Background—The exposome concept refers to the totality of exposures from internal and external sources, including chemical and biological agents from conception throughout the lifetime. Exposome is also made up of psychosocial components such as socio-economic status (SES), which will focus on in this review. Despite exposures to the same environmental nuisances, individuals and groups are impacted differently. According to the literature, health inequalities exist among different socioeconomic groups, and SES may influence the association between environmental nuisances and health outcomes. However, the variation of this interaction across ages has rarely been studied. There is a need to adopt a life course approach to understand the history of diseases better. Objective—The main objective of this review is to document how SES could modify the association between environmental nuisances and health outcomes, across different ages, as a first crucial step introducing the emerged concept of social exposome. Methods—The PubMed database was searched from January 2010 to August 2021 for systematic reviews published in English addressing the interaction between SES, environmental nuisances, and health outcomes. Socio-economic indicators considered include education, level of income, neighborhood environment. Environmental nuisances considered many environment nuisances, mainly air pollution and noise. Results—Among 242 literature reviews identified, 11 of them address the question of the effect modification. Overall, our work reveals that environmental nuisances were mostly associated with poorer health outcomes and that SES modified this association, increasing the health risk among the poorest. Very interestingly, our work reports the existence of this interaction across different ages, including pregnancy, childhood, and adulthood, and for various environmental nuisances. Conclusion—In conclusion, our work confirms that we are not all equal to face environmental nuisances. The poorest are more vulnerable to the health effect of environmental nuisances. Policy decisions and interventions should target this high-risk population as a priority. Further investigations are needed to formalize the concept of social exposome more precisely and then communicate about it. Environmental nuisance refers to the unreasonable interference or likely interference with the environmental value caused by air, noise, water, soil pollution, and heat emissions and are harmful to the environment and the wellbeing of the local population . EnvironOver the past decade, environmental exposures have become increasingly recognized as a risk factor underlying many health outcomes such as cardiovascular diseases, respiratory diseases, and neuropsychological diseases, leading to many premature deaths. For example, air pollution (both indoor air and outdoor air pollution) causes up to at least seven million premature deaths yearly. The deaths disproportionately affect marginalized populations of lower SES . HoweverExposome is a concept in Public Health introduced by Dr. Christopher Oscar Wild to the scientific community in 2005. Through this concept, he shared his vision for the need to develop a field that provided an environmental complement to the genome. He defined it as the totality of exposures from various internal and external sources from conception onward over a complete lifetime ,5. The cThe exposome concept considers the lifelong environmental condition from the conception period, which accumulates from the sensitive period of conception to old age and can impact health status . HoweverLife-course approach has become a guiding framework for researchers in health, policymakers, and health practitioners. This had led to research in different fields such as chronic diseases, epidemiology, biology, genetics, economics, sociology, etc., into a cohesive conceptual health model better to understand the history of diseases . The lif‘’Inequalities in health, thus refers to the composite measure of the differences in health status across individuals or groups in a population’’  while soTo document how environmental exposures might interact with social determinants to contribute to health inequalities, the following hypotheses were advanced:The first hypothesis is the differential exposure: deprived populations or those living in a deprived area are more likely to be exposed to a higher number of environmental nuisances or a higher level of environmental exposure.The second hypothesis, the vulnerability differential suggests that deprived population or those living in a deprived area is particularly vulnerable to health effects of environmental exposures.For example, the health consequences of air pollutants exposure during the pregnancy stage can be modified by her SES, which influences her ability to afford and access healthcare. The neighborhood environment where pregnant women live also plays a role . FurtherDifferential vulnerability refers to the potential negative effects caused by external factors on human health. These factors could be natural or man-made or disease outbreaks and vary among communities. Three dimensions underline vulnerability which are exposure, susceptibility, the capacity to respond through coping and adaptability, and the ability to recover. The notion of risk with vulnerability implies that everyone is potentially vulnerable or at risk of developing health problems, but its effects vary from person, community, and system. Most studies suggest that vulnerability is increased for individuals or groups with the lowest SES, and this influences their health outcomes and their capacity to respond .Many studies investigate the environmental inequalities of one part of the general external exposome such as air pollution, noise, or green space. As already mentioned, many studies state that environmental exposure may contribute to health inequality through a different pathway. However, even the external exposome includes the social dimension as one health determinant, today, it remains unclear whether, over its life, all parts of the external exposome are similar or not according to the SES stratum. It is what Robinson and al. recently explored restricted to the pregnant women population . SeveralGiven the recent literature, it seems necessary to summarize the scientific evidence to identify whether socio-economic status could modify the health impacts of environmental nuisances across different age groups. We hypothesize that low SES combined with cumulative adverse environmental conditions  may influence the health status of people at each stage of life from conception throughout the lifetime.In this context, we perform a scoping review structured in three consecutive steps:Firstly, a summary of the studies by extracting several information related to external exposome, social vulnerability, and health consequences;Secondly, an analysis of the underlying concepts of the external exposome and social vulnerability defined by the different studies;Finally, a combination of evidence addresses the question of whether or not the health consequences from environmental nuisances may be modified by SES at each stage of life, resulting in the definition of several exposomes according to the socioeconomic status. It tends to appear in the scientific community called the social exposome.A scoping review was conducted using the PubMed platform providing access to the MEDLINE databases, among articles published between January 2010 and August 2021. The search strategy followed the PRISMA  guidelines and was performed with the following equation:Only literature reviews were considered in our work as many have already been published in this environmental health area.The criteria for inclusion were peer-reviewed articles written in English, with no restrictions on geographic location and human studies. We limited our scoping review to systematic reviews that were already published.(i)The database PubMed, with the search date from January 2010 to August 2021 was used. This time frame was used to work with the most recent guidelines and policy framework regarding environmental issues as countries keep on changing their policies over time. This was performed to achieve homogeneity among the studies.(ii)The titles of articles and their abstracts were reviewed based on the inclusion and exclusion criteria.(iii)As a classical step, the reference list of the selected articles was also screened for possible additional articles.(iv)The initial search yielded 242 results. Thirty systematic review articles were retained to document the two different mechanisms known to explain the relation between socioeconomic status, nuisance, and health; namely, it is the differential of exposure and the social differential of vulnerability. This work aims to document only the second mechanism, as the first one has been already published.(v)Systematic reviews of 12 articles were retained solely for the work on exposome and social vulnerability.(vi)During the data extraction, one article was excluded as there is no quantitative result.A summary of the search strategy used is as follows:The studies were selected by one author, myself, and a second (WKT and SD) verified the selection. Any discrepancies in the selection were discussed by the team. The screening process involved the evaluation of the titles and abstracts of the retrieved studies, in accordance with the inclusion criteria. The full text of the articles retrieved was assessed. Where there were disagreements, they were resolved through discussions till the team reached a consensus.The data from the included studies were extracted using an adapted piloted Excel form. The excel instrument was adjusted during the review. For each study, we extracted and reported in the table the following information: General information , main study characteristics , outcome measures .Synthesis of the results—The present study is a scoping review, so there was no statistical analysis planned or executed. Only descriptive synthesis was conducted.The preliminary search yielded 242 studies for the literature review published between 2010/2011-2021. Based on titles and abstracts, 212 studies were excluded. Reasons for exclusion were: (i) studies without socio-economic indicators (ii) animal studies (iii) Duplicates. The 30 articles were assessed in detail reading the full texts, 11 articles were retained as they dealt with social exposome.Among the literature reviews, one was published in 2014, three in 2015, one in 2016, two in 2017, zero in 2018, two in 2019, one in 2020, and one in 2021. In total, seven (66%) of the literature review studies used descriptive analysis and did not perform quantitative analysis and four (33%) of the literature review studies performed meta-analysis. All 11 studies assessed multiple regions: Europe, the Americas, and Asia. However, one of the studies focused on Ireland. In all, nine systematic reviews examined Europe, seven, America, four, North America, and three Asia. The average number of individual studies included in the systematic reviews was eighty (80) studies. The lowest study had 14 included studies, and the highest number of included studies was 146.The systematic review conducted by Paterson et al. included 15 studies and assessed people of low SES and urban dwellers as vulnerable groups. There is increased vulnerability to heat stress among urban dwellers due to overcrowding in homes, inability to afford air conditioning, poor general health, lifestyle risk factors, and living in densely populated areas.The authors also identified outdoor workers as a vulnerable population ; here, wBenmarhnia et al. assessed 61 studies in their review and defined vulnerable groups based on individual SES. The authors identified the following as vulnerable groups, individuals with low SES, the population living in high-density areas, and unmarried individuals (to account for isolation) .Fuller et al. assessed 30 articles in their review and examined vulnerable groups based on psychosocial stress and material resources as indicators of SES .In the recent review, Mathiarasan et al. focused on children with low SES as a vulnerable group. The study assessed children’s health and their vulnerability through social determinants, including lack of access to resources and treatments, social discrimination, and low level of education .Hibbert et al. also examined children with low SES as a vulnerable population. The authors found that the assessment of social vulnerability was based on economic measures including wealth, income, disposable income, or an index such as socioeconomic status (SES) or position (SEP), or poverty .Alderton et al. included 14 studies in their review and also assessed low SES children as a vulnerable group [Wong et al., examined the impact of physical exposures on the development and response to chronic diseases in later life and the influence the vulnerability of the individual including such as income, food security, education, and access to comprehensive health care . GelormiAs we describe below, the concept of “social vulnerability” differs between studies according to the type of data used. Some authors used individual characteristics such as the income of unmarried individuals; others used neighborhood characteristics such as density and inadequate nature or public open spaces in the neighborhood. Some authors used home characters including overcrowding in homes or poor housing quality.The pollutants reviewed in the articles selected under the inclusion criteria were: Nitrogen dioxide (NO2), Nitrogen oxides (NO), Sulfur dioxide (SO2), Carbon monoxide (CO), Ozone (O3), Ethanol, Black carbon, p353-nonylphenol, Chlorfenvinphos, Chlorpyrifos, Nicotine, Organophosphates, smoke, polycyclic aromatic hydrocarbons (PAHs) and particulate matter with an inhalable coarse fraction , the fine respirable fraction (PM 2.5 ≤ 2.5 µm) and the ultrafine fraction . Nine out of the eleven studies examined environmental pollutants in the neighborhood environment and the remaining two studies analyzed exposures related to heat–health vulnerability and mortality.Exposome looks at all the exposures an individual is subjected to during the lifetime and how those exposures affect health outcomes. All the 11 articles  in this The exposures examined by Mathiarasan et al. include environmental injustice on the health outcomes of children. The authors explored air pollution and climate change and its interaction with SES and how it affects the health of children . PatersoIn summary, to answer the research question “How the socioeconomic status modifies the environmental exposure health consequences at different stages of life?”, we considered the different important life stages from conception through to old age. We have analyzed the environmental health consequences and more precisely the effect modification of this relation by the socioeconomic status/conditions measured at individual or contextual level. All results are summarized in the following table. It shows the diversity of health consequences related to various environmental exposure; association modified by the socioeconomic status. These results are in favor of the existence of a social exposome.This review has provided a starting point to explore the exposome and social vulnerability of an individual/or a population and its subsequent health outcomes. The review shows the concept of social exposome being documented for different life stages throughout the studies included in this literature review although the exact terminology of exposome was not referred to in the included studies. More than 6 out of the 11 studies for this literature review, assessed pregnancy and childhood accounting for more than 50% of the studies which were included. However, there was not anyone document that looked at all the life stages is from conception through to old age. Only a few studies provided evidence on the older population as only two 2 studies reviewed the effect of exposome on this vulnerable group. Three 3 studies had a contrary opinion; (1) overtime one study found higher difficulties in children whose mothers were highly educated but had no access to green space (private garden) at home, (2) women of higher SES who used assisted reproductive services for childbirth recorded high adverse birth outcomes and (3) finally noise pollution negatively affected persons from high SES in their neighborhood environment in a study conducted in France.This review provides an overview of the evidence of vulnerability and exposome using a life course approach from conception through to old age thus providing a starting point for increasing interest. The strength of this study is that the search strategy was not limited to specific health outcomes or age groups (which was the case in the literature reviewed), for instance, one of the studies focused on incident asthma and children and also during the literature search one of the studies focused on a particular organ, for instance, the skin or kidney with regards to exposome. This review gives an overall life course approach or holistic approach to health looking at the environmental insults accumulated from conception to old age and different health outcomes.Many studies have established that to comprehensively evaluate the cause and progress of chronic diseases, there is the need to complement the genome with the exposome . HoweverIn addition, the exposome covers not only longitudinal environmental exposure from conception to old age but also overlapping domains of exposure namely, general external, the specific external, and the internal environments. General externals include the socio-economic environment , specific external include lifestyles, pollutant exposure, and occupations all these different aspects of exposome increase the complexity of the subject ,34. InteHeterogeneity of measurements and definitions of variables affect comparability, for instance the definition of vulnerability and susceptibility and how neighborhood characteristics are assessed such as quality. There have been different efforts from individual research teams to define and develop methodologies for measuring exposome. In the Human Genome Project, for instance, there were both national and international efforts for the sharing of data and coordination. This helped to minimize measurement error and also help in the development of the appropriate methodology. The National Institute of Environmental Health Sciences (NIEHS) has helped in the building of a centralized system for the provision of tools, data, and methods for exposome study, but there has been a limitation in terms of the number of proofs of the concept studies and there is no universal consensus in selecting what, when, and where to measure with regards to the concept of the exposome. Such heterogeneity makes it difficult for comparability .Some of the studies in the review focused on the environmental factors and their influence on the mental health of children; however, these studies did not analyze how they influenced mental health outcomes such as depression. Consequentially these studies focused on the negative aspects of mental health without analyzing the mental health competence and the potential for modifications in the built environment to reduce health inequalities and social vulnerability.To complement the limitations described earlier, our scoping review presents its own strengths and limitations. First, our search could suffer from study selection biases. Non-English publications of relevant articles may have been ignored. Furthermore, we cannot exclude the possibility that our review could be impacted by publication bias. Indeed, unpublished results  may influence our findingsGender should be considered in the assessment of social vulnerability for various reasons. For instance, the genetic makeup of males and females affects their responses to environmental pollutants.The occupation of the individuals during the time of their working life influences greatly the level of exposure to environmental pollutants. However, among the studies reviewed only one study assessed occupation. Research has shown that most of adult life is spent on the job hence much attention should be given to the occupational environment, especially for outdoor workers. The focus of the included studies was on residential and neighborhood-built environments which characterized more than 90% of the studies, the occupational environment should also be considered in future studies in light of gender roles.Ethnicity/race should be considered in future studies when assessing social vulnerability and exposome. To better understand and help marginalized areas and populations their unique circumstances (culture) need to be considered. There also are many studies for instance that have shown differences in pregnancy outcomes among women from different race/ethnic backgrounds. For instance, non-Hispanic black women and non-Hispanic white women have different causes of death-related outcomes due to pregnancy, while deaths from pregnancy are a result of preeclampsia, for most non-Hispanic black women, deaths from pregnancy-related outcomes among non-Hispanic white women are due to mental health . This wiBreaking down the barriers between disciplines; research on the exposome calls upon many disciplines: biology, medicine, physics, chemistry, epidemiology, sociology, public health, etc. However, the dialogue between the quantitative sciences and the social sciences is not always self-evident. For instance, the importance of the gender concept in environmental health risk when included in research could strengthen methodologies used and study designs adopted . An inteThe focus should be channeled towards children living in poor conditions to improve preventive measures by educating the parents to be aware of exposure impact on children population at an early age and most specifically among the poorer population.In addition, there is the need to improve the pedagogy for parents that have difficulties to well understand the different messages . To do that, we need to implement a universal screening mechanism for social factors that identify children at risk from early exposure to harmful pollutants and link them to community resources to improve their health outcomes in later years, for example, children who are at risk of heart diseases can be identified during early screening to determine the family at risk or the vulnerable families and provide the needed assistance.An information system to monitor child poverty can be developed in France to know where they live and to prioritize environmental interventions in areas with the highest level of environmental exposure. Interventions such as facilities to cater for the aged and most vulnerable populations can be implemented, through increasing and improving conditions in homes for the aged especially in marginalized areas, providing rehabilitations centers, and proper management and care for children or persons with disabilities or special needs children as a result of birth defects.Lastly, community-level interventions should be employed in improving vulnerability at an early stage. The first point of call for children is their community where they grow up hence interventions through community level, with different strategies can aid in improving social vulnerability.In conclusion, our work confirms that we are not all equal to face environmental nuisances. The poorest are more vulnerable to the health effect of environmental nuisances. It is known as a concept of social vulnerability, as defined by several authors ,39. For For building a healthy environment for all, and especially for the most vulnerable population, is a crucial issue if we want to design and implement measures for a greener and more equitable territory. The effect modification has been observed at different ages of life. Interventions should target in priority these high-risk populations. This review has identified gaps in the current research evidence on the importance of considering individual characteristics and behavior to fully understand vulnerability and exposome. Different disciplines are also required to fully explore the benefit of the exposome in understanding health outcomes. Further investigations are needed to formalize more precisely the concept of the social exposome and then communicate it.


Currently, reimbursement decisions based on health technology assessments (HTA) in the Netherlands mostly concern outpatient pharmaceuticals. The Dutch government aspires to broaden the systematic application of full HTA towards other types of health care in order to optimise the content of the basic benefit package. This paper identifies important challenges for broadening the scope of full HTA to other types of health care. Based on a description of the Dutch reimbursement decision-making process, five important characteristics of outpatient pharmaceuticals were identified, which are all relevant to the successful application of HTA: (i) closed reimbursement system, (ii) absence of alternative policy measures, (iii) existence of marketing authorisation, (iv) identifiable and accountable counterparty, and (v) product characteristics. For a selection of other types of health care, which may be subject to HTA more frequently in the future, deviations from these characteristics of outpatient pharmaceuticals are discussed. The implications of such deviations for performing HTA and the decision-making process are highlighted. It is concluded that broadening the application of HTA will require policy makers to meet both important policy-related and methodological challenges. These challenges differ per health care domain, which may inform policy makers which expansions of the current use of HTA are most feasible. In fact, only a limited number of other health care technologies have been subject to an HTA process in the Netherlands. Outside the scope of outpatient pharmaceuticals, HTA appears to be most used in the context of (expensive) inpatient pharmaceuticals [pharmaceuticals exclusively provided by hospital pharmacists  to overcome them in the Dutch context. This article will provide Dutch policy makers who are responsible for broadening the application of HTA the possibility to prioritise between different health technologies and to anticipate on some of the issues that need to be addressed in the coming years. In discussing these challenges, we take the decision processes and criteria developed for outpatient pharmaceuticals in the Dutch context as the comparator for other health technologies. Our results can also serve as an input to a research agenda aimed at the development of policy solutions and methodologies that would facilitate the broader application of HTA in research and policy. Furthermore, depending on their similarity to the Dutch context, findings may be of relevance for other countries considering the broadening of the systematic application of HTA.In order to address these issues, we first introduce the Dutch reimbursement system and HTA process (Section 2). Then important characteristics of outpatient pharmaceuticals in relation to the application of HTA in the Netherlands are highlighted (Section 3). Section 4 discusses these characteristics and the resulting challenges of five types of health technologies which may be subject to Dutch HTA research in the future.2.Zorgverzekeringswet), which covers a broad range of curative interventions. This plan is provided by competing private health insurance companies, regulated under public law . Most of the content is described in legal descriptions of reimbursed health care, defining the health care domains concerned . This allows for an ‘open system’, which follows the developments in the relevant fields without interference from the MoH. One overarching requirement for the health technologies included in the BBP through the open system is that they have to be part of the ‘established medical science and medical practice’. Otherwise, they need to be regarded in the relevant field as responsible and adequate care and services. This overarching requirement is referred to as the requirement of ‘effectiveness’ ZIN, . In someet al., Much of the practical content of the BBP thus is determined at the level of care providers and health insurers, without direct involvement of the MoH. Only in exceptional circumstances, the Dutch National Health Care Institute , an independent governing body and advisor to the MoH regarding the BBP, determines whether specific health technologies meet the requirement of effectiveness. This is often done to inform care providers and health insurers in cases where they do not agree on inclusion . Their coverage within the BBP is arranged through a ‘positive list’. Only when an outpatient pharmaceutical is on this list , of the intervention compared to a relevant comparator (like best current care) and calculating an Incremental Cost Effectiveness Ratio (ICER). This ICER is subsequently judged against a reference value to determine whether the intervention is cost-effective. Four different reference values are used in that context, depending on the burden of disease established under the criterion ‘necessity’: €0, €20,000, €50,000 and €80,000 per QALY. The highest reference value is used for interventions falling in the highest burden of disease category as shown in et al., The criterion ‘feasibility’ is assessed by mapping out pragmatic issues that can hamper or promote the successful coverage and implementation of an intervention in practice. It for instance explores the (im)possibility to provide the intervention in practice as well as the financial sustainability of covering the intervention in the BBP, using a supporting checklist  of ZIN. The ACP consists of eight independent experts appointed by the MoH. Their fields of expertise range from clinical practice and patient representation to ethics and health economics. The ACP performs a deliberative societal weighing of the assessed criteria, combined with other aspects considered relevant for the decision, also in a societal context, like the availability of alternatives, orphan status of disease, patient vulnerability and palliative vs curative interventions. The ACP meetings are public and open to participation by external stakeholders. The minutes of these meetings are public as well. Note that not all interventions that go through the assessment phase also necessarily go through the appraisal phase. In fact, for most outpatient pharmaceuticals, this latter phase is omitted, while highly expensive inpatient drugs are more often subject to elaborate appraisal. Four appraisals were conducted in 2018, three of which concerned expensive inpatient drugs, placed in the lock ZIN, .During the final phase, the executive board of ZIN, based on the information obtained in the assessment and appraisal phase, formulate their advice to the MoH on inclusion in the BBP. The MoH subsequently decides, often in line with this advice. Besides direct inclusion or exclusion, price negotiations with manufacturers, coverage with evidence development  and arrangements with care providers aimed at the improvement of care delivery can be part of that decision. Such instruments are currently especially used in the context of expensive, inpatient drugs. The final outcome of a decision-making process is published in the Law Gazette (Staatscourant).3.The fact that the focus of HTA applications has been on pharmaceuticals seems to be related to both policy decisions and inherent characteristics of the market for and product of outpatient pharmaceuticals. Below we highlight five important characteristics, as assessed by the authors using previous descriptions of the Dutch reimbursement system, which in general are associated with the Dutch outpatient pharmaceutical sector. Note that this list serves as an illustration of relevant defining characteristics of (the Dutch market for) pharmaceuticals that are important in the context of the need and possibility for performing HTA, and is not intended to be exhaustive. In addition, we address pharmaceuticals here in a very general way, abstracting from the large underlying diversity in this area .3.1The structure of the GVS is an important feature. It obliges both stakeholders as well as policy makers to use HTA in the decision-making process in the Netherlands. As highlighted above, the GVS forms a closed reimbursement system using a positive list. As a result, before and during the process of decision making, a new pharmaceutical is not yet reimbursed. Only after completion of the HTA process and a positive reimbursement decision, the intervention may be reimbursed and becomes available to clinicians and patients in practice. This dependency provides a strong incentive for stakeholders to contribute to a timely start and completion of the HTA process by fulfilling their roles. These roles include applying for admission, providing evidence on effectiveness and cost-effectiveness, and participating in meetings aimed at determining the scope of the HTA. In addition, the closed reimbursement system obliges policy makers to apply HTA to all submitted interventions. It moreover does not require Dutch policy makers to actively search for new interventions that could be made subject to HTA; these interventions actively present themselves through application for reimbursement by their manufacturers. Note that (the possibility of) having a closed system may also relate to the other mentioned characteristics of outpatient pharmaceuticals.3.2Related to the previous point is the absence of alternative policy measures to guide and control health care expenditures. Given this absence, the perceived need to apply HTA is likely to increase. Once outpatient pharmaceuticals are admitted to the BBP, no specific budgeting policies, or other policies enforcing economic considerations, are in place in the Netherlands. As a result, the consideration of the economic aspects of an intervention is formally limited to the HTA-based reimbursement decision, giving this process a unique role. As a consequence, from a policy maker's perspective, this process is positioned as an important, non-optional component of the institutional constellation when economic aspects are to be considered.3.3The requirement and process of marketing authorisation is an important feature of the market for pharmaceuticals. It provides a base for HTA assessments as it produces evidence on the safety and efficacy of these health interventions  pharmaceuticals. Many manufacturers have the resources to initiate and finance the studies needed to obtain evidence on effectiveness and cost-effectiveness of their products. They can be and are held responsible by policy makers to produce this evidence if applying for reimbursement in the Dutch context. These characteristics are related to market features and the proprietary nature of pharmaceuticals. A manufacturer of a new pharmaceutical is typically holder of a patent which provides the exclusive right to manufacture and market this new intervention during several years. Consequently, the expected financial revenues of reimbursement of the intervention during those years will benefit a single, identifiable entity. This entity can thus be obliged by policy makers from the start of HTA to produce required evidence for a coverage decision. This makes clear who needs to produce the evidence, which normally is an entity who is in principle capable of actually producing it. The  risk of evidence gathering is thus placed outside ZIN in the Dutch context, and even outside the public domain.3.5et al., Pharmaceutical interventions are often standardised products with clearly defined use and functioning, which are aimed at improving patients' length and health-related quality of life. Their effectiveness is mainly determined by the active substance, or substances, they contain. Consequently, when these products are correctly dosed, their effectiveness is relatively independent of the person administering them , non-pharmaceutical curative mental health care interventions (including psychotherapy) and non-curative and social care (including care for the elderly). These types of health technologies were selected as an illustration, covering a broad range of health technologies, differing from outpatient pharmaceuticals in different ways. We will only generally address these health technologies, simplifying their characterisation and ignoring the large variations within each type of health technology, for the current purpose. Besides the identification of challenges specific to these types of health technologies, we highlight potential ways forward, again with a focus on the Dutch situation.4.1et al., et al., et al., In contrast to outpatient pharmaceuticals, the five other types of health technologies used here as illustration of the challenges expanding the scope of HTA in the Dutch situation are part of the open system for reimbursement in the Netherlands. Therefore, the requirement for manufacturers to apply for admission and to submit evidence on effectiveness and cost-effectiveness is not present for these types of health technologies. Consequently, policy makers are not ‘automatically’ provided with an inventory of subjects for assessment, let alone with HTA dossiers for these technologies. As a result, they will need to screen and select interventions for assessment, which requires additional effort, clear processes and rules by which to do so. Horizon scanning methods . This could lead to attempts to avoid, postpone or delay the HTA process and to provide less clear evidence . Expanding the scope of ‘the lock’ , current4.2Budget restrictions exist for each of the other types of health technologies, in the Dutch setting. Hospitals, for example, are funded by health insurers with whom they agree on budget ceilings and fixed budgets NZa, . These rA downside of these budget restrictions is that differences between care providers can occur if budget holders make different choices about the use of certain interventions. This can lead to unwarranted treatment variation across care providers and patients . Moreover, the choices made at lower levels in the health care system may not align with the principles and goals set at the central level. Put differently, the resulting use of resources may not be the most necessary, effective and cost-effective. Expanding the use of HTA may help in overcoming such differences and suboptimal decisions, but requires central decision-making bodies to perform an increased number of assessments as well as ensuring that other actors act in line with their decisions, which may require much effort and better instruments to ensure adherence to centrally made decisions or guidelines.4.3For most non-pharmaceutical interventions, no market authorisation procedure is in place. This means that information regarding effectiveness and safety, as well as regarding the exact intended use of the intervention is not available at the onset of an HTA process. Medical devices form an exception . Developing methodologies and processes to scan for new or ‘risky’ interventions, also to prioritise these for HTA, may contribute to formulating solutions to these challenges. As mentioned above (see ‘Closed system for reimbursement’), broader horizon scanning for new health technologies has been implemented in some other jurisdictions, which is important to take into consideration in implementing this in the Netherlands.4.4Like for inpatient and outpatient pharmaceuticals, medical devices normally have a manufacturer who may own the exclusive right to manufacture and market a particular device. This would make them an identifiable and accountable counterparty in the HTA process similar to pharmaceutical companies. However, numerous manufacturers in this sector are small and medium enterprises (SMEs)  arrangements with. In the absence of such a counterparty, both a (selectively) closed system of reimbursement and market authorisation requirements cannot ensure adequate evidence generation. Creating evidence in the absence of an accountable counterparty then logically would become a public task. This has been shown to be feasible in the Netherlands in previous research programmes  pharmaceuticals can be distinguished. First, their outcomes may be more context-dependent: personal characteristics of the care provider and the organisational context can influence how a device is used and hence the associated costs and effects  of care users. This focus on well-being brings specific methodological challenges. Although outcome measures aiming to capture well-being in different ways and comprising various life domains have been developed , others may be specific to the Dutch jurisdiction . Nonetheless, the presented challenges will, at least partly, exist in other jurisdictions than the Netherlands as well. For instance, Drummond et al.  already   deviations from the characteristics of outpatient pharmaceuticals, broadening the scope of HTA may be challenging – and more so in some areas than in others. Consequently, it is important for (Dutch) policy makers aspiring to broaden the application of HTA, to do so gradually and aware of the various challenges they are likely to face. A logical route forward may be to start the expansion in those areas in which the number and difficulty of the existing challenges may be least. Interventions relatively similar to outpatient pharmaceuticals, like inpatient pharmaceuticals and medical devices, may be logical first steps in coming to a broader use of HTA in defining the Dutch BBP. Meanwhile, necessary preparatory steps can be taken that would facilitate a further expansion of the use of HTA in more challenging health technologies, both in terms of policy context as well as in methodological development. Such a route forward in the broader application of HTA is encouraged. While a bumpy road may lay ahead, a conscious planning may ease the travel, and the destination certainly is worthwhile.


Female reproductive aging is, in a way, a biological phenomenon that develops along canonical molecular pathways; however, it has particular features. Recent studies revealed complexity of the interconnections between reproductive aging and aging of other systems, and even suggested a cause-effect uncertainty between them. It was also shown that reproductive aging can impact aging processes in an organism at the level of cells, tissues, organs, and systems. Women at the end of their reproductive lives are characterized by the accelerated incidence of age-related diseases. Timing of the onset of menarche and menopause and variability in the duration of reproductive life carry a latent social risk: not having enough information about the reproductive potential, women keep on postponing childbirth. Identification and use of the most accurate and sensitive aging biomarkers enable the prediction of menopause timing and quantification of the true biological and reproductive ages of an organism. We discuss current views on reproductive aging and peculiarities of using available biomarkers of aging. We also consider latest advances in the search for potential genetic markers of reproductive aging. Finally, we posit the importance of determining the female biological age and highlight potential research directions in this area. It’s a fact of life that every human moves down one and only path, which is aging. This path, as scientists suggest, starts in the embryonic development period — the so-called “zero point” — when both life and aging of an organism begin simultaneously . ResearcCurrently, the concept implying that aging is not a disease prevails in the academic community. However, we believe that despite the existing conceptual differences, these processes can be neither called parallel nor completely isolated from each other. Having no specific symptoms, unlike disease, aging still has its own, inherent pathological features , 7. MoreInterestingly, the attempts of researchers to delve into the deep insights of aging face numerous challenges—particularly because this condition is not regarded as disease. Natural, inevitable, and, most importantly, physiological, this process also does not imply any “treatment.” But, as we all know, “everyone wants to live long yet no one wants to be old.” With greater age comes a heavier burden of conditions and, subsequently, lower quality of life. Potential strategies for “anti-aging” and searching for corresponding biomarkers are becoming increasingly relevant for the aging world population.To work out these strategies, scientists are trying to simulate the processes that occur in the body with age. Pregnancy seems to be an interesting case to consider (see for review . With unSuch studies add to our knowledge of the complex interrelation between aging processes (and hence accumulation of diseases) and hormonal changes in the body. There is much already known about the role of female sex hormone deficiency in development of aging-associated diseases . ReproduIn particular, recent analysis of mutations in the genomes of various types of cancer showed that the mutation accumulation rate in ovarian and uterine tumor cells is 20 % higher than that in tumors of other tissues, which, after extrapolation suggests a 20 % increase in the reproductive aging rate . The decDesynchronization of the reproductive and somatic aging rates causes a woman's post-reproductive lifespan to be about 30 years of her total life expectancy , 16. SinBiomarkers are condition indicators that reflect whether an organism or a cell has such condition . The conIt is important to note that the American Federation for Aging Research (AFAR) proposed in 2013 that all biomarkers of aging should meet the criterion of being able to predict the rate of aging . But witAt the same time, infertility is just the tip of the iceberg of reproductive aging. Numerous studies have demonstrated that menopause is associated with a higher risk of cardiovascular and other diseases , 27. MenNot only the onset of menopause itself but the time of the onset can significantly contribute to the development of medical conditions in women. The cardiovascular risk is known to increase as the age of menopause onset comes down , 30, 31.The reproductive lifespan of a woman depends on presence of multiple somatic diseases and all possible causes of death , 38. DurThe reproductive lifespan varies a lot. The time of the menarche onset depends on hereditary factors, ethnicity, girl's characteristics at birth, factors in play at early infancy, as well as lifestyle and environmental factors . The timThere are many genetic and non-genetic determinants that affect the reproductive aging rate and the onset of menopause. It has been found that birth weight, presence of twins, mother's bad habits during pregnancy, as well as life history of smoking and exposure to hazardous substances  are associated with an earlier onset of menopause in women –50.The reproductive lifespan of a woman, which is controlled by ovarian function, also determines reproductive behavior and reproductive events during life. A large multicenter study has shown that early menarche and childlessness aggravate the risk of premature and early-onset menopause by 80 % and 2 times, respectively, while their combination can turn the risk of these conditions five times higher . A recenUp to the present day, researchers who are actively engaged in the search for biomarkers of aging have faced significant difficulties, since it is effectively impossible to measure all molecular and cellular processes that occur in the whole body with age due to versatility and multifactorial nature of this phenomenon as well as differences in aging rates of different tissues . The proAging of the body, as many gerontologists believe, is a consequence of accumulation of various damages in the cells  . Female For at least the past 100 years have the scientists been trying to explain this phenomenon . AccordiAnother explanation for the “immortality” of oocytes may be the asymmetric cell division during maturation (after the first and second divisions of meiosis) resulting in a fully-formed egg cell and polar bodies being formed (which are subsequently reduced) . This prHowever, the quality of egg cells still deteriorates with age, the mutational load on the offspring grows, and the risk of children with developmental abnormalities increases . That isWhatever the causes and despite this feature of the sex cells it was mentioned above that the reproductive system ages faster than other systems in the body. And to detect it at early stages, we need to realize what we are going to ultimately measure (in terms of biomarkers). Despite the fact that, to some extent, all the structures of the reproductive axis age, according to the accepted dogma, reproductive aging is nowadays is defined as a decline in ovarian follicle number and decrease in the quality of egg cells in the ovaries .The exact molecular mechanisms that determine the decline in oocyte/follicle quality are still to be determined. Having received evidence that the results of ART programs, as well as the ovarian follicle number, tend to deteriorate in correlation with age. The scientists have accepted the follicle number as an indirect marker of follicle quality , 63. AltAt the moment, there is still no international consensus on whether neo-oogenesis can be observed in the ovary or whether the pool of follicles is fixed and cannot increase or renew –69. SomeThough widely spread, the concept of “ovarian reserve” causes confusion among scientists and clinicians when it comes to defining it. Commonly, the problem lies in attempts to evaluate the ovarian response to ovulation stimulation instead of true ovarian reserve, although these parameters are related . This isThere are also some difficulties in distinguishing the concepts of “decreased ovarian reserve” (DOR) and “premature ovarian insufficiency” (POI). DOR is not the equivalent of POI but rather applies to women with existing infertility and an increased risk of poor response to ovulation stimulation  . It is iTherefore, there are many definitions of the physiological and deteriorated (to some extent) ovarian function. But what are we really trying to measure? Since true ovarian reserve, including resting and growing follicles, can only be confirmed histologically, the currently known markers are more applicable to functional ovarian reserve — i.e., to growing follicles. To some extent, we can extrapolate these data to the indicator of true ovarian reserve, given that the number of growing and the number of resting follicles are intrinsically related to each other . LeadingIt is known that any screening test has a number of parameters with sensitivity and specificity having special statuses. In the case of ovarian reserve markers , it is impossible to balance the sensitivity/specificity ratio without having either of the parameters decreased ; for theIn this review, we will focus on the biomarkers of ovarian aging that are recommended due to their proven benefits and value of information they give. We would also like to focus on new promising areas of research in the field of reproductive aging as well as on the search for molecules that identify this process.For a long time, the chronological age of female patients, nature of their menstrual cycle, certain hormonal parameters (such as estradiol (E2), follicle-stimulating hormone (FSH), inhibin B, etc.), ultrasound characteristics , and dynamic tests, such as the clomiphene citrate challenge test (CCCT), have been used as potential markers of ovarian reserve as well as for prediction of the reproductive potential in IVF programs and other areas . AccordiFollicle stimulating hormone (FSH) is a biochemical marker and is a dimeric glycopeptide produced by the anterior pituitary gland. It has a regulatory effect on growth of follicles at the hormone-dependent stage of folliculogenesis. Clinical interpretation of actual (absolute) FSH levels is usually performed on the third day of the menstrual cycle, since its increase is better registered at the beginning of the first phase against a decrease in inhibin B and estradiol levels .Individual variations in FSH levels have been observed during the menstrual cycle as well as from cycle to cycle in the same woman . StudiesAnother biochemical parameter, which is currently the most promising and frequently used marker of ovarian reserve, is anti-Müllerian hormone (AMH). It is a glycoprotein that belongs to the transforming growth factor beta (TGF-β) family and is exclusively produced by granulosa cells of preantral and small antral follicles with a diameter of about 4 mm. In larger-diameter (6–8 mm) follicles, AMH is no longer secreted. Against a background of sharp drop in the AMH level, there occurs an increase in the activity of the aromatase enzyme and increased synthesis of estradiol, which indicates the presence of a feedback mechanism between the synthesis of estradiol by the granulosa cells of the dominant follicle and AMH. This hormone mainly exerts two types of effect on the ovary: it suppresses the primary stages of follicle growth and suppresses hormone-dependent growth and selection of preantral and small antral follicles . HoweverAMH shows less variability within and between the cycles compared to FSH . For a lAMH, along with antral follicle count (AFC), shows consistency with the pattern of oocyte loss seen in histology specimens , which aAFC is one of the most popular methods of interpreting the functional state of the ovaries employed in current clinical practice. AFC, as well as AMH, varies less between menstrual cycles compared to FSH or, for example, ovarian volume. But the imaging examination methods are subjective . AFC is Although there has always been vigorous discussion on the ways to compare the effectiveness of the two key markers, AFC and AMH, with regard to different parameters of ovarian function , 93, 94,Other candidates for the role of biomarkers of ovarian reserve (reproductive aging) are less meaningful. According to the Practice Committee of the American Society for Reproductive Medicine, neither the basal inhibin-B level nor the ovarian volume or estradiol level values should be used as independent screening test indicators in the diagnosis of decreased ovarian reserve .Both menarche and menopause are fundamental events in a woman's life. The interval between the beginning of the reproductive life and its end is referred to as the reproductive lifespan, while a specific period within this interval is referred to as the reproductive age. While, with the knowledge of the female patient's reproductive age , the doctor would only be able to assess her ability to conceive and give birth to a child at a specific time. On the other hand, information about the reproductive lifespan would offer more counseling options. Genetic markers may be the central point in this context, and, in this case, the strong genetic component of age at menarche and menopause promises scientists good opportunities and prospects for research .Currently, the only genetic marker widely used in clinical examination of patients with suspected POI is determination of 5'-UTR a triplet-base-repeat  in the FMR1 gene  localized on the long arm of the X chromosome at locus Хg27.3. This gene is considered mainly responsible for one form of mental retardation  when the number of triplet repeats are located at the 5' untranslated region of the gene exceeds 200 (complete mutation). The expression of the product of this gene also plays an important role in formation of physiological ovarian reserve. The increase in triplet CGG repeats in the FMR1 gene within the range of 55–200 (gene premutation) is well known to reproductologists, since it is this range of CGG repeats that is most often associated with POI and infertility. Another deviation is represented by the number of repetitions being within the range of 35–54 (the “gray zone”), which is typical both of patients with the conventional form of POI and patients with periodically fluctuating FSH levels , 97. HowRecent studies have provided a large amount of previously unknown information about the molecular and genetic basis of reproductive aging . The seaA kind of revolution was made just over 10 years ago by genome-wide association studies (GWAS), the philosophy of which is to identify the interrelations between disease and genetic variants (polymorphisms) of individual nucleotides . DespiteDNA repair appears to play a significant role (much more important than previously thought) in the decline in the ovarian follicle number. Oocytes can be highly susceptible to DNA damage occurring in response to metabolic and environmental impacts, including due to prolonged cell cycle arrest . DNA damA series of GWAS studies suggested that certain items in the sets of genes responsible for age at natural menopause and POI are the same, which revealed common pathways of genetic susceptibility of these two conditions . Other eAllelic heterogeneity is also observed in the loci of genes associated with the age at menopause, energy homeostasis, regulation of lipid metabolism, etc. These findings largely shed light on the gaps in understanding of the interrelation between reproductive aging and various adverse health outcomes, which have been confirmed by numerous epidemiological studies .Physiological and pathological reproductive phenotypes have polygenic nature . DiagnosThis approach is promising for the molecular diagnostics of reproductive aging (which is a complex heterogeneous phenomenon) and, in particular, diagnostics of premature ovarian insufficiency. Despite the established contribution of the genetic component to the pathogenesis of POI (including for the isolated form) and identification of several dozen genes involved in this condition, there is no complete understanding of the genetics of POI, and most patients do not receive genetic diagnoses . In ongoOverall, GWAS and NGS have identified common genetic and molecular pathways in reproductive aging. Some of the results obtained have already been confirmed in a number of other studies, and some have yet to be clarified. Another important conclusion made after more than 10 years of successful use of such large-scale studies is that the identified genes are often difficult to associate with the development of medical conditions since most of them do not encode proteins and many features can be considered quantitative due to the subtle interaction of many genes. Another thing to keep in mind is that in the case of polygenic inheritance we are dealing with the phenomena of incomplete gene penetration and varying relevance to the disease progression, which makes it hard to identify responsible candidate genes. Scientists suggest that the candidate genes for the disease progression function consolidated in networks, and it is the discovery of these networks and understanding of the principle of their action that is a priority for future research. In this regard, there is great potential in using individual approaches to each case of POI, NGS, and sequencing with pre-analyzed coding and regulatory regions of genes for diagnostic and prognostic purposes.The etiology of early and premature menopause, which is an example of premature reproductive aging, is extremely diverse. Chronic conditions that maintain inflammation in the body can indirectly or directly cause premature reproductive aging. Premature ovarian insufficiency is associated with genetic predisposition, autoimmune diseases, and infectious diseases , 121. ThThe mechanisms underlying reproductive aging are complex and their pathological signaling pathways, apparently, run into numerous intersections as the disease progresses. There is evidence that premature and early-onset menopause are associated with mitochondrial dysfunction , 124. ThAs is known, being widely recognized in the scientific community, mitochondrial free radical theory of aging puts Increased production of mitochondrial reactive oxygen species (ROS) and oxidative stress at the center of processes that contribute to aging of cells , 126. MiThe number of mitochondria and mtDNA copies varies in different cell types depending on their energy needs. Oocytes, the largest cells in the body, require the maximum number of mitochondria and contain the largest amount of mtDNA . They reStudies demonstrate that decreased mitochondrial biogenesis, impaired mitochondrial homeostasis, and free radical imbalance, associated with the latter, play a critical role in ovarian aging . QualitaThe number of mtDNA is significantly reduced in the oocytes of old animals compared to young ones . This alScientists believe that changes in mtDNA act as markers of mitochondrial aging, while mitochondrial aging reflects the essence of systemic aging . MitochoMutations of mtDNA accumulate over time and worsens cellular function. Based on the above, the accumulation of mtDNA mutations is now considered as the “biological clock”, which is of great interest today , 140. AlChronological age is clearly a determining factor of aging and accumulation of aging-associated diseases. However, among the elderly, the rate of these processes and outcomes is significantly heterogenous. Determination of biological age as a true indicator of aging has become a priority for gerontology recently, and the scientific research in the field of identification and implementation of the corresponding biomarkers continues . In the Cells “report” aging by stopping the cell cycle and triggering the so-called secretory aging-associated phenotype (“senescence-associated secretory phenotype” (SASP). This phenotype is associated with the expression of typical biomarkers  . AttemptIn recent years, significant progress has been made in the development of the so-called epigenetic “aging clock”. Epigenetic mechanisms control gene expression programs, thereby determining the cellular homeostasis. The main epigenetic mechanisms come down to DNA methylation and processes that induce changes in the state of chromatin (associated with histone modification and other molecular events) and non-coding RNA . DNA metNowadays, telomere length is considered to be one of the most meaningful markers of biological age . TelomerThe cause-effect relationship between the processes of reproductive and general somatic aging is complex. In 2016, two groups of researchers tried to identify the interrelations between biological aging, accumulation of diseases, epigenetic changes, and reproductive aging , 163. ThOne model suggests that certain factors  independently predispose affected individuals to both accelerated biological and accelerated reproductive aging as well as to accumulation of various diseases. In this case, the true biological age, which differs from the chronological age, can be considered a marker of accelerated reproductive aging, while its determined value may be sort of an indicator of age at menopause.According to another model, the loss of ovarian function  can be considered the main cause of acceleration of general aging processes, increase in epigenetic age, and accumulation of multimorbidity. In this case, determination of biological age provides important additional information about the patient's state of health, which may affect therapeutic strategies and recommendations (including those regarding the ability to bear a child).As is known, different organs age at different rates, moreover, biomarkers appear to track different biological processes and, therefore, could have low correlation with each other. Obviously, sets of biomarkers, rather than any single biomarker, are the most effective means of assessing the health status; in the case of aging biomarkers, scientists suggest using the most holistic approach to collecting information about aging structures of the body for comprehensive assessment of the obtained biomarkers . DevelopWith the modern tendency of women emancipation, the need to make them aware both of their reproductive potential and the reproductive lifespan, which is important for their social and labor functioning, is growing. Needless to mention, we would like the markers of these parameters to be highly meaningful, low-cost, and able to predict age at menopause and the endpoint of the reproductive period as early as possible. If a decrease in ovarian reserve is diagnosed at a younger age, we can personalize the approach to managing patients and take possible effective measures aimed at facilitating their reproductive function capacity .In the modern world, there is a certain illusory opinion that delayed childbearing is not a problem in the context of the developing modern technologies, including IVF programs. However, it is not always possible to solve the problem of infertility, even with the use of the latest technologies. Perhaps, availability of prognostic information about the true reproductive lifespan would allow women to correctly and timely set the necessary priorities in life. Determination of the true biological age of a woman may be an additional and very important option, regardless of whether we consider it as a predictive marker of reproductive health or as an indicator of overall health and a powerful tool for selecting the most suitable approaches to treatment and prevention of various diseases.The number of potential biomarkers of reproductive aging continues to grow, and it is necessary to carefully plan the strategies of their development. To date, prediction of the length of a woman's reproductive lifespan is still a goal that we have not achieved yet. Future studies should be aimed at identification of more markers, validation thereof, and widespread implementation in clinical practice.


The global utilization of the physician assistant/associate (PA) is growing. Their increasing presence is in response to the rising demands of demographic changes, new developments in healthcare, and physician shortages. While PAs are present on four continents, the evidence of whether their employment contributes to more efficient healthcare has not been assessed in the aggregate. We undertook a systematic review of the literature on PA cost-effectiveness as compared to physicians. Cost-effectiveness was operationalized as quality, accessibility, and the cost of care.Risk of Bias in Non-randomised Studies—of Interventions (ROBIN-I) tool. The literature search produced 4,855 titles, and after applying criteria, 39 studies met inclusion . Ten studies had a prospective design, and 29 were retrospective. Four studies were assessed as biased in results reporting. While most studies included a small number of PAs, five studies were national in origin and assessed the employment of a few hundred PAs and their care of thousands of patients. In 34 studies, the PA was employed as a substitute for traditional physician services, and in five studies, the PA was employed in a complementary role. The quality of care delivered by a PA was comparable to a physician’s care in 15 studies, and in 18 studies, the quality of care exceeded that of a physician. In total, 29 studies showed that both labor and resource costs were lower when the PA delivered the care than when the physician delivered the care.Literature to June 2021 was searched across five biomedical databases and filtered for eligibility. Publications that met the inclusion criteria were categorized by date, country, design, and results by three researchers independently. All studies were screened with the Most of the studies were of good methodological quality, and the results point in the same direction; PAs delivered the same or better care outcomes as physicians with the same or less cost of care. Sometimes this efficiency was due to their reduced labor cost and sometimes because they were more effective as producers of care and activity. Healthcare systems across the globe face several challenges to meet patient demand and deliver high-quality healthcare. The challenges are primarily population growth, increasing chronically ill patients, rising patient expectations, and longevity . At the The gap between physician capacity and patient demand is expanding and requires a change to the medical workforce. At least 18 countries have introduced the Physician Assistant/Associate (PA) as a solution . These hIn labor economics, if a PA replicates the activities of a physician, then that is a ‘physician substitute’ . If, on What is the cost-effectiveness of PAs compared to physician services?Because of their increasing utilization worldwide, understanding the economic value has become essential to their utilization. To date, no published systematic reviews have examined the cost-effectiveness of the PA. Therefore, the aim of this project was to review the effects of quality of care, accessibility of care, and costs of physician substitution by PAs in a variety of settings. This was operationalized as a research question: A systematic review was undertaken using the reporting criteria developed at the University of York . The proThe following international bibliographies were systematically searched: PubMed, Web of Science core collection (WoS), CINAHL (with full-text EBSCO), Embase-Ovid, and The Cochrane Library. A detailed search strategy was developed in consultation with two experts; a librarian experienced in systematic reviews and a health workforce researcher. The search strategy used PubMed as a format and then adapted it to the other database results. Searches were performed in 2021 and spanned all published studies through June 2021. Subsequently, the included articles and references were examined using a backward and forward snowball citation search method in Web of Science and Google Scholar to identify relevant other studies.The literature search included all original empirical research studies on PAs with a comparative quantitative evaluation design written in English or Dutch. There were no date restrictions on publications. Both ‘Physician Assistant’ and ‘Physician Associate’ were included in the review, as they have a similar scope of practice. In addition, studies of ‘Clinical Assistants’ working in South Africa were included because their role is similar to, and modeled after, the PA , 9.Studies that encompassed nurse practitioners (NPs) and PAs but the provider type was missing were excluded. We omitted findings in which PAs were still in training, or the setting had an educational purpose. Articles were excluded when the outcome of care did not fit the protocol or where the care outcome of PAs was not compared to those of physicians.Rayyan QCRI, a systematic review computer-based application system  or as a need to expand the medical staff –18. AlonWe note that in the majority of studies in this review, the profiles of the PAs were missing. Most findings came up short on information as to the experience the PA brought to the setting. The exception was the de Lusignan study that noted the provider’s gender and experience .Supervision of the PA by the physician was considered a necessary activity, especially during the first decade or so of the introduction of the PA profession. When a supervising physician took time off from their patient schedule to supervise the PA’s care or medical notes, the time was deducted from the PA’s employment benefits . In 11 s“As a theory, productivity is a simple concept: it measures changes in the total output that occurs when small changes are made in one factor of production, with all other factors and circumstances held constant. Because these conditions can be met in the real world only rarely, productivity numbers are almost always rough estimates. Certainly, that is the case concerning PAs.” . Another strength was the breadth of the search that provided clear insight into the PA profession’s different effects and development. With the help of an experienced librarian, the research question was carefully operationalized. Combined with a reference check at the end of the process, the risk of missing relevant articles was significantly reduced.st century is a semi-autonomous health professional who is a part of contemporary medical treatment teams. When peer-reviewed published studies spanning three continents were examined for quality of care, accessibility, and cost-effectiveness of employment, the PA was comparable to the physician in producing similar results in almost every case. Although some of the studies suggest that the addition of a PA resulted in a similar quality of care as physicians, in a few instances, their utilization enhanced the overall quality of care. In most instances, the introduction of a PA leads to the same or an improved quality of care, and their employment is cost-efficient when considering the labor and educational costs. These economic findings were observed in prospective and retrospective designs and various settings, whether primary care in outpatient offices or secondary [hospital-based] care. The results of the collective studies have produced a sizeable contextual understanding of efficient outcomes of care when the PA is a part of the medical team.The PA of the 21S1 Checklist(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.


Precision agriculture has the potential to contribute to the broader objective of meeting the growing demand for food, ensuring the sustainability of primary production, based on a more accurate and resource-efficient approach to crop and livestock management. The aim of this paper consists of a brief review of the recent scientific and technological tools and sensors in precision agriculture and their application in crop and livestock farming. This literature review allowed us to realize that precision agriculture has been proven to be a highly researched and constantly evolving area due to the needs of farmers to use resources in a more optimized way.In the last few decades, agriculture has played an important role in the worldwide economy. The need to produce more food for a rapidly growing population is creating pressure on crop and animal production and a negative impact to the environment. On the other hand, smart farming technologies are becoming increasingly common in modern agriculture to assist in optimizing agricultural and livestock production and minimizing the wastes and costs. Precision agriculture (PA) is a technology-enabled, data-driven approach to farming management that observes, measures, and analyzes the needs of individual fields and crops. Precision livestock farming (PLF), relying on the automatic monitoring of individual animals, is used for animal growth, milk production, and the detection of diseases as well as to monitor animal behavior and their physical environment, among others. This study aims to briefly review recent scientific and technological trends in PA and their application in crop and livestock farming, serving as a simple research guide for the researcher and farmer in the application of technology to agriculture. The development and operation of PA applications involve several steps and techniques that need to be investigated further to make the developed systems accurate and implementable in commercial environments. Agriculture has played a key role in the global economy in recent years . EstimatPA technologies are used in the important stages of the crop growth cycle . However, it is not just crop and fruit farming that has benefited from precision farming technologies—farmers engaged in livestock rearing are also experiencing the positive benefits derived from precision farming technologies . PA coulThe current paper aims to briefly review the recent scientific and technological trends of precision farming and its application in crop and livestock farming. This study can serve as a research guide for both the researcher and the farmer in applying technology to agriculture. The remainder of this paper is organized as follows. Precision crop farming or site-specific crop management is a concept based on sensing or observing and responding with management actions to spatial and temporal variability in crops. The “sensing” component of the concept is a fundamental element of precision crop farming . SensorsThere are a range of sensors available used to measure and calculate the parameters of an agricultural field, namely the soil sensors , which c3, NH4, K, and PO4 and followed on from previous studies exploring the potential for on the-go soil sampling for nitrate using electrochemical sensor platforms and ion-selective electrodes [Soil electrical conductivity (ECa) sensors measure the soil solute concentration while assessing the soil salinity hazard . Mobile ectrodes . There aectrodes ,16. Addiectrodes .Precision seeding has become the main feature and developing direction of modern seeding technologies in recent years. Precision seeding can save seeds and effectively control the sowing depth, densities, or distance. According to statistics, the output of precision seeding increases by 10–30% compared with that of the conventional drill . Recent One of the most important aspects to achieve the consistent emergence of the crop desired is the use of a uniform seeding depth. Consistent crop emergence influences final crop yields, as the seedling growth process affects the variability of crop biomass. In this sense, Nielsen et al.  developeIn light of the problem that small seeds are not easy for mechanized seeding at present, Jin et al.  developeDue to the particular characteristics of the wheat seed grain geometry, Haibo et al.  designedJianbo et al.  designedA high-speed precision seeding device enables one to obtain better seeding quality. This system consists of a seed supply device (including a seed box and a wheel) and a venture tube. In this sense, Gao et al.  designedThe efficient and effective management of water in irrigation is one of the main benefits that comes from precision agriculture technologies , being oIn recent years, the literature has provided several studies on the optimization of irrigation water management. Ortega et al.  evaluateIn the south of Italy, Corbari et al.  developeKrishnan et al.  proposedAl-Ali et al.  developeBenyezza et al.  designedRecently, Liao et al.  developePrecise fertilization techniques are the future of agriculture, in which nutrients are supplied in a controlled way with minimized losses to the environment, caused by over-fertilization and leaching of microelements to deeper soil layers, ground water, and surface water .As an important part of precision agriculture, variable-rate technology (VRT) offers an effective way to protect the environment and increase economic benefit while farming with site-specific fertilizer inputs. Song et al.  developeTo reduce the labor workload and costs, thus increasing the efficiency of the organic fertilizer mixing process, Ishak et al.  developeFrom another aspect, robots are perfectly suited to be used in agricultural operations, particularly in the spraying of fertilizer, which can carry large storage reservoirs, be operated safely and autonomously, and be deployed at a fraction of the costs compared to the traditional methods. In this sense, Ghafar et al.  developeAdditionally, fertigation technology is recognized as a new agricultural technology with high-efficiency water and fertilizer control. Lin et al.  developeMonitoring and predicting above ground biomass yield are of key importance for crop management. According to Beukes et al. , a 15% iTraditional methods of measuring grass yield include destructive grass sampling coupled with weighing systems on mowers, trailers, or balers . OpticalCurrent developments in unmanned aerial vehicle-based (UAV) sensing systems allow for the acquisition of image data at a ultrahigh spatial resolution for important stages of plant phenological growth ,38. FurtThe capacity to yield-map crops is relevant and provides a decision support tool for improved crop management. An on-the-go pasture meter was developed in New Zealand to meet this need. The equipment uses optical sensors to determine sward height and needs to be calibrated for herbage density. It can be used as a stand-alone sward meter or with GPS for sward-yield mapping .Finally, we should also refer to the grass measurement optimization tool (GMOT), which is designed to utilize basic pasture management and geo-spatial information to develop a spatially balanced and non-biased grass measurement protocol. Calibrations to predict herbage mass that were built into the GMOT could utilize herbage management information such as fertilization rates and the number of previously performed paddock grazing or cutting events to increase herbage mass prediction precision .Mechanization is one of the main drivers of efficient farming systems, involving numerous operations in the crop’s production cycle and throughout the value chain . AgriculRecently, the accomplishment of agricultural operations carried-out with tractors has been heading toward the integration of traditional mechanics with geolocation technologies to bring farming procedures closer to the logic of precision agriculture. The possibility of controlling the tractor steering by using GNSS is an important contribution to improving the efficiency of agricultural practices and allows savings of time, fuel, labor, and production factors contributing to the economic and environmental sustainability of the agricultural process . The autThe latest developments in ICT and the prevailing lack of interoperability between agricultural tractors, implements, and on-board computers has led to the development of the ISO 11783 (ISOBUS) international standard for securing a more effective communication between these entities. Precision agriculture requires an increasing amount of information in order to be sufficiently managed and the abilities of the ISOBUS protocol is a significant step toward this goal as it will provide a wealth of automated data acquisition for improving the management of crop production .In addition, mechatronic systems can also play an essential role in modern agricultural machinery, especially on intelligent and robotic vehicles . The terMechatronics enables the practical implementation of variable rate application (VRA) equipment for precision agriculture. As VRA technology is progressing quickly, intelligent applicators are becoming available commercially. A smart system can automatically adjust the number of inputs dispersed in response to needs, even allowing for the simultaneous use of different types of treatments, resulting in new ways of managing agricultural production. Thus, an intelligent VRA seeder can, for instance, change the number of seeds laid out in the soil according to its potential, either provided by prescription maps or detected using on-board sensors. Control of the seeding rate is achieved by actuating the opening of the distributing device to allow the desired number of seeds to go through. In many cases, a feedback control system is required to achieve accurate control of the application rate. For example, in applying liquid chemicals, the application rate may be affected by changes in the moving speed of the vehicle as well as the environmental conditions. Some smart sprayers are programmed to accurately control the amount of liquid chemical by adjusting the nozzles in response to changes of sprayer forward speed. This is normally accomplished using electronically controlled nozzle valves that are commanded from the on-board processor .Today’s commercial farmer, who has a full command of the existing farming skills and knowledge, will need to become a sort of information technology (IT) manager operating from an office or in front of a screen , rather than a machine operator working in the field, handling machine steering, and adjusting equipment manually. For livestock management, skilled operators will still be needed, but with new sets of skills related to ICT and automatization .As part of precision farming, managing livestock is one of the current challenges for agriculture . The terPLF uses a combination of tools and methods to measure different variables from each animal with high precision, supporting farmers to make decisions concerning the livestock production systems . DecisioSuccessful grazing and pasture management require an understanding of the adjustment mechanisms behind the grazing behavior  that enaThe use of GNSS technology allows for the characterization of grazing behavior including grazing patterns, paths, and favored areas. Grazing activities can also be differentiated based on the speed of movements. The increased knowledge conveyed using GNSS receptors in grazing sheep can become a valuable tool to support the decisions that are essential to a more precise pasture management .Tracking location on pasture, through the large dissemination of global positioning system (GPS) sensors have been successfully used to detect static or dynamic unitary behaviors differentiated through changes in path speeds: foraging or grazing, resting, and walking . LikewisBehavior of cattle can also be monitored by means of a collar characterized by a behavior-monitoring series of sensors. Through analysis of rumination rate and the feeding and resting behavior, estrus events can be detected, according to a study by . SimilarPosture analysis was developed using accelerometers and based on the position of the head: up or down. This information, in combination with GPS-based data, allowed for discrimination between several kinds of feeding related behaviors for grazing animals with high accuracies (>90%). These accuracies were obtained with a brief time window of 5 to 10 s while the data acquisition from the GPS and the accelerometer ran between 4 Hz and 10 Hz .Finally, we monitored cattle movements using accelerometers. Through diverse analysis methods, accelerometers recording data at 10 Hz could be used to classify behaviors using a basic statistical method to classify lame and non-lame cows, reaching an average accuracy of 91% . SimilarAmong the solutions to detect the animal behavior and collect data with a reduced uncertainty , image aIn addition, a review carried out by Meunier et al.  describeAnimal health is of key importance in the livestock industry as it impairs production efficiency through growth retardation or even mortality, animal welfare through pain and discomfort, and it can even impair human health through the misuse of antibiotics or zoonosis . In fact®, and Fancom B.V.) has been developed for automated pig cough detection that is based on a mathematical algorithm that processes all incoming sound and identifies the number of coughs automatically [Animals can be monitored by methods based on the sound, with the potential to be automated for large-scale farming . A soundatically . In addiatically  evaluateatically .2 sensors will allow the automatic evaluation of thermal discomfort in the house [Nowadays, automated sensors and algorithms can reliably predict and reduce the risk of mastitis in cows. Air sensors in the poultry industry can predict the onset of Coccidiosis by constantly monitoring the concentration of volatile organic compounds in the air increase, as the number of infected birds increases. Air sensors could detect this change much earlier than a farmer or a vet could . In othehe house .Precision feeding is a key component of PLF . Based oThe implementation of automated feeding systems (AFS) can provide a cost-effective alternative to manual regimes. Feeding units have been developed for a variety of animal systems including cattle, sheep, and pigs. These systems can be advantageous by providing an interface that monitors time and date of feeding, the electronic identification of each animal, the weight of the feed consumed, and the duration of feeding .Demmers et al.  used an RGB-D cameras can also help farmers to measure feed intake for individual cows . In addiThe measurement of average live weight gain (speed of growth) of a distinct group of animals is one of the most important measurements to be undertaken on livestock farm as the speed of growth will affect both the financial performance of the farming enterprise as well as the final body composition of the animals . Recent The milking robot is a classical PLF application . The groThere are numerous offers for automatic milking systems (AMSs) in the market. Recent technological advances have included the integration of more modern sensors/vision systems, the addition of animal monitoring features, and the integration of robots in rotary milking parlors. Time of flight (ToF) depth sensing cameras have been used in many recent developments in AMSs. Acceptable accuracy (teat location detection within 5 mm) has been achieved when the search space is limited to a region of interest 150 mm wide by 80 mm deep . Teat deCycle time of the milking operation must also be minimal so that both the cow and farmer can be more productive with their time. Therefore, an intelligent control of the robot is required using visual feedback to navigate the cluster onto the cow accurately, safely, and quickly. A system that can milk cows with unusually shaped udders or that do not take to a robot milker, which would otherwise have to be culled as is the case with some existing AMSs, would also be a considerable advantage .It is important to understand how farmers interpret the value of technology in the context of their farms. On one hand, farmers look at value to their farming business in the adoption of the usage of new technologies to solve future problems . On the With increasing population pressure around the world and the need to increase agricultural production, there is a concern for improved management of the world’s agricultural resources while minimizing the negative impact on the environment. Information on crops, rangeland, livestock, and other agricultural resources is critical for effective management of depleting and scarce resources. The implementation of the PA involves the integration of smart technologies in both farming and livestock, allowing the farmer to manage field variability to maximize the cost–benefit ratio and also to continuously and/or automatically monitor the main animal performance indicators.This literature review allowed us to realize that PA has been proven to be a highly researched and constantly evolving area due to the needs of farmers to use resources in a more optimized way. Many techniques presented in this study were applied under strict controlled conditions for research and their implementation on the farms would also require some ability for auto-calibration of the device or tools. The development and operation of PA applications involve several steps and techniques that need to be investigated further to make the developed systems accurate and implementable in commercial environments and diverse farming systems. In addition, future research should also focus on the current need for farmers to acquire more knowledge regarding PA, as this may be one of the main factors dissuading them from implementing smart technologies in their fields.