmission, and the resulting number of months of transmission suitability in each pixel recorded for all of Africa. The aridity mask was applied, and pixels falling in masked areas were given no value.Seasons of transmission were defined based on the numbers of months of suitability, and criteria established by MARA were followed in defining malaria transmission suitability, with very slight additional granularity to better illustrate the impact of changing climate Table .Table 1D2 at the equator). Population data for each scenario were summarized by region, shown in Fig. In order to estimate the population at risk (PAR) for each geospatial research question, the suitability data were aggregated by a factor of 10 and aligned to the climate data, such that all analyses were conducted at 5 arc-minute resolution  transmission suitability for malaria is concentrated in the Central African region, with additional areas along the southern coast of Western Africa, and along the eastern coast of Eastern Africa, and in the north of Madagascar . This includes large portions of Zambia, Malawi, and Tanzania, eastern South Africa, Botswana, the highlands of Zimbabwe, northern Mozambique, and the Zambezi River Basin. Hotspots of seasonal malaria transmission suitability are predicted to either continue to concentrate or shift both northward and southward into the highlands of Ethiopia and Southern Africa toward the latter part of the 21st century.Examining the results of projected climate transmission risk models—RCP 4.5 and RCP 8.5, across the 3 future time horizons of 2030, 2050, 2080—a low of 196 million and a high of 198 million people in Eastern and Southern Africa are predicted to be burdened with some degree of malaria transmission risk in the future due to shifting suitability by the 2080s. Regionally, by the year 2080, the worst-case scenario (RCP 8.5) predicts an additional 73.4 million people at risk from year-round exposure to transmission in Eastern Africa , eliminating suitability across Central Africa. The end-of-the-century scenarios (2080) predict concentrated areas of endemism in previously unsuitable or marginally suitable areas, namely the highlands of East Africa and Southern Africa. Where the number of months of suitability for Anopheles survival decrease, opportunities will emerge to alter and define more targeted seasonal responses, either reducing the cost of interventions or providing a window into potential eradication to malaria exposure. Targets of opportunity include Central Africa  and coastal East Africa (Tanzania and Kenya).These shifts in the geographic range of malaria suitability, broadly consistent across both scenarios of future climate, suggest both decreases and increases in the number of people exposed, depending on the climate scenario. The geographic and temporal evolution of future suitability of areas for malaria-transmitting ios Fig. . As tempios Fig.  and 5, sSome parts of sub-Saharan Africa currently predicted to experience no malaria transmission suitability risk will experience shifting suitability, resulting in novel areas with no history of malaria transmission becoming suitable for endemic and seasonal transmission in the future. As seen in Fig. The changes in the geographic range of malaria suitability, broadly consistent across both scenarios of future climate pathways modelled here, suggest that the number of people exposed to conditions of malaria suitability will both increase and decrease in sub-Saharan Africa, depending on the region. Thus, as some populations experience reduced burden of malaria risk in the future, shifting suitability will increasingly place naïve populations at risk for outbreaks, particularly in Southern and Central Africa. Malaria outbreaks that occur where people have little or no immunity to the disease can lead to epidemic conditions, especially among vulnerable groups such as women and children , 20. ThiAnopheles survival decreases, opportunities will emerge to alter and define more targeted seasonal responses—either reducing the cost of interventions or providing a window into potential eradication to malaria exposure. An increase in the number of months where conditions are suitable for mosquito survival will require responses to be extended for longer periods of time, increasing resource needs  as well as costs [These results identify regions where interventions need to be revisited to consider how climate will alter risk profiles in the future. The strong seasonal cycle of malaria across Southern Africa is related to climate and weather conditions , 26. Thuas costs . In examA fundamental underpinning of modelling the response of vector-borne diseases to climate and ecology is the choice of model process. Previous approaches, such as that of the Malaria Atlas Project (MAP) and the Mapping Malaria Risk in Africa (MARA) project, are essentially top-down, wherein empirical data collected on the ground are matched to local climate conditions, and suitability established via geostatistical methods. In contrast, the modelling approach used here is mechanistic and “bottom-up,” wherein the life history of mosquitoes and pathogens, and their responses to temperature, are explicitly quantified based on empirical, laboratory-based data and incorporated into the model to predict where suitability for transmission is likely to occur. A mechanistic model, built independently of case outcome data, allows for validation with empirical, field-collected data, and obviates the bias of modelling data while intervention is ongoing, as is inevitably the case with previous approaches . In thisWhile substantial progress has been made in recent years in the provision and use of climate projections, considerable uncertainties remain with their use . Using cFor the population data specifically, it is important to recognize that the projected population for 2020 is used to calculate the numbers of people potentially affected by changing suitability conditions across all future time periods. As with climate models, these projections do not necessarily capture all the factors that drive population movement and growth, and should be taken as best modelled estimates rather than exact values. Future studies can incorporate the additional projected population responses to climate change scenarios themselves, via such projects as the Shared Socioeconomic Pathways (SSP) projections, which offer multiple scenarios of population changes in response to potential social, environmental, and other drivers of societal development and change, as the climate changes into the future . Given tAnopheles mosquitoes and malaria pathogens. Nevertheless, many studies point to the critical role that rainfall plays in vector survival across sub-Saharan Africa [Anopheles survival is critical, the available projections of rainfall are uncertain at the geographic scale of this work and, therefore, are not considered in this analysis.The study results are based on the temperature response curves of both n Africa , 14, 15.n Africa , 38. Simn Africa . The appGeographically projected model outputs are a useful component of a planning and intervention framework, providing a means of communicating key areas of risk and affected populations to decision makers. Anticipation of not only the location and time, but the duration of potential outbreak events will facilitate the development of efficient and timely agency responses. Moreover, this framework serves as a foundation for scenario analysis, explicitly modelling risk of exposure for different climate scenarios and time horizons. The range of potential outcomes allows governments and agencies the flexibility needed to reasonably anticipate resource use and funding needs, enabling the development of adaptive intervention strategies for both near and long-term outcomes.Addressing the changing risk profiles projected in this suitability analysis will require modifying current interventions and programmes and implementing new ones to explicitly consider climate variability and change. While these projections of mechanistic models coupled to ensembled climate predictions for fixed time horizons  and fixed population projections are simplified, they present a framework within which those potential futures can be explored, and examine both where and when changing risk is anticipated. Opportunities for improved responses also exist, including detailed geographic targeting, optimizing strategies and seasonal alignment with interventions. Identifying high risks in new areas of suitability present opportunities for informed action. Where malaria suitability is currently nonexistent to newly suitable, whether seasonal or endemic, the risks are critical, especially given that local populations’ immunity will be low. This could lead to the potential emergence of novel strains, rapid resistance, and untimely identification, translating into epidemic outbreaks. To respond, targeted and informed geographic surveillance in these regions could help to prepare timely responses before epidemic outbreaks occur. Knowing where and when more people will potentially be exposed offers an opportunity to increase the investment timeframe , optimize vector control, and improve case management, with the evidence base to support these actions. Moving down the path toward elimination for some regions, where malaria transmission suitability decreases, opportunities will arise to focus resources on making surveillance and response systems increasingly sensitive and focused to identify, track, and respond to malaria cases and any remaining transmission foci.


Low- and middle-income countries (LMICs) account for a higher burden of noncommunicable diseases (NCD) and home to a higher number of premature deaths (before age 70) from NCDs. NCDs have become an integral part of the global development agenda; hence, the scope of action on NCDs extends beyond just the health-related sustainable development goal (SDG 3). However, the organization and integration of NCD-related health services have faced several gaps in the LMIC regions such as India. Although the national NCD programme of India has been in operation for a decade, challenges remain in the integration of NCD services at primary care. In this paper, we have analysed existing gaps in the organization and integration of NCD services at primary care and suggested plausible solutions that exist.The identification of gaps is based out of a review of peer-reviewed articles, reports on national and global guidelines/protocols. The gaps are organized and narrated at four levels such as community, facility, health system, health policy and research, as per the WHO Innovative Care for Chronic Conditions framework (WHO ICCC).The review found that challenges in the identification of eligible beneficiaries, shortage and poor capacity of frontline health workers, poor functioning of community groups and poor community knowledge on NCD risk factors were key gaps at the community level. Challenges at facility level such as poor facility infrastructure, lack of provider knowledge on standards of NCD care and below par quality of care led to poor management of NCDs. At the health system level, we found, organization of care, programme management and monitoring systems were not geared up to address NCDs. Multi-sectoral collaboration and coordination were proposed at the policy level to tackle NCDs; however, gaps remained in implementation of such policies. Limited research on the effect of health promotion, prevention and, in particular, non-medical interventions on NCDs was found as a key gap at the research level.This paper reinforces the need for an integrated comprehensive model of NCD care especially at primary health care level to address the growing burden of these diseases. This overarching review is quite relevant and useful in organizing NCD care in Indian and similar LMIC settings. Four major noncommunicable diseases (NCDs) such as cardiovascular diseases, cancer, diabetes and chronic respiratory diseases are the leading global causes of death and are responsible for 70% of deaths worldwide in 2015 , 4 suggeNCDs contribute to around 5.87 million deaths in India, accounting for 60% of all deaths in the country , and morThe government of India launched the national NCD programme called the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases & Stroke (NPCDCS) in 2008. This national programme merged into the flagship National Health Mission (NHM) in 2013 aiming to integrate NCD-related programme activities related to health promotion, early diagnosis, treatment and referral and further facilitate partnerships with the private sector . DespiteIndia was the first country to set national targets on NCDs in line with the global NCD action plan  and was Through a narrative review of the literature, we used the WHO ICCC framework as a theoretical framework of knowledge to identify and organize gaps under four major themes—at the community, facility, health system and gaps at the health policy and research. We adapted sub-themes and components of the ICCC framework to the local context (India and Karnataka).We hypothesize gaps at community, facility, health system and policy level hampers effective integration and continuity of care for NCDs.Integrating NCD services into primary health careIntegrating NCD services from a health systems lens: Integration of all interventions at community level , facility (towards disease management and follow-up) and overall systems level  and finally at the level of policy and research.Integration of NCD services through a unified management approach: Integration of cross-cutting components like health promotion, prevention, screening of population, training, referral services, emergency medical services, public awareness programme management, monitoring and evaluationWe have contextualize ‘Integration of NCD Services’ by following definitions , 21:IntSimilarly, for the purpose of this study, we have defined ‘Continuity in Care’ more in terms of ‘management continuity’ and ‘informational continuity’ rather than ‘relational continuity (therapeutic relationship between a patient and one or more providers)’ . We haveWe included all articles and reports published after the year 2000 in the review and used information from peer-reviewed articles, reports, guidelines and policy documents to identify the gaps.We conducted the literature review using MEDLINE  and Google Scholar as search engines. Common search terms were ‘chronic disease care’, ‘primary care’, ‘NCD in primary care’, ‘NCD and urban health’, ‘early screening of NCDs in community’, ‘health system challenges in NCD care’, ‘programme management and NCD’, ‘NCD and policy’ and ‘India’ as an adjunct search item. The initial literature review yielded some 343 articles (including reports) of which some 117 were initially screened for abstracts and results, and 77 full-length articles and reports were included in the final review. Finally, we reviewed 54 documents including full-length peer-reviewed articles, reports and policy documents  is allocated per 1000 population in rural area but in case of urban areas this cadre is only allocated for 2500 in vulnerable and marginalized communities. In addition to this challenge, there is frequent vacancy of ASHA posts in urban areas given better availability of other job opportunities. Although recent government guidelines have delineated the role of FLWs such as auxiliary nurse midwives (ANMs) and ASHAs in early screening, referral and follow-up  of NCDs,Community groups such as Village Health Sanitation and Nutrition Committee (VHSNC) and MAS  . Preventintegrating NCDs at primary health care helps in managing NCDs at an early stage and therefore is a better investment than diagnosing and managing them at a later stage [Thus, er stage . Enumeraer stage  to aid ter stage . There ier stage , 71. It er stage  are vitaer stage , and staSimilarly, programme monitoring and evaluation are important for strategic planning; it is timely to revisit monitoring indicators of the national NCD programme and strive for a sustainable surveillance system . UnderstAn understanding of the patient landscape and specific global models can inform technological policy innovations which can lower barriers to effective NCD screening, diagnosis and management . The WHOAdditional file 1:. Mapping of reviewed studies across identified gaps. All reviewed studies presented in the result section are mapped for study locations  across identified gaps


Glyphosate continues to attract controversial debate following the International Agency for Research on Cancer carcinogenicity classification in 2015. Despite its ubiquitous presence in our environment, there remains a dearth of data on human exposure to both glyphosate and its main biodegradation product aminomethylphosphonic (AMPA). Herein, we reviewed and compared results from 21 studies that use human biomonitoring (HBM) to measure urinary glyphosate and AMPA. Elucidation of the level and range of exposure was complicated by differences in sampling strategy, analytical methods, and data presentation. Exposure data is required to enable a more robust regulatory risk assessment, and these studies included higher occupational exposures, environmental exposures, and vulnerable groups such as children. There was also considerable uncertainty regarding the absorption and excretion pattern of glyphosate and AMPA in humans. This information is required to back-calculate exposure doses from urinary levels and thus, then compare these levels with health-based guidance values. Back-calculations based on animal-derived excretion rates suggested that there were no health concerns in relation to glyphosate exposure (when compared with EFSA acceptable daily intake (ADI)). However, recent human metabolism data has reported as low as a 1% urinary excretion rate of glyphosate. Human exposures extrapolated from urinary glyphosate concentrations found that upper-bound levels may be much closer to the ADI than previously reported. Glyphosate (N-(phosphonomethyl)glycine) is a broad-spectrum, post-emerging herbicide, which is highly water-soluble and affects the shikimate metabolic pathway mechanism of plants. It was first synthesized as a herbicide in the 1970s by the US firm Monsanto (later acquired by the German company Bayer in 2018). Glyphosate is the highest volume used herbicide in the world; the active ingredient is in over 750 products. Over the past decade, over 8 million metric tons of glyphosate have been applied worldwide .Scientific and public discussions on glyphosate have stepped up considerably since 2015 when the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) classified the chemical as ‘Group 2A—probably carcinogenic to humans’ . EuropeaAlthough regulatory agencies and authorities are predominantly aligned in their evaluation of glyphosate, there are some ambiguities regarding the possible adverse health effects and the magnitude and range of human exposures in both occupational and environmental settings. Some review studies have concluded that exposure to glyphosate is associated with cancer in humans ,8. A stuIn recent years, there has been an increasing amount of literature focusing on the evaluation procedures for regulatory risk assessment of pesticides ,18,19,20Gillezeau et al. (2019) highlighted that ‘additional studies are urgently needed to evaluate levels of glyphosate and related metabolites in the general population and workers’ are crucial for improving exposure assessments and thus ensuring a more accurate risk characterization . A pauciHuman biomonitoring (HBM) of exposure is the systematic assessment of the levels of chemicals and their metabolites through the analysis of human samples such as blood, urine, hair, or breast milk. HBM, as a measure of actual internal exposure, is considered an essential tool for comprehensive exposure and risk assessments . HBM canThere have been a limited number of HBM studies on glyphosate. Some studies cover occupational exposure levels only or do not include AMPA, glyphosate’s major biodegradation product/metabolite. Moreover, rather surprisingly, for a chemical used for so long and in such quantities, there is considerable ambiguity about the rate of oral absorption of glyphosate, its systemic availability, its metabolism to AMPA, and the urinary excretion fractions of both compounds in humans. Understanding human absorption, metabolism, distribution, and excretion are of general importance for toxicological considerations but is also essential for back-calculating daily intakes of glyphosate from urinary levels (of glyphosate and/or AMPA) and to compare these calculated intakes with effective doses from animal studies (such as the NOAEL) and health-based guidance values for humans such as the acceptable daily intake (ADI)  or the rThus, the overall objective of this manuscript is to evaluate and standardize the results of the current state-of-the-art in glyphosate exposure assessment using human biomonitoring (urine samples), to evaluate the internal glyphosate concentrations to health-based guidance values, to outline the gaps in knowledge that are still required for interpretation of HBM data (human glyphosate metabolism and excretion), and to propose recommendations for sampling strategies, all of which could inform future studies investigating population exposures to glyphosate.A critical review of the literature for glyphosate exposure studies using human biomonitoring was conducted by initially researching previous review studies ,22,32 anThe data was extracted from the publications using the following headings: author, year, country of the study, the type of study , the sampling population, the type of urine sample collected , the analytical method used, and for both glyphosate and AMPA  the limit of detection/quantification (LOD/LOQ), the frequency of detection (% above LOD/LOQ), the average and maximum values.The studies presented their quantitative urinary concentrations using various approaches, and this study attempted to standardize the results as far as was possible. Thus, in an effort to make comparisons between the studies, results were presented in the most transparent way possible, by standardizing the table for all glyphosate concentrations to micrograms per litre (µg/L) for comparability and reported the average  and the maximum values. The central tendencies were sometimes reported as geometric means, arithmetic means or median values. However, in this study, values were only displayed for studies that had a detection rate of over 50% and if these values referred to the whole population investigated (or a defined sub-population). Several studies evaluated only those samples above the respective LOQ . We excluded such reported values from the evaluation in our tables because they are not comparable with each other and strongly depend, among other things, on population composition and the chemical-analytical sensitivities. Due to the small number of studies available, no further statistical analysis was conducted on these studies.conc is the concentration of glyphosate measured in urine; Volurine is standardized as two litres; BW is bodyweight which is standardized at 60 kg; the Fue is the urinary excretion fraction (0.01 Fue); and ADI is the acceptable daily intake allowance for glyphosate (0.5 mg/kg b.w./day). To further evaluate these studies, the results were compared to the appropriate health-based guidance values. In 2015, the European Food Safety Authority (EFSA) published an acceptable daily intake (ADI) value for glyphosate, calculated on the no observed adverse effect level (NOAEL) based on animal studies and by applying a standard uncertainty factor (UF) of 100. The ADI is expressed as the mass of glyphosate, per kilogram of body weight per day (mg/kg b.w./day) . As thesTo date, there is a dearth of peer-reviewed human biomonitoring (HBM) studies internationally that report glyphosate exposures. The majority of HBM exposure studies focus on glyphosate (and only some on its biodegradation product AMPA) in urine samples. There have been studies that report glyphosate concentrations in other biological matrices  also analyzed for AMPA, of which only eight found detectable levels.Interpretation and comparison of these datasets need to be conducted with caution, as they do not all follow a similar sampling strategy and are focused on different populations, apply various detection/quantification principles , and have inherent differences in selectivity/specificity, as well as a wide range of the limit of detection/quantification (LOD/LOQ) ranging from 0.02 to 100 μg/L. Moreover, data presentation and quantitative evaluation within the studies differ considerably. Of the 20 peer-reviewed human biomonitoring studies (plus one non peer-reviewed report) investigating glyphosate exposure via urine sampling, approximately half of the studies  and urinary dilution adjustments  have also varied, with the majority of these studies adopting the collection of spot urine samples. Although urine volume and urinary dilution can vary between voids and between subjects , only thIn total, 7 of the 21 studies did not include a urinary dilution adjustment metric; of these seven studies, most of the studies collected spot urine samples. Of the studies that did include a measure of urinary dilution, most measured for creatinine and only a few for relative density, although some of these studies did not report the values. Jayasumana et al. (2015) in their study of agricultural nephropathy reported both unadjusted and creatinine adjusted values, appropriate to the study objectives, as underlying diseases  could cause fluctuations in creatinine levels .Glyphosate levels found in occupational studies among farmers ,39,40,43Of the occupational studies that have evaluated glyphosate, only four have also measured AMPA. However, probably because of the higher LOQ/LOD in these studies, AMPA was not detected ,46 or deHBM studies with a focus on non-occupational exposure to glyphosate have been conducted in Germany ,41,51, IThe Rancho Bernardo Study (RBS) of Healthy Aging in Southern California (from 1993 to 2016) collected 100 samples from residents older than 50 years of age (mean age of ~72 years old) and found mean glyphosate concentrations over the years investigated between 0.024 and 0.314 µg/L . In the Of the 13 environmental studies that evaluated glyphosate , only siOnly four studies looked at mother and child exposures to glyphosate ,24,39,40Human biomonitoring (HBM) data reports concentrations of a chemical (or its metabolites) in human tissues  but requires further calculations to derive estimates of external exposure levels . Thus, the interpretation of the relationship between external doses and HBM data is highly dependent on the toxicokinetics of the substance and the knowledge thereof.Toxicokinetic extrapolation from HBM data is used in the development of HBM guidance values , which are the equivalent for health-based guidance values ). A prerequisite for extrapolation is the availability of reliable toxicokinetic information, preferably from humans. To back-calculate urinary data to oral dose equivalents, the correct urinary excretion fractions are essential. Some studies refer to the urinary excretion fractions as the oral absorption rate. It is important to highlight that these two terms only have the same numerical value if all (100%) of the orally absorbed glyphosate is excreted as glyphosate in urine . There has been a number of studies that have presented methods for performing back calculations from HBM data to extrapolate for the external dose ,58,59,60For glyphosate, until recently, the urinary excretion fractions were based on animal studies, and these fractions ranged from 19–34% of glyphosate being excreted in urine after oral exposure, and 20% was regarded as the most appropriate assumption ,61. MeanFor a substance that has been in use for such a long time and in such large quantities worldwide, there have been surprisingly few human biomonitoring (HBM) studies that measure glyphosate as an exposure biomarker in human biofluids, in either occupational or environmental settings. Even fewer studies are available that provide additional, quantitative and confirmatory AMPA data.In this review, we identified 21 HBM studies that measured urinary glyphosate and/or AMPA across different populations . A rangeHBM data on glyphosate can not only be used to compare body burdens between different populations, identify highly exposed subpopulations, or follow time trends of exposure for statistical and epidemiological purposes, but it can also be used to perform back-calculations for exposures (such as daily intakes) and inform risk assessment and risk management procedures. In order to achieve this aim, interpretation of HBM data heavily relies on basic (human) toxicokinetic data and conversion/excretion fractions of exposure biomarkers (urinary glyphosate and AMPA in this case). Information on the rate and time period of absorption, elimination, and the calculated urinary excretion fractions of a compound allows internal concentrations to be back-calculated and to extrapolate for external exposures. de minimis risk [The most significant impact on HBM based dose extrapolations for glyphosate have been two recent human metabolism studies by Faniband et al. (2020)  and Zollmis risk . Table 3mis risk  6% 24],,de minimmis risk , and 87%mis risk  of the Amis risk . Howevermis risk  and in amis risk    calculatZoller et al. (2020) also provides valuable first insights into human urinary excretion kinetics with peak concentrations occurring in urine approximately 5 h after oral uptake and an elimination half time of around 9 h . InteresFor AMPA, even less information is available on toxicity, human metabolism , and exposure levels. From the environmental HBM studies , we can Irrespective of the final quantity of this urinary excretion fraction of AMPA from glyphosate exposure (or from AMPA exposure), it can be assumed that the majority of the urinary AMPA observed in environmental HBM studies stems from exposure to AMPA and not from exposure to glyphosate. Thus, analyzing both AMPA and glyphosate in urine is important to elucidate reasons for some differences in internal concentrations of glyphosate and AMPA potentially caused by different exposure sources and pathways ,70, whicGlyphosate is the highest volume used herbicide in the world and has been found to be ubiquitous in the environment. Nevertheless, there is a dearth of information about glyphosate exposures and very few HBM studies for glyphosate, as well as its main degradation product aminomethylphosphonic acid (AMPA) exist. Additionally, further data is required to understand the role of AMPA in relation to glyphosate exposures and the human toxicokinetics of both glyphosate and AMPA.Consequently, glyphosate and AMPA were selected as priority substances in the Human Biomonitoring for Europe initiative (HBME4U) . HBM4EU


Globally it has been estimated that only one third of applied N is recovered in the harvested component of grain crops. This represents an incredible waste of resource and the overuse has detrimental environmental and economic consequences. There is substantial variation in nutrient use efficiency (NUE) from region to region, between crops and in different cropping systems. As a consequence, both local and crop specific solutions will be required for NUE improvement at local as well as at national and international levels. Strategies to improve NUE will involve improvements to germplasm and optimized agronomy adapted to climate and location. Essential to effective solutions will be an understanding of genetics (G), environment (E), and management (M) and their interactions (G x E x M). Implementing appropriate solutions will require agronomic management, attention to environmental factors and improved varieties, optimized for current and future climate scenarios. As NUE is a complex trait with many contributing processes, identifying the correct trait for improvement is not trivial. Key processes include nitrogen capture (uptake efficiency), utilization efficiency (closely related to yield), partitioning  and trade-offs between yield and quality aspects (grain nitrogen content), as well as interactions with capture and utilization of other nutrients. A long-term experiment, the Broadbalk experiment at Rothamsted, highlights many factors influencing yield and nitrogen utilization in wheat over the last 175 years, particularly management and yearly variation. A more recent series of trials conducted over the past 16 years has focused on separating the key physiological sub-traits of NUE, highlighting both genetic and seasonal variation. This perspective describes these two contrasting studies which indicate G x E x M interactions involved in nitrogen utilization and summarizes prospects for the future including the utilization of high throughput phenotyping technology. Evaluation of crop performance needs to consider genetic variation (G), environmental conditions such as climate  and location (E), together with farm agronomic management (M). It is the combination of these parameters and their interactions (G x E x M) which will determine sustainable and secure crop yields. Each parameter is composed of, or determined by, specific factors as indicted in Globally, wheat yields have steadily increased over time as a result of genetic improvement and better agronomy. Regional wheat yields also differ considerably across the globe and locally vary on an annual basis, primarily depending upon fluctuating climatic conditions, but also as a result of pest and pathogen pressures. Plant breeding seeks to increase yield potentials and produce more resilient germplasm able to resist these abiotic and biotic stresses. Agronomic practice also seeks to negate or at least moderate the influence of these factors and enable farmers to approach yield potentials for any particular crop and environment. In recent years the trend of increasing annual yields of some crops may have plateaued in some environments, for example wheat in northwest Europe . Whilst The need to improve yields with efficient fertilizer use has led to a number of G x E studies on breeding trends for wheat crop improvement and NUE traits specifically. For example studies have focused on partitioning of N between tissues , variatiA widespread management strategy which has a major impact on crop performance and has implications for NUE is crop rotation. Individual crops should not be considered in isolation and NUE should be evaluated as part of the whole cropping system when considering economic or environmental impact. For example, one modeling study highlighting the importance of looking at the cropping system and not just individual crops, clearly identifies that NUE of one crop will impact on succeeding crops .Further management practices critical in influencing NUE will be the variable utilization of N-fertilizer depending on timings, amounts and chemical formulation. For example, coated urea for controlled release of N, more effective timing of applications, and appropriate dose rates, taking into account soil N supply, to optimize yield and quality whilst minimizing losses and avoiding contravening legislation. A recent overview outlining strategies for reducing crop N requirements highlights the importance of taking a holistic view combining elements of improved germplasm and agronomy .To consider the impacts of G x E x M, as individual factors as well as in combination, on NUE, it is necessary to define NUE and consider how the key constituent components may be affected individually and as a whole. NUE may be considered as the efficiency of nitrogen recovery from applied fertilizer, or from the N available to the crop, and this gives rise to the 33% efficiency of crop recovery . AlternaWhichever definition is used, plant growth and yield require nitrogen, and furthermore are dependent upon multiple physiological processes Figure 2Other useful measures of efficiency of N use include the nitrogen harvest index (NHI), which is the fraction of total N taken up by the crop which is partitioned to the grain, and is a refinement of harvest index (HI) which descibes partioning of dry matter alone. However, NHI is independent of yield and uptake efficiency, and a low yielding crop may have a high NHI, but leave substantial unrecovered N in the soil. High grain protein concentration (GPC) is required for end-uses such as flour for breadmaking, however, it is difficult to increase GPC without decreasing yield due to the negative relationship between the two, as high yield usually reflects high carbohydrate content which in turn dilutes N concentration. The desired trait, to increase GPC without reducing yield, can be defined as grain protein deviation (GPD), the deviation from the negative linear relationship between yield and N concentration, and reflects an ability to acquire more N in the grain for a given yield . There iEach of these NUE parameters are complex traits involving many underpinning physiological and biochemical reactions and pathways. Genetic studies indicate the multigenic and heritable nature of the major traits and the underpinning processes. However, unravelling the traits and breeding for improved NUE is complex. Genetic variation in many traits is apparent in modern germplasm and to an even greater extent in historic material, landraces and wild relatives, and could be the basis for germplasm selection. Yield is commonly the major commercial target for selection, usually at a constant N input, hence selection for NUE and NUtE is consequentially also selected for. Differentiation between NUpE and NUtE is not made consciously, however higher yielding, high protein genotypes (and hence high GPD types) will have high NUpE also. Efforts have been made to consider management protocols (M) by including selection at different N-inputs , howeverArguably the greatest genetic improvement (G) has been the introduction of short straw (dwarf) varieties, and as a consequence, HI and NHI have increased. The immediate effect is that biomass allocation to the grain is favored, maximizing grain yield at the expense of straw biomass. Another direct consequence of utilizing dwarf varieties is that the reduced stature facilitates resistance to lodging, a problem particularly encountered at high levels of N fertilization, particularly when combined with conditions of high wind and rainfall. The ability to exploit higher N-rates has led to a management strategy (M) of increased N-inputs, which promotes greater yields but at lower efficiency. Higher N fertilization can increase disease and weed pressure, requiring additional agrochemical inputs.2 trends, which are affecting yield potentials and can be predicted to have substantial influences in the future by altering timing of phenology or favoring photosynthetic processes determining NUtE  consider location (and soil type) and local biotic and abiotic stresses. In the latter case heat and drought are the most major impactors limiting yield and decreasing N requirements . Long teing NUtE . ClimatiThese genetic, environmental and management interactions in nitrogen fertilizer use and expression of crop NUE traits are amongst the clearest examples of the importance of G x E x M. Fertilizer use underpins crop performance and the interactions between these factors is complex but vital for efficiency. An exemplar dataset is described in the next section.The Broadbalk long term experiment, which was initiated in 1843 at Rothamsted Experimental Station, in the United Kingdom, is the world’s oldest continuously running agricultural experiment . OriginaProgress in wheat breeding (G) is demonstrated as, since the start of the experiment, the variety planted has been changed periodically, and has been usually a variety commonly in use commercially at the time. The major change was the adoption of shorter strawed varieties from Capelle Desprez onwards in 1968. While all varieties have good yield potential, the modern shorter varieties are better adapted for the higher N-inputs, as they are less likely to lodge. The development of plant growth regulators has also enhanced the effect of shorter varieties and further reduced the occurrence of lodging.The dataset is ideal for examining long term trends due to climatic factors (E) over a considerable period of time, however analysis is complicated by changing agronomic practice, which again, has followed typical commercial practice and, along with improving genetics and changing varieties, has contributed to increasing yields. One recent study focused on datasets from 1968 to 2016 to minimize some the impact of the changing agronomic practice but still enable longer term trends to be evaluated. This study highlighted the strong climatic influence on year to year variability of yield and N-responses in wheat, and also barley in a separate experiment, of particularly temperature and rainfall in specific months .Several management interventions (M) are represented in the Broadbalk experiment. Key amongst these are the rotations and specifically the comparison between continuously grown wheat and the first wheat in a 5-year rotation comprising successive wheat crops combined with break crops. A first wheat outperforms the continuous wheat partly due to a lower root disease pressure. Other notable agronomic practices having a positive effect on crop performance are the introduction of herbicides and fungicides. While the former replaced manual weeding or fallowing, the latter became essential with increased canopy disease favored by the greater canopy biomass achieved from the addition of high rates of nitrogen. The key agronomic treatments with respect to NUE are the differential rates of N, with higher N inputs resulting in increased yield, particularly with modern varieties, variations in the patterns of applications (single versus split doses) and forms of applied N (inorganic versus organic sources). The Broadbalk experiment has also been used to investigate, utilizing buried drains, the detrimental effects of N leaching, which occur following excess or inappropriately timed N applications, and will reduce NUpE.As illustrated above, the Rothamsted “classical” long-term trials are an ideal dataset to examine long term trends due to climatic factors over a considerable period of time, since their inception in 1843. However, for any single year these trials lack the multi-germplasm genetic factor. Therefore many recent trials have sought to introduce genetic variation by working with germplasm panels or multi variety datasets . One suchttp://www.wgin.org.uk). In most years there were four N rates, from zero to 350 kg N/ha/yr, which represents no input through to excess applied N. All trials were conducted following local commercial agronomic practice, at the Rothamsted Farm in Hertfordshire in the UK. Whilst more than 60 varieties were examined in total, a smaller subset of 15 core varieties have been grown for most years. The mean grain yield trends of this core set for the 4 N rates over the period of the trial are presented in The Wheat Genetic Improvement Network (WGIN) germplasm diversity trial is an example of a multi-variety, multi-N treatment series of trials conducted over multiple years. Data from the initial years (2004–2008) of these trials reported variation in yield and N-responses and contributing physiological processes . The triAn indication of genotypic variation in a high-level nitrogen use trait, NUE, and the interaction with the N fertilizer treatments is illustrated in Applied N impacts on yield, however this response is non-linear see Figure 4A more detailed analysis of G, E, M and their interactions for 4 varieties within this dataset is presented in In summary, within this germplasm panel, the N-rate, as the major management treatment (M), is the dominant factor. Variety (G), differentiating higher and lower yielding types, and year (E) (higher and lower yielding seasons) also have roles in determining yields, N-uptakes and NUtE. Whilst all three factors and their interactions determine yield and NUE, a clear understanding of the interactions of G x E x M will require larger and more detailed datasets.The Broadbalk experiment and similar trials are extremely useful for examining long term trends in (wheat) crop performance and additionally illustrates importance of variety and management. Trials of diversity panels, such as that described here, enable an examination of the genetic components influencing crop performance, however examining the importance of environment and management become a major undertaking in terms of scale and investment of resources. A major gap in effective G x E x M analysis is in having enough contrasting environments with appropriate germplasm and management ranges. An elegant solution is to conduct meta-analyses, bringing together multiple studies. An example is an analysis of 55 individual studies conducted between 1974 and 2014 in multiple global locations, in which a clear non-linear relationship between yield and N uptake was observed and indications of greater opportunities for improved NUtE at higher yielding sites .In addition to the challenges of larger trials conducted at multiple sites and in multiple years, there is an increasing demand for higher resolution data, both spatially and temporally. Solutions to this challenge exploit new technologies for automated and high throughput phenotyping, for example using remote sensing and robotics. An example of an automated robotic system is shown in For most high throughput technologies emphasis has been placed on growth and biomass accumulation, both indicators of final performance and yield. Such data may be derived from height measurements or spectral indices, indicative of canopy cover. In addition, spectral parameters, including the growth indices mentioned above, are measures of chlorophyll content and hence the nitrogen status of the canopy. These measurements can be used to assess N uptake and be indicative of NUE parameters. As spectral measurements are non-destructive there is the opportunity to measure in real time, continuous kinetics of N uptake and utilization.Further applications of these phenotyping approaches will aid pre-breeding and breeding programmes for improved varieties, improved management practices, and better understanding of environmental impacts, and will advance the development of precision farming technologies. Technology, both hardware and interpretive algorithms developed as a result of these platforms can be transferred to less sophisticated and cheaper devices suitable for mass use by growers. Together these advances in accurate and high-resolution monitoring of crop performance will facilitate crop production, best agronomic practice, and minimize environmental impacts on broad field commercial cropping.MH and AR contributed equally to all aspects of this manuscript.Rothamsted Research receives support from the Biotechnology and Biological Sciences Research Council (BBSRC) of the UK, and this work was funded by the Designing Future Wheat project (BB/P016855/1), and the Department for Environment, Food and Rural Affairs (Defra) sponsored Wheat Genetic Improvement Network project (CH1090).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 effects of the physical environment on metabolic syndrome (MetS) are still largely unexplained. This study aimed to analyze the associations of relative humidity of residence, lifestyles, and MetS among Ecuadorian adults. Data from 6024 people aged 20 to 60 years were obtained from an Ecuador national population-based health and nutrition survey  and the mean annual relative humidity (%) from the Ecuador National Institute for Meteorology and Hydrology (2012). Odds ratio (OR) with 95% confidence intervals (CI) for MetS according to groups of relative humidity were calculated using multiple logistic regression. Living in high relative humidity (>80%) increased ORs of reduced high-density lipoprotein (HDL) cholesterol  and MetS  in women. Furthermore, physically active men living in high relative humidity showed lower OR of elevated triglycerides  while menopausal women living in high relative humidity showed increased ORs of MetS , elevated blood pressure , and increased waist circumference . Our results show that residence in high relative humidity and menopausal status increase ORs of MetS and its components in Ecuadorian women; however, physical activity significantly reduces the OR of elevated triglycerides in men. The obtained findings may help make public health policies regarding environmental humidity management, nutritional education, menopausal care, and physical activity promotion to prevent the onset of MetS among Ecuadorian adults. Metabolic syndrome (MetS) is comprised of elevated fasting glucose, hypertension, dyslipidemia, and abdominal obesity  and can Biological factors  and age (>40 years old)) and lifestyle patterns  are recognized as risk factors for MetS development. In addition, physical environments, including elevation and climatic factors, have been reported to be associated with onset of metabolic diseases ,13,14,15Humidity is linked to physiological responses through heat stress and hydration states . DespiteWe hypothesized that relative humidity is associated with risk of MetS and that lifestyle patterns could modify the risk. To this end, we determined the associations of relative humidity, lifestyles, and dietary patterns with MetS among Ecuadorian adults based on data from the ENSANUT-ECU 2012 and the National Institute for Meteorology and Hydrology (INAMHI).A cross-sectional study was performed using ENSANUT-ECU, a nation-wide population-based health and nutrition survey conducted by the Ecuadorian Government and its Ministry of Public Health. Detailed explanations of the study design and data source profiles of ENSANUT-ECU are available elsewhere . In brieWritten informed consent was obtained from all participants using consent forms, and a protocol of the study was approved by the Institutional Review Board of Seoul National University .n = 493) as well as participants who took medication for hypertension (n = 361). Thus, 6024 adult Ecuadorians (1964 men and 4060 women) were finally included in this study, as illustrated in A total of 11,044 participants over 20 years of age was initially included for ENSANUT-ECU with complete variables related to MetS. Among these individuals, we excluded 4166 rural residents who did not have physical activity data and other risk factors  and others ; education level was classified as primary, secondary, and college or higher; and economic status of family was classified as poor (Q1), middle (Q2 and Q3), and rich (Q4 and Q5). For menopause status, we subdivided women in two groups: menopausal stage “yes” for ≥50 years of age and “no” for <50 years old. This classification was based on the WHO parameters.Information regarding lifestyles was included as follows: current alcohol consumption and smoking (“yes” or “no”) were based on alcohol beverage intake and smoking in the past 30 days according to the United States National Survey on Drug Use and Health and WHO-Ecuador . PhysicaAnthropometric measurements, including body mass index (BMI), height, weight, and waist circumference of participants, were performed at their residence by trained technicians using standardized procedures and portable equipment . Blood pFor dietary intakes, trained technicians collected data using the 1-day 24-h dietary recall method at the participants’ houses. The daily energy intake was calculated using the food composition table of the Food Dietary Guidelines for the Ecuadorian population (GABA) . AnalyseThe mean annual relative humidity (%) of the urban area for 2012 was obtained from the National Institute for Meteorology and Hydrology INAMHI  and was The diagnosis of MetS was based on the harmonized guidelines of the National Cholesterol Education Program Adult Treatment Panel III and the Latin American Diabetes Association as the presence of three or more of the following components: waist circumference (men ≥ 94 cm and women ≥ 88), blood pressure (systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg), HDL cholesterol (men < 40 mg/dL and women < 50 mg/dL), elevated triglycerides (≥150 mg/dL), or fasting glucose (≥100 mg/dL).p-value < 0.05 in a two-tailed manner. Statistical analyses were performed using the PROC SURVEY procedures of SAS version 9.4 software  [All analyses were stratified by sex and relative humidity, with data presented as percentages or means with standard errors depending on the type of analysis. Differences in groups were compared using Chi-square and t-tests depending on the variable that was analyzed. Odds ratios (OR) and 95% confidence intervals (CIs) for MetS across the relative humidity groups were estimated using multiple logistic regression analysis. In the regression model, general and sociodemographic variables , anthropometric measurements , lifestyles , elevation of residence, and menopausal status were considered. Statistical significance was defined as NC, USA) .p < 0.05). However, age and smoking were significantly different in women only .The analyzed characteristics of the participants according to sex and relative humidity are shown in p = 0.0461). Both sexes showed higher HDL cholesterol in high relative humidity . Additionally, in the high relative humidity sex groups, a significant increase of energy intake and EER (%) was observed (p < 0.05).The prevalence and ORs for MetS according to relative humidity are presented in Additionally, ORs for MetS in women according to their menopausal status and relative humidity of residence are presented in This study showed a positive association between relative humidity and MetS as well as reduced HDL cholesterol in women. Menopausal women living in high relative humidity showed higher ORs of MetS, elevated blood pressure, and increased waist circumference. Moreover, physically active men living in high relative humidity had lower OR of elevated triglycerides compared to physically inactive men living in the same humidity. To our knowledge, this is the first study to suggest that relative humidity is associated with MetS in an adult population using nationally representative data.The prevalence of MetS in adult Ecuadorians shows similar trends with other Latin American countries and the USA ,21. HoweTo further explore our findings, we performed additional analyses of MetS abnormalities, lifestyle patterns, and relative humidity. In women who reside in high relative humidity, who consume alcohol, and who smoke, higher ORs of reduced HDL cholesterol and physical inactivity increased the OR of MetS. These lifestyle factors could play moderating roles in MetS. Apart from the lack of previous studies on relative humidity and MetS, complementary research has investigated the effect of physical environment  on people’s health ,36,37,38Ecuador has four different geographical regions. The coast and the Galapagos Islands have the highest prevalence of MetS , while the highlands and the Amazon have prevalence of 29.9% and 26.6%, respectively . The meaIn order to identify a difference between sex, we analyzed sex and relative humidity individually. It was found that women living in high relative humidity had higher ORs of MetS and low HDL cholesterol. These pathophysiological differences may be explained by the effects of sexual hormones on the human body physiology ,46. The p < 0.05). This association suggested a regulatory role of hormones on appetite regulation and the onset of metabolic abnormalities. In contrast with our findings, other studies reported that exposure to high ambient temperatures and humidity under resting conditions caused poor appetite and reduced energy intake [Energy intake differed by sex and relative humidity , physical activity data was collected only for the urban population; thus, we excluded rural residents (n = 4166) and others (n = 854), resulting in a total of 6024 urban participants included for this study. Therefore, we cannot exclude the possibility of residual bias, and our results should be interpreted with caution. Second, casual inferences were excluded due to its cross-sectional design. Third, we could not infer the individual’s usual energy intake using a 1-day 24-h dietary recall. Forth, missing data on leptin and/or irisin concentration, which may help to better elucidate the association between humidity and MetS, is another limitation of the study. Therefore, further studies in the fields of human biology and environment are needed to determine the influence of relative humidity on MetS in the adult population. Despite these limitations, we utilized data from the ENSANUT-ECU 2012 which was conducted on a nation-wide scale across the entire country using standardized protocols and instruments and is the only survey the collected all the required biomarkers for diagnosis of MetS. Moreover, to our knowledge, this is the first study determining the association of relative humidity with MetS in a nationally representative population sample.This study must be interpreted considering the following limitations. First, among initial participants (Our study suggests that living in high relative humidity (>80%) increases ORs of MetS and reduces HDL cholesterol in women. Furthermore, menopausal status enhances increase in OR of MetS and augments ORs of elevated blood pressure and increased waist circumference, while performing physical activity decreases the OR of elevated triglycerides in men. These findings come from nation-wide data and highlight the importance of management of relative humidity and lifestyles in Ecuadorians. Intersectoral programs aimed at controlling relative humidity in homes and work environments, providing nutritional education and menopause care, and increasing physical activity are needed to promote healthy life conditions and to prevent metabolic disorders.


The aim of this article is to present a short review of noninvasive, nonpharmacological treatment methods used in somatic illnesses that fall under the umbrella of approach called behavioral medicine.  The narrative review method was applied in the study. Science paper databases, including PubMed, had been used to retrieve papers on therapeutic methods used in clinical setting that meet the broad criteria of behavioral medicine definition as stated in the Charter of International Behavioral Medicine Society  Main groups of methods, disorders in which they are being employed and their effectiveness, have been identified.  Behavioral medicine is grouping treatment methods and interventions that hold large potential for clinical setting. Two groups of methods can be distinguished by the scrutiny and level of evidence gathered in their effectiveness assessment; for biofeedback, guided imagery, and hypnosis techniques, comprehensive evidence reports in the framework of U.S. Evidence Synthesis Program exist. Meditation techniques, disclosure therapies, and relaxation methods are less well assessed. Broader employment of behavioral medicine therapies in clinical setting is possible after addressing two major problems in the field, which are deficiencies in quality evidence of effectiveness for many of the methods and their insufficiencies in underlying therapeutic mechanism knowledge. With rise of behaviorism and works of figures such as Ivan Pavlov, previously undescribed connections, like between central nervous and digestive system, mediated by conditioning, became exposed. Accumulation of such knowledge leads to eventual advent of psychosomatic medicine [Since before the emergence of modern medicine, it has been observed that behavior and states of mind have relation with health and illness. This important understanding, broadly present in ideas of ancient thinkers like Aristotle, Galen, and Islamic Golden Age Persian physicians like Abu Zayd Al-Balkhi and `Ali b. al-`Abbas al-Majusi , had been somewhat subsided over time with the successful raise of mechanistic paradigm in medicine that followed works of academics such as William Harvey and his explanation of heart functioning as a pump or Rene Descartes notion of mind and body as utterly separate “machineries” , 2. As lmedicine  and latemedicine , 5.Behavioral medicine is interdisciplinary field, integrating and using psychosocial, behavioral, and biomedical knowledge relevant to health and illness, in an effort to understand fundamental biobehavioral mechanisms of well-being and serve the needs of clinical diagnosis, intervention, disease prevention, and health promotion –8. It inbio-psycho-social  approaccultural .Due to its interdisciplinary aspect, the essence of combining knowledge from broad spectrum of areas with the aim to facilitate synergy, blending skills and ideas, behavioral medicine has proved to be currently, and ventures to be in the future, a fertile ground for deriving useful and innovative strategies for the prevention, diagnosis, and treatment of a wide range of health problems. Much potential is being recognized in this field in terms of new treatments and improving cost-effectiveness of health care systems .Realization of behavioral medicine potential depends on proper research and availability of information regarding existing solutions in that framework. The aim of this paper is to review contemporarily applied and researched interventions used in the treatment of somatic conditions, falling into the domain of behavioral medicine by its definition. Although formal birth of this discipline had taken place just in the year 1977 , treatmInterventions falling into behavioral medicine category are primarily nonpharmacological techniques, originating from the appreciation of the interrelations between the body and mind. Many of them are based on the employment of principles of learning (conditioning), or recognition of the importance stress (of various origins) has on organism (including its significant impact on functioning of the immune system). Treatment approaches include a group of biofeedback methods, relaxation techniques , disclosure interventions, hypnosis, guided imagery and visualization techniques, meditation, and bulk, stress-management programs. Some of the methods amalgamate and share common features, benefiting from nonidiosyncratic mechanisms; for example, types of meditation can include focus on briefing, visualizations, and relaxation, and several of the methods possess common aspect of being founded on principles of learning. Many of the separate techniques are often combined and administered under a joint umbrella of stress-management programs –24.Two separate groups of methods can be distinguished by the scrutiny and level of evidence gathered in their effectiveness assessment; for biofeedback, guided imagery, and hypnosis techniques, comprehensive evidence reports in the framework of U.S. Evidence Synthesis Program exist, and so unified style summarizing tables depicting condition and outcome area effectiveness are provided. The remaining methods' effectiveness and area of application are reported in the text or different form of tables.Associated with the founding roots of behavioral medicine movement in science and connected with the first sense of term “behavioral”—meaning related to behavioral therapy and methods—biofeedback techniques rely primarily on the principles of operant conditioning. The essence of the wide group of these interventions is learning by individual how to voluntarily control body processes—which are commonly falsely considered involuntary—for health benefits or symptom control. That is why, the term “treatment,” emphasizing the curing goal of these methods, but accentuating passivity, is better replaced here with the word “training,” highlighting the need of active patient participation in the learning and thus curing process. Biofeedback methods substantially employ equipment that converts physiological input from the body into auditory or visual signals that constitute the feedback for the patient. With such feedback, a person can clearly learn how their mental states are resembled in the physiological state of the system targeted in particular biofeedback intervention and try modifying and managing it, typically with support of a qualified practitioner. Instrumentation used in different biofeedback methods measures muscle activity, skin temperature, electrodermal activity (sweat gland activity), respiration, heart rate variability, blood pressure, brain electrical activity and blood flow . BiofeedOne of the most common biofeedback trainings involves electromyography (EMG), conveying feedback regarding muscle activation, the intensity of muscle contraction, and manifestation of muscle fatigue . ElectroAnother biofeedback method is thermal biofeedback. It is associated with self-regulation of skin temperature . This tyThe idea behind yet another biofeedback mode—skin conductance feedback—is to deliver person information about sweat gland activity, which is closely correlated with sympathetic nervous system functioning . With veAnother example of biofeedback technique is heartrate variability (HRV) feedback. It involves monitoring either heart rate alone or heart rate plus respiration. Data regarding heart rate is collected via electrocardiograph (EKG) monitors or plethysmographic sensors on the finger or earlobe . It is hArguably, the most popular biofeedback application could be electroencephalogram (EEG) neurofeedback (EEG-NFB)—a method which takes advantage of the fact that particular brain wave patterns correlate with specific disorders and syndromes . ImproveEEG neurofeedback is widely used to treat epilepsy ; it is aDoubts about utility of neurofeedback methods exist and stem mainly from three reasons, as comprehensively outlined by Thibault and Raz . One reaCurrent EEG neurofeedback techniques serve as an inspiration for developing more advanced brain-subject feedback loops, employing the functional Magnetic Resonance Imaging (fMRI) systems. This relatively new (emerging in year 2003) biofeedback expanse area is still mostly field of ongoing research with potential yet to be evaluated, less a ground of mature clinical applications –75. The st century, the Task Force of the Association for Applied Psychophysiology and Biofeedback plus the Society for Neuronal Regulation formulated criteria for designated levels of evidence-based clinical efficacy of psychophysiological interventions. They span from level 1—not empirically supported—to level 5—efficacious and specific [In the beginning of the 21specific . Accordispecific , who ratMore recent report compiled under the auspices of the US Veterans Health Administration Evidence Synthesis Program (EVP) , 78 concHypnosis is a method of inducing in an individual a state of hypnotic trance, a mode of deep relaxation and focus with increased suggestibility and suspension of critical faculties. In this special state of consciousness, two types of suggestions can be made to the affected person: direct hypnotic suggestion, made while the person is in trance, which alters behavior or perception while the trance persists, and posthypnotic suggestion that alters behavior or perception after the trance ends. Typical hypnotherapy consists of hourly or half-hourly sessions with a practitioner; additionally, group hypnosis interventions also exist. Some medical health specialists introduce hypnosis in 10-15-minute sessions along with their regular clinical work. In some cases, patients are taught to induce self-hypnosis  .Similarly to other techniques described here, hypnosis has been tried in many medical contexts. Effectiveness has been reported in irritable bowel syndrome , headachSome authors suggest hypnosis is underused in medical setting, considering its already known utility . ApplicaA precise definition of guided imagery has been stated by Rider and Achterberg  in theirThere are reports suggesting stress reduction effects and elevation of the immune system functioning in people treated with the guided imagery technique . AdditioThe EVP report  notes a Relaxation techniques are a large set of methods that are commonly being divided into two main categories: somatic-  and cognitive-  based approaches. The physical category includes for example pure behavioral relaxation training, progressive muscle relaxation, deep breathing, the Alexander technique and Feldenkrais method (education techniques aiming at establishing a heightened awareness of movements), and Mitchell's simple physiological relaxation –96. CognRelaxation techniques have been administered to support curing and treatment of various clinical conditions see . MultiplThe theoretical basis of the disclosure intervention methods lays in the supposition that inhibition of psychologically significant thoughts and feelings has adverse health consequences, , 110. InThe most commonly employed technique in this approach is “written emotional disclosure” or “expressive writing” that consists of 15 to 30-minute long sessions (often repeated in consecutive days) of writing essays on personally experienced stressful events. Sometimes instead of written, verbal descriptions are used , or the The disclosure-based methods have been employed in many health problem contexts, exhibiting modest benefits in chronic pain   and notisamādhi, etymologically meaning “gathering the mind and placing it upon an object” [Meditation is a practice in most general terms grounded in controlling focus of attention. It is referred in the classical languages of Buddhism—Sanskrit and Pali—as  object” . It can  object” , 128.Mindfulness meditation is the basis of mindfulness interventions. These interventions share the core premise of mindfulness—a process of openly attending, with awareness, to one's present moment experience—however referred by name to intervention schemes and programs .A substantial body of research evidence, comprehensively reviewed by Sampaio and colleagues, cites important effects of meditation on not only body function parameters like reduction in respiratory frequency, slower heart rate, and reduced electrical conductivity of the skin  but alsoA short review of the most prominent groups of therapeutic methods in the field of behavioral medicine shows a large potential in the context of contemporary health care system use. One of the main advantages of the reviewed methods is their intrinsic noninvasive and pharmacology free essence. This characteristic positions them as promising alternatives for treating conditions in which pharmacological or other types of therapies are burdened with harmful risks. A good example here might be the problem of pain treatment. Currently, opioid analgesics are associated with one of the biggest US public health crises: the opioid crisis. Research showed that overwhelming majority of the opioid abusers began their addiction with prescription medications, primarily for chronic pain , 139. PaAnother distinctive advantage of behavioral medicine treatments is the fact that many of them are founded on learning processes and rely on training. This provides possibilities unavailable to other therapies, like surgery or pharmacotherapy. Persons treated with the learning-based therapies acquire skills and knowledge, meaning that in very many cases , they can apply the treatment to themselves whenever necessary on their own. Furthermore, they keep the trained skill and can use them long after they acquired it and also possibly apply it outside the original illness context. Relaxation, expanding mindfulness, and self-hypnosis are skills which can beneficially be applied in health and even outside of health related context, for the rest of life. This means contact with some of the behavioral medicine techniques means arming people with useful techniques they can apply for promoting their health and improve wellbeing in the long term. This in turn might equal more years lived in better health and less strain on health care system.Another leverage associated with many of the reviewed methods is their big potential in the context of convenient, remote, offsite use  , 142. UsBehavioral medicine-derived medical treatment field is also affected with problems. The issue repeatedly mentioned in the literature is deficiency of high-quality research that would enable drawing definitive conclusions regarding the effectiveness of many of the considered methods , 93. TilA behavioral medicine framework provides wealth of methods for use in the treatment of multitude somatic health conditions. Those alternative approaches hold substantial potential in terms of reducing risks and unwanted negative consequences in cases where they can effectively substitute pharmacological or invasive therapies. Another useful area of employment for these methods is complementary and supporting role along the main treatment. Broader dissemination and popularization of these techniques can occur when insufficiencies regarding evidence of effectiveness and underlying curing mechanisms will be tackled.


Chili is the most heavily and frequently consumed spice, either as a flavouring or colouring agent, and it is also a major source of pro-vitamin A, vitamin E and C. The main capsinoidcapsaicinoid found in chili peppers is capsaicin. It has been demonstrated that capsaicin acts as a cancer-suppressing agent through its antioxidant and anti-inflammatory effects, by blocking several signal transduction pathways. Oral squamous cell carcinoma is one of the most prevalent cancer worldwide. It is noteworthy that in countries where populations of diverse ethnic groups co-exist, differences have been observed in terms of incidence of oral cancer. The variances in their diet could explain, at least in part, these differences. The objective of this systematic review is to explore if there is evidence of a possible relationship between capsaicin intake and the incidence of oral squamous cell carcinoma, and discuss such association. A bibliographical search was made in PubMed, Scopus and Web of Science databases, and finally 7 experimental studies were included; OHAT risk of bias tool was used to assess their quality. allAll the studies confirm that capsaicin is a chemopreventive agent that prevents the development of oral cancer, through inhibition of malignant cell proliferation and increase of apoptosis. More human studies are needed in order to clarify the real link between consumption of chili (capsaicin) and the prevalence of oral cancer. Key words:Chili, capsaicin, oral epithelial dysplasia, oral cancer, cell proliferation, apoptosis. Peppers, chilis or Capsicum are versatile crops included in most daily diets, especially in some geographical areas like China, Mexico, Turkey and Indonesia . CapsicuChili is the most heavily and frequently consumed spice, as a flavouring or colouring agent, and it is also a major source of pro-vitamin A (carotene), vitamin E (α-tocopherol) and vitamin C (ascorbic acid) . Mature In addition to its use as a major spice and food additive, capsinoids have also been used for medical and therapeutic reasons -9. It haCancer is a major global public health problem; according to World Health Organization (WHO) it is the second leading cause of death globally . The assOral squamous cell carcinoma (OSCC) is one of the most prevalent cancer worldwide [incidence rate: 4 per 100.000 worldwide], and accounts for 90% of all malignancies of the oral cavity . Main riIt is noteworthy that in countries where populations of diverse ethnic groups co-exist, differences have been observed in terms of incidence of oral cancer . In thisThe objective of this systematic review is to explore if there is evidence of a possible relationship between capsaicin intake and the incidence of oral squamous cell carcinoma, and discuss such association.- Information sources and search strategyThe design of this study fulfils the PRISMA guidelines . We perf- Inclusion and exclusion criteriaUsing PICOs criteria , in thisin vivo). Meanwhile, exclusion criteria were: 1) previous reviews, 2) studies that did not investigate the oral carcinogenesis, and 3) studies that did not use capsaicin as therapeutic agent.The inclusion criteria for the articles were: 1) studies published up to April 2020, 2) studies written in English or Spanish, and 3) experimental studies (in vitro and - Study selection and data extractionThe bibliographic research was performed by two independent reviewers (AMS and ILIM). All titles and abstracts that met the search criteria were red and then, the potentially eligible articles were analysed for their inclusion. Any disagreement between them was solved by a third and fourth reviewer (AMT or JMAU) to minimize bias of inclusion. Data from the included studies was collected by two reviewers (AMS and ILIM) and cross-checked by another (AMT or JMAU) to guarantee integrity of contents.The information extracted from each study was: the author and year of publication, type of oral squamous cell carcinoma model , number of cases, type of capsaicin intake, effect of capsaicin intake on oral carcinogenesis .- Risk of bias and quality assessment of the studiesin vitro and in vivo studies, to evaluate their methodological quality . In contrast, SCC4 control xenograft tumours grew nearly two-fold greater than CPZ treated cases, and showed more apoptotic Figures.Gonzales et al.  tested det al.  also caret al.   Nevertheless, more studies are needed to further understand the mechanism by which these compounds prevent oral carcinogenesis, and to develop novel therapeutic agents for clinical application against oral cancer.In summary, this study gives a comprehensive view of the relationship between capsaicin and oral carcinogenesis. Both capsaicin and capsazepine are chili substances that may prevent the development of oral epithelial dysplasia and oral squamous cell carcinoma. The steps in which these compounds could have a chemopreventive activity against oral cancer are: inhibition of malignant cell proliferation and increase of malignant cell apoptosis. These findings elucidate why dietary intake of capsaicin could explain the existing differences in the prevalence of OSCC in certain world populations. Future research should focus on humans, to investigate the relationship between consumption of specific foods such as chili (capsaicin) and the prevalence of oral cancer, through well-designed studies .