The primary objective of this research is to establish the extent to which small and medium-sized businesses (SMEs) in the Ha’il region benefit from a significant competitive advantage brought about by an entrepreneurial mindset . To achieve these objectives, the study used a questionnaire to collect data. A total of 220 SMEs in the Ha’il region were surveyed. The participants completed an online self-administered survey and used the PLS-SEM technique. The researchers found a robust link between differentiation advantage and higher levels of innovativeness, proactiveness, risk-taking, competitive aggression, and autonomy. In addition, the outcomes of the survey reveal that a greater cost advantage is substantially associated with vastly greater innovativeness, proactiveness, risk-taking, and competitive aggression overall. However, cost advantage is not strongly correlated with autonomy. These findings are significant because they shed new light on how competitive advantages are formed through the entrepreneurial orientation of entrepreneurs in the Ha’il region. This is a significant theoretical contribution to the literature on entrepreneurial orientation, specifically in the context of SMEs. The findings may also be valuable in supporting SMEs in being successful by enhancing their competitiveness, as SMEs are key contributors to the development and growth of the economy. The idea of a competitive advantage refers to a group of characteristics or competencies that give a company an advantage over its competitors in terms of its ability to consistently generate higher profits . A compeSuch resources and capabilities drive innovation, reputation, and relationships and help a firm capitalize on its core competencies . Core coA sustainable competitive advantage is usually attained when firms generate exceptional value through capitalizing on their unique mix of resources, capabilities, and core competencies . This asNetwork effects are another source that can be harnessed to develop a competitive advantage. For example, if a firm’s offerings are of greater quality, then consumers are typically attracted to that firm and inclined to use its offerings. When Microsoft developed its user-friendly Windows operating system, it was easier than the older DOS system because it had a user interface. People, therefore, liked it and started recommending it through word-of-mouth to people in their networks. Those people then did the same and spread the word through their networks. This is an example of how network effects can also be used to sustain a competitive advantage .The number of small and medium-sized businesses (SMEs) has grown tremendously in the Ha’il region because of economic development plans, such as Vision 2030, and prior economic development schemes that aim to enhance the competitiveness of every region in Saudi Arabia. The Ha’il region has the potential to build an entrepreneurial environment to attract SMEs and help them grow. Activities have taken place between the SME authority in Saudi Arabia (Monsha’at) and the Commission for the Development of the Ha’il region, as well as the University of Ha’il. Therefore, more needs to be researched and understood regarding the mix of resources, capabilities, and core competencies in the Ha’il region that can be utilized to build an entrepreneurial environment conducive to SMEs’ competitiveness.An enterprise’s competitiveness is its ability to outperform the competition in terms of revenue generated. There are two sources of an organization’s competitiveness: differentiation in terms of niche markets or superior quality offerings, as well as lower cost, which stems from economies of scale. For a competitive advantage to be sustainable over the long term, its sources must be unique and difficult to replicate .This research project aims to help these efforts by enhancing the current understanding of the different factors that influence the competitiveness of SMEs in the Ha’il region and of what can be done to build a unique entrepreneurial environment in the Ha’il region. This project will focus on entrepreneurial orientations in the Ha’il region that can be harnessed to help SMEs develop and sustain a competitive advantage. This research project will conduct a thorough study of the dimensions of entrepreneurial orientations in the Ha’il region that might shape the formation and endurance of an organization’s competitive advantage. The focus will be on SMEs, given that one of the priorities of economic development in this region is to foster an entrepreneurial environment that promotes the development of SMEs.Competitive advantage has always been defined as an institution’s potential capacity to distinguish its products or services from those of its competing industry rivals. Furthermore, a competitive advantage is necessary to create an effective business strategy aimed at achieving protected economic growth . Jones  efficient goods and services at cost leadership, (2) fully branded, differentiated company goods or services, and (3) the product or service responds to specific customers’ needs in a particular geographical location in terms of target market segmentation. The competitive advantage strategies chosen for SMEs and new entrepreneurs must be highly adaptable because they are heavily reliant on market trends, industry structure, and environmental forces that promote the emergence of significant strategic competitive advantages . In thisEach organization’s potential to maintain a competitive advantage tends to vary with the corporate business environment, regardless of whether advanced technologies or interorganizational collaborative efforts are used to gather information. The 17 According to Furthermore, a business organization has a competitive advantage when it can provide relatively similar economic advantages of competing companies at a relatively lower cost or when it can provide economic benefits that exceed the normal benefits or satisfaction given to customers. Therefore, the basic component of a competitive edge can be something that the business organization does that is completely unique, new, or extremely difficult to replicate .Essentially, competitive advantage must be created and preserved while satisfying customer requirements . ConversThe primary emphasis on competitive cost discounts is perhaps the most important factor in predicting commonly used components by organizations, particularly those in markets where employees and customers appear to be responsive to price changes. Key factors that contribute to cheaper prices include comprehensive guides, academic credentials, professional training, fruitful expenditure, the implementation of appropriate manufacturing, and dissemination of policy initiatives . Today, Organizations perceive product differentiation as a far more essential element and distinguishable way of accomplishing a competitive advantage than that of a low-cost product business strategy . AccordiThe business organization’s innate ability and financial power to provide the same wide range of important distinctions, as well as changes in the level of the customer base, result from its willingness to manage technological advancements. Instead, they design goods and services based on consumer expectations . OrganizAccording to A business consumer’s motivation is the willingness to pay a comparatively high price for the products or services they typically use in a given timeframe . BusinesBusiness organizations that provide goods and services have always been concerned with the perceived value of those goods and services, which would, in turn, manage to achieve some level of service quality and reasonable and fair customer demand expectations through the visual structural design of the goods and services, particularly in terms of the perceived value of the customer’s new company’s products . NumerouAccording to Innovativeness is a company’s proclivity to foster the development of truly innovative concepts, integrate advanced technologies, and move ahead with current product lines or service offers. Innovativeness reflects a company’s natural propensity to pursue and continue to support new innovative thoughts, uniqueness of ideas, research, and experimentation, which might also lead to more efficient offerings or technological improvements . The difSignificant risk-taking has always been defined as the proclivity to actively participate in extremely brave but conservative behavioral responses. Proactiveness, however, can be defined as a way for a business organization to perform its functions for enterprises in a complex, turbulent system or in early-stage areas of the economy where environmental circumstances are constantly changing and growth opportunities and chances for success abound. Proactivity is a forward-thinking, excellent opportunity mindset that entails implementing innovative goods and services better than competition and planning and preparing for a possible market to make a real change happen and maintain the environment . ProactiThe propensity to actively participate in courageous rather than conservative behavioral actions is known as risk-taking . ChoosinCompetitive aggressiveness corresponds to whether businesses respond to existing market trends and new demands throughout the competitive global consumer market system. Competitive aggressiveness considers the concentration of a company’s business and continued attempts to outperform rival companies, as manifested by a confrontational position or an aggressive reaction . LumpkinThe term “autonomy” refers to whether an individual or a group of individuals within an organization has the freedom to formulate and implement a start-up business idea. Individuals in a slightly elevated business organization have the freedom to hire those who introduce different concepts and are free from the straitjacket of bureaucratic inefficiency. Autonomy enables individuals and business organizations to more efficiently and successfully investigate and implement innovative thoughts without being constrained by organizational values and traditional practices . From anThe innovation metric is concerned with the introduction of innovative products and services, as well as the creation of enhanced versions of current products and services, as well as the introduction of unique techniques and procedures for the manufacture of those products. It was also stated that a firm’s tendency to be on the cutting edge of new technologies demonstrated that it had an entrepreneurial spirit if the organization tended to be at the forefront of such innovations .In addition, “proactiveness” is defined as the degree to which a company strives to set the standard in critical business areas such as the introduction of new products or services, operating technology, and administrative practices, rather than merely following competitors in these areas . ProactiAn entrepreneurial strategy that incorporates components of risk-taking and experimentation, such as a mindset that is bold, directive, and opportunity-seeking, is consistent with risk-taking in the same way . Taking The evidence implies that risk-taking and competitive aggressiveness should share a component with proactiveness . IndepenThe dimensions are distinct from one another in terms of the activities they engage in and the ways in which they handle different situations. The new business-venturing component of the company focuses on seeking and entering new companies within the existing organization that are relevant to the company’s current products or markets. When it comes to the innovativeness component, the primary focus is on the development of cutting-edge goods, processes, and technologies. This is because innovation is directly correlated to increased competitive advantage . The selThis suggests that the basis of intrapreneurship can be found in the fact that various dimensions can be separate from one another while also being associated with one another. From these points of view, the concept of “intrapreneurship” is made up of these dimensions, which are different enough from each other to keep them from being duplicated but similar enough to be thought of as part of the same concept.The personality aspects of entrepreneurship were previously used to characterize a person’s “big 5” personality traits have been renamed “OCEAN,” by  and the Because it makes it easier to find new opportunities for business, being open to new ideas is an essential quality for entrepreneurs to possess because it speeds up the process of finding new ventures to pursue . TherefoA person who actively looks out for business opportunities and turns them into viable entrepreneurs is referred to as an “entrepreneur.” When beginning a business, one of the most critical skills to have is the ability to recognize opportunities ahead of time and capitalize on them before others do. Consequently, the first step toward being an entrepreneur is being able to recognize an opportunity.People who fall under the category of extraverts are typically self-assured and authoritative, in addition to being vivacious, daring, and exuberant. Because of this, it was discovered that people who owned their own businesses had a more positive attitude toward life than people who did not own their own businesses. Extroverts have a greater propensity to be upbeat, cheerful, and enthusiastic than introverts do.In addition, The term “agreeability” refers to a broad variety of human attributes, any one of which may have a favorable or negative impact on one’s ability to run a successful business . EntreprAs a result, those that venture out on their own in business face significant entrepreneurs while attempting to adapt. On the one hand, working with entrepreneurs may be motivating because of their unlimited excitement, charismatic personalities, strong competitiveness, and laser concentration on accomplishing their goals. This means that an individual’s unhealthy preoccupation with micromanaging every aspect of their business could have a detrimental impact on the quality of their personal relationships.The stereotype of entrepreneurs is that they are eccentric people whose behavior and ideas are shocking to others and go against the grain of society . BecauseHence, entrepreneurs’ tendency toward impulsivity, unhappiness, rejection, or lack of control may undermine their confidence. When faced with these challenges, business owners and entrepreneurs may develop a fixation on opportunities to demonstrate their authority and autonomy, which may prevent them from meeting the requirements of individuals in their immediate environment. Therefore, the majority of the research that has been carried out up to this point reveals that neuroticism has a negative correlation with the ownership of an entrepreneurial enterprise.Regarding strategy information (generic strategies) in conjunction with strategic planning, shaping the processes of entrepreneurial success appears to have become a rational and reasonable line of independent investigation. This orientation provides a framework for developing and incorporating competitive strategies. Thus, researching and developing the actual content of entrepreneurial orientation and competitive strategy is a potentially fruitful undertaking of research . AccordiThe proposed conceptual structure of this research study, which was designed to evaluate the research question, is illustrated in Through social media platforms, including WhatsApp, LinkedIn, and email groups, a survey was made available online to Saudi SMEs in the Ha’il region. The respondents had to complete the survey in Arabic using Google Forms, which were utilized to gather the data. It took approximately 2 months to acquire all the data. Of the 231 questionnaires received, 11 were rejected due to missing or incomplete information. For additional analysis, 220 responses were recorded. A total of 109 service SMEs and 111 product SMEs participated in this study, accounting for 49.5 and 50.5% of the total participants, respectively. With regard to the participants’ work experience at their respective firms, 104 (47.3%) had less than 1 year of experience, 63 (28.6%) had 1–5 years of experience, 26 (11.8%) had 5–10 years of experience, 20 (9.1%) had 11–15 years of experience, and 7 (3.2%) had more than 15 years of experience. Similarly, 62 (28.2%) of the participants were owners, 47 (21.4%) were managers, 90 (40.9%) were owners and managers of their firms, and 21 (9.5%) were staff. In terms of the number of employees at the firm, 119 firms had fewer than 25 staff members, 56 firms had 26–49 staff members, 36 firms had 50–150 staff members, and 9 firms had 151–250 staff, accounting for 54.1, 25.5, 16.3, and 4.1% of the total participants, respectively see .The research examined five facets of EO, including three items pertaining to innovativeness, three items pertaining to proactiveness, three items pertaining to risk-taking, three items pertaining to competitive aggressiveness, and three items pertaining to autonomy as a sense of self-reliance. The items’ compositions were taken from Both cost advantage and differentiation advantage (consisting of four separate factors) were investigated in this study as potential components of competitive advantage (three items). In this particular study, 5-point Likert scales were utilized to quantitatively analyze several aspects of competitive advantage .Data were analyzed using the statistical program SmartPLS v4.0.6.9. In the first step of this process, various measurement model methodologies, such as Cronbach’s alpha (CA), extracted composite reliability (CR), heterotrait-monotrait (HTMT) ratio, and average variance (AVE), were investigated. Second, to examine the theoretical model, this study employed discriminant validity. The structural model was evaluated in the third phase by looking at the common method bias (variance inflation factor), coefficient of determination (R2), predictive relevance (Q2), and standardized root mean square residual (SRMR). Structural equation modeling (SEM) was another approach that was utilized in this investigation to examine the hypotheses.In several instances, CA was utilized to obtain the reliability of the different scales. The measuring scales’ validity was determined to be substantial, with values of 0.870 for Autonomy, 0.852 for Competitive Aggressiveness, 0.834 for Innovativeness, 0.838 for Proactiveness, 0.801 for Risk-Taking, 0.768 for Cost, and 0.860 for Differentiation. The internal consistency reliability was deemed to be adequate  to investigate collinearity problems and common technique bias. Because In this particular investigation, a Harman single-factor test was also utilized to assess common technique variance . If a faFurthermore, the results showed that EO explained 55.5% of the variance in cost. EO also explained 61.6% of the variance in differentiation. According to According to SRMR, as suggested by p < 0.05; see p < 0.05; see The purpose of this research was to investigate the impact of EO factors on the competitive advantage (differentiation and cost) of Saudi SMEs in the Ha’il region. It was hypothesized that differentiation (DIFFER) would be influenced by innovativeness (INNOV). The results showed that INNOV had a positive effect on DIFFER  on DIFFER was also investigated in this study. There was a statistically significant correlation between PROAC and DIFFER  has a direct and positive impact on DIFFER  on DIFFER was investigated in this study. The results show that taking risks (RISK) has a significant impact on DIFFER . In addition, the findings of this research have the potential to act as a reliable reference for those who work in commercial settings. The findings indicate that EO variables are key and relevant elements in cost strategy and differentiation.According to the findings of this study, if the owners or managers of SMEs utilize the findings by considering the structures, strategy-making processes, and business attributes that are characterized by their inventiveness, proactiveness, risk-taking, aggressiveness in competition, and autonomy, they will increase their firms’ competitive advantage. The findings may also be valuable in supporting SMEs in being successful, as SMEs are key contributors to the development and growth of the economy.The research was conducted in the Ha’il region of Saudi Arabia on SMEs to see how the entrepreneurial practices of these companies affected their competitive edge. In the Ha’il context, the study placed particular emphasis on the advantages that SMEs have over larger corporations in terms of competitive advantage. These advantages include autonomy, innovativeness, risk-taking, proactivity, and aggressive competition.Although all of this study’s objectives were accomplished, there are certain limitations that should be addressed, and relevant suggestions for future research should be made. A very small sample size calls for an extensive amount of replication. Since this study is based on cross-sectional data, further longitudinal research is needed to learn more about the problem, determine how the different parts interact with each other, and see if the results would be different if longitudinal data were used instead of cross-sectional data. Second, this study’s data were collected from 220 SMEs in Ha’il, Saudi Arabia. Therefore, future studies could expand the sample to include all other SMEs from different parts of Saudi Arabia so that the results can be used in a wider range of situations.Third, the current study adopted a quantitative methodology and distributed questionnaires to the managers or owners of SMEs. Thus, future studies should consider obtaining more in-depth qualitative data from SMEs’ owners or managers. Future research may employ both quantitative and qualitative approaches to produce more accurate and comprehensive findings.Fourth, the investigation of mediating factors, such as strategic orientations, Organizational Citizenship Behavior (OCB), learning orientation, and knowledge management, should be covered in future research. Links between the model’s direct and indirect paths may be examined using a variety of methods.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.MT: conceptualization, literature review, resources, data collection, writing—original draft preparation, and project administration. MAl: conceptualization, literature review, resources, data collection, and writing—original draft preparation. YA-M: conceptualization, methodology, software, validation, formal analysis, resources, data collection, and writing—original draft preparation. MAb: conceptualization, methodology, software, validation, formal analysis, resources, data curation, and writing—original draft preparation. All authors contributed to the article and approved the submitted version.This research has been funded by the Scientific Research Deanship at the University of Ha’il—Saudi Arabia, through project number RD-21 107.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Inhibitory control (IC) is a fundamental cognitive function showing age-related change across the healthy lifespan. Since different cognitive resources are needed in the two subcomponents of IC (cognitive inhibition and response inhibition), regions of the brain are differentially activated. In this study, we aimed to determine whether there is a distinct age-related activation pattern in these two subcomponents. A total of 278 fMRI articles were included in the current analysis. Multilevel kernel density analysis was used to provide data on brain activation under each subcomponent of IC. Contrast analyses were conducted to capture the distinct activated brain regions for the two subcomponents, whereas meta-regression analyses were performed to identify brain regions with distinct age-related activation patterns in the two subcomponents of IC. The results showed that the right inferior frontal gyrus and the bilateral insula were activated during the two IC subcomponents. Contrast analyses revealed stronger activation in the superior parietal lobule during cognitive inhibition, whereas stronger activation during response inhibition was observed primarily in the right inferior frontal gyrus, bilateral insula, and angular gyrus. Furthermore, regression analyses showed that activation of the left anterior cingulate cortex, left inferior frontal gyrus, bilateral insula, and left superior parietal lobule increased and decreased with age during cognitive inhibition and response inhibition, respectively. The results showed distinct activation patterns of aging for the two subcomponents of IC, which may be related to the differential cognitive resources recruited. These findings may help to enhance knowledge of age-related changes in the activation patterns of IC. Inhibitory control refers to the ability to suppress unwanted actions that are not appropriate for the current situation or to resist distractions and adapt to conflicting situations . By doinIn the recent years, there has been an increase in the number of studies examining the behavioral and neural developmental trajectory of inhibitory control across the lifespan refer to . HoweverIn neuroimaging research examining the neural developmental trajectory of inhibitory control, the results are also not consistent. Increased frontal activation in adults compared with children has been observed in some fMRI studies . Rubia ePrevious meta-analyses have also compared brain activation across different age groups to explore the age effect of brain activation during the process of inhibitory control . For exaThe lack of agreement in the existing studies on the behavioral and neural developmental trajectory of inhibitory control across the lifespan may be due to studies including samples with limited age ranges or the fact that few existing studies or theories have systematically differentiated age-related changes in different inhibitory control tasks. For example, Most current studies on the behavioral and neural developmental trajectory of inhibitory control across the lifespan include only a single type of inhibitory control task . For exaIn the recent times, an increasing number of studies have not only focused on explaining the diversity, scope, and range of inhibitory control functions, but have explored the intrinsic variability of different components of inhibitory control. These studies have suggested that inhibitory control is not a unitary construct, but is the one which can be further differentiated into different subcomponents . For exaTo differentiate the cognitive process during inhibitory control, inhibitory control can also be classified into two subcomponents—cognitive and response inhibitions—depending on the cognitive process of different inhibition targets in inhibitory control tasks . CognitiDifferences between inhibition difficulties and complexity of the two types of inhibition tasks might originate from the differences in cognitive resources recruited in these subcomponents of inhibitory control tasks . Stahl eCognitive inhibition can be captured by paradigms including the Stroop, Flanker, and Simon and stimulus response compatibility (SRC) . In the In line with the findings of behavioral studies regarding cognitive inhibition and response inhibition, studies characterizing the neural correlates of inhibitory control have also found a significant difference in neural correlates between the two components. For example, In this study, we investigated how neural activation during the two subcomponents of inhibitory control changes across the healthy lifespan with aging using meta-analytic technology. The study had two aims: that first was to characterize the common or distinct neural correlates in the two subcomponents of inhibitory control and the second was to identify the distinct age-related activation pattern in the two subcomponents of inhibitory control. Since the cognitive resources recruited in the two subcomponents are different, we hypothesized that the activation patterns of inhibitory control may show distinct age-related trajectories in the two subcomponents of inhibitory control, or differential activation patterns may be shown across different age groups in cognitive and response inhibitions.First, two online citation indexing services—PubMed and Web of Science—were searched. This search used the keywords “fMRI” with “interference resolution,” “action withholding,” “action cancellation,” “response inhibition,” “cognitive inhibition,” “inhibitory control,” “stop signal,” “stopping,” “go nogo,” “action restraint,” or “countermanding,” including articles published prior to April 2020, yielding a total of 9,419 articles. After removing duplicates, a total of 7,985 articles were screened. We then compiled 39 eligible articles identified in a previous meta-analysis . The folWe extracted the following information from each study: authors, year of publication, sample size, experimental design, paradigms, mean age with the age range, task contrasts, stimulation types, and cluster coordinates in the MNI or Talairach space.Cognitive inhibition is the inhibitory process of suppression of competing cognitive processing to solve relevant problems . For theResponse inhibition is the process of suppression of a prepotent response to perform a different, more context-appropriate response . To meas1 to identify the brain regions activated during inhibitory control. Peak effect coordinates from each study were convolved with a spherical kernel (r = 16 mm)   toolbox1= 16 mm)  to generp < 0.05, FWE-corrected across the entire brain). Specifically, to characterize brain activation patterns, first, we identified brain regions that showed significant convergence across 278 studies comprising 4,393 foci from 290 contrasts. Then, contrast analyses were conducted to verify the differences in cognitive demand for the two subcomponents of inhibitory control and capture the selectively or preferentially activated brain regions for two subcomponents of inhibitory control: cognitive inhibition vs. response inhibition. All cluster coordinates were analyzed in Montreal Neurological Institute (MNI) standard stereotaxic spaces.Previously used meta-analyses, such as the activation likelihood estimate (ALE), count how many peak coordinates are within each voxel divided by the brain regions and compare this to the number expected by chance if the peak coordinates were randomly distributed in the brain. This method is limited by the consequence that the peak coordinates in any single study may overly influence the results from analyses . Using Mp < 0.05 to control for family-wise error rate. We performed two meta-regression analyses in ES-SDM. Data involved in the meta-regression analyses were derived from response inhibition contrasts and cognitive inhibition contrasts separately. Given that different age ranges were reported in the original articles, the age computed in the meta-regression analysis as a continuous variable was determined by the mean age of each sample in the original articles. The results from the two regression analyses were then compared to identify brain regions with distinct age-related activation patterns in the two subcomponents of inhibitory control.To further assess age-related change in activation patterns in the subcomponents of inhibitory control, the effect-size seed-based d mapping (ES-SDM) toolbox (SdmPsiGui-v6.21 from the Seed-based d Mapping project) was used to perform meta-regression analyses because the ES-SDM software can provide accurate results of regression analyses incorporating meta-regression methods. This is achieved by first using peak coordinates and their statistical values to recreate statistical parametric maps and then conducting an image-based meta-analysis . The fulFurther, given that age was computed in the meta-regression analysis as a continuous variable determined by the mean age of each sample in the original articles, the mean age was affected by extreme values, which cannot well represent the age distribution of all subjects in each original study. As mentioned above, to more completely explore the age-related changes in the two subcomponents of inhibitory control within individuals of different ages, we performed additional MKDA analyses as validation analyses. We divided the datasets from all articles included in the current meta-analysis into four age groups: under 18 years for under-aged children, 18–35 years for young adults, 35–55 years for middle-aged adults, and 55–80 years of age for older adults. Then, we performed contrast analyses and computed the differences among all age groups in the two subcomponents of inhibitory control: under-aged children vs. young adults, young adults vs. middle-aged adults, middle-aged adults vs. older adults, under-aged children vs. middle-aged adults, young adults vs. older adults, and under-aged children vs. older adults.Additional validation analyses were performed to reduce the impact of the number of experiments, the different types of inhibition tasks, and the behavioral performance reported in the studies included in the results of the current meta-analysis.First, studies on response inhibition  included a much larger number of experiments compared to those on cognitive inhibition (54 experiments). To test the effect of the number of experiments, we randomly selected 54 contrasts from the response inhibition data and repeated the MKDA and meta-regression analysis with age as a variable using the same settings.Second, leave-one-out analysis was performed to test homogeneity in the cognitive inhibition tasks and response inhibition tasks separately. For the two subcomponents of inhibitory control, we removed each type of inhibition task one at a time: including Flanker, Simon, Stroop, WCST, and other tasks for cognitive inhibition, and tasks including antisaccade, Go/NoGo, and stop signal tasks for response inhibition. MKDA analyses were separately performed on the remaining studies with a total of five activation maps for cognitive inhibition and three activation maps for response inhibition. Then, we pooled the activation maps to obtain the overlapping rate maps for cognitive and response inhibitions, respectively. The overlap rate maps obtained from leave-one-out analysis and the results from MKDA on cognitive or response inhibition were then contrasted to test whether different tasks employed in studies influenced the activation patterns in the subcomponents of inhibitory control. Furthermore, since the meta-analysis results of cognitive inhibition and response inhibition identified different major regions , we conducted contrast analyses on the regions identified in the leave-one-out meta-analysis results for cognitive inhibition and response inhibitions separately.Third, to investigate whether older adults that performed a task similarly to younger adults may show different patterns of activity to older adults who underperformed relative to younger adults, we selected a total of 81 studies which reported task performance with successful inhibition in response inhibition tasks. Then, we performed a meta-regression analysis and several contrast analyses separately.The MKDA of the 278 studies showed significant activation of clusters in both hemispheres, including the frontal cortex, the angular gyrus, and the supplementary motor area . The resIn both hemispheres, activated areas during the cognitive inhibition tasks included the inferior frontal gyrus, precentral gyrus, anterior insula, inferior parietal lobule, supplementary motor cortex, superior parietal lobule, superior frontal gyrus, middle cingulate gyrus, inferior frontal gyrus, and angular gyrus . UnilateData from response inhibition experiments revealed activations in the right middle frontal gyrus, the right angular gyrus that extended to the middle temporal gyrus and superior temporal gyrus, the right inferior temporal gyrus, and the left middle cingulate gyrus. In addition, activation areas in both hemispheres were observed in the supplementary motor cortex, middle cingulate gyrus, superior frontal gyrus, precentral gyrus, inferior frontal gyrus, anterior insula, inferior parietal lobule, and supramarginal gyrus .Activation patterns common to the two subcomponents of inhibitory control were derived by conjunction analysis . RegionsContrast analyses of cognitive inhibition and response inhibition revealed that significantly different regions were activated in the two subcomponents of inhibitory control. Specifically, compared to response inhibition, a higher level of activation was found during cognitive inhibition in the left superior parietal lobule . On the In the cognitive inhibition tasks, results from the meta-regression analysis with age as a continuous variable across all studies showed a positive association with clusters in the followings: (1) the middle cingulate cortex, anterior cingulate cortex, and insula in both hemispheres; (2) the angular gyrus, superior parietal lobule, inferior frontal gyrus, and supplementary motor cortex in the left hemisphere. In addition, a negative association between age and clusters was found in the bilateral middle frontal gyrus, left inferior parietal lobule, right angular gyrus, and right inferior frontal gyrus .Activation in the response inhibition tasks showed significant positive correlations with age in the right angular gyrus, right middle frontal gyrus, bilateral inferior parietal lobule, and bilateral middle cingulate cortex, whereas a negative correlation with age was found in the followings: (1) the anterior cingulate cortex, inferior frontal gyrus, insula, hippocampus, and superior parietal lobule in the left hemisphere and (2) the superior frontal gyrus, cerebellum, insula, and inferior frontal gyrus in the right hemisphere .To characterize distinct brain regions with age-related changes in activation patterns in the two subcomponents of inhibitory control, we overlapped the results from regression analyses in the two subcomponents with age and found different age-related activation patterns in the subcomponents . ActivatContrast analyses among different age groups for cognitive inhibition showed that regions with significantly higher levels of activation in adults  than under-aged children were located in the bilateral inferior frontal gyrus, right insula, and left supplementary motor area . CompareContrast analyses among different age groups for response inhibition showed that regions with significantly higher levels of activation in adults than under-aged children were located in the bilateral angular gyrus, insula, and right middle frontal gyrus . CompareThe evaluation of the number of experiments contrasting the two subcomponents showed no significant differences between the real contrasts and the randomly selected 54 experiments for response inhibition. The activated brain areas are reported in The results from leave-one-out analysis  were highly consistent with the results of brain activation patterns in each component of inhibitory control derived from MKDA analyses. Further details are reported in Meta-regression and contrast analyses on successful inhibition showed a similar activation pattern of brain regions including the inferior frontal gyrus, supplementary motor area, inferior parietal lobule, insula, angular gyrus, middle cingulate cortex, and occipital gyrus as compared to current MKDA analyses on response inhibition. The activated brain areas and activation maps are reported in Applying MKDA and ES-SDM allowed the current meta-analysis to characterize the neural correlates and age-related effects in different subcomponents of inhibitory control. We observed brain areas including the inferior frontal gyrus, insula, middle cingulate cortex, and inferior parietal gyrus being activated in the two subcomponents. Contrast analyses conducted to elucidate the distinct neural substrates for each subcomponent revealed that relative to response inhibition, cognitive inhibition produced stronger activation in the left superior parietal lobule, whereas response inhibition primarily recruited the right inferior frontal gyrus, insula, middle temporal gyrus, and angular gyrus. Importantly, by performing a meta-regression analysis with age as a continuous variable, we found distinct age-related activation patterns in different subcomponents of inhibitory control in brain regions including the left anterior cingulate cortex, left inferior frontal gyrus, left superior parietal lobule, and bilateral insula. Overall, our results indicated common and distinct neural correlates and distinct age-related activation patterns in the two subcomponents of inhibitory control.The MKDA results showed that brain regions including the inferior frontal gyrus, insula, middle cingulate cortex, and superior parietal lobule were activated by both inhibition subcomponents. Therefore, this suggests that the inferior frontal gyrus, insula, middle cingulate cortex, and inferior parietal lobule played the core roles in inhibitory control , which iThe main clusters of activation in the two subcomponents of inhibitory control were observed in the followings: (1) the inferior frontal gyrus extending to the insula and (2) the middle cingulate cortex and the superior parietal lobule. The inferior frontal gyrus is known to engage in the process of inhibiting automatic but irrelevant actions while activating task-relevant responses at the same time . MoreoveThe anterior insula has been considered as the center that controls brain activity across different tasks and stimulus modalities and regulates inhibitory control mechanisms W. . Wager eAdditionally, our research found that the right superior occipital gyrus and left middle occipital gyrus were commonly activated in the two subcomponents of inhibitory control, which is in line with the results from previous studies and meta-analyses . InteresIn this meta-analysis, the inhibitory control paradigms classified as cognitive inhibition required conflict resolution and inhibition of response tendencies for successful responding . When peIn contrast, for response inhibition, the Go/NoGo and stop signal tasks encompass future action selection and inhibition of a predominant response tendency or an ongoing response, respectively. As mentioned above, the inferior frontal gyrus plays an inhibitory role in resolving conflicts during response execution, and the anterior insula is involved in the regulating process of response inhibition. Thus, there were more activated regions in response inhibition than cognitive inhibition, primarily located in the inferior frontal gyrus and anterior insula. The distinctiveness of response and cognitive inhibition, we suggest, may partly be due to the different cognitive demands in these inhibitory control tasks. Participants are required to resolve conflicts and to involve more sensory or stimulus-related neural activity in cognitive inhibition tasks, whereas the demand for inhibitory control may further increase in response inhibition tasks, which require inhibiting a predominant tendency or stopping of already-initiated actions. Furthermore, these tasks differ in terms of task-related complexity. Suppressing a response tendency or canceling an ongoing action might increase the inhibitory demand as compared to suppressing interference due to irrelevant information or resolving conflicts, as is the case in cognitive inhibition tasks . As the Interestingly, results from contrast analyses of cognitive inhibition and response inhibition showed a predominantly lateralized differential activation between response inhibition and cognitive inhibition. We hypothesized that the underlying reason may be the different types of stimuli  materials used in inhibitory control tasks. By compiling a list of all types of stimulation used in the included literature refer to , we founIn this meta-analysis, we observed neither a completely coherent increase nor a decrease in the inhibitory network with increasing age in the two subcomponents. In the cognitive inhibition tasks, activation showed a positive association with age in the anterior cingulate cortex, insula, superior parietal lobule, and inferior frontal gyrus. The results from contrast analyses among different age groups also showed that compared to under-aged children, activation in the inferior frontal gyrus and insula was stronger in adult groups. These age-related changes fit with the existing literature showing that prefrontal regions, including the inferior frontal gyrus and the middle frontal gyrus, become more active with aging . A previA different pattern of functional age-related changes was found in the response inhibition tasks. We found the activation of the response inhibitory network, including the left anterior cingulate cortex, bilateral inferior frontal gyrus, insula, left superior parietal lobule, and right superior frontal gyrus, was negatively correlated with age. Contrast analyses also showed a linear decline with increasing age in the activation of brain regions including the bilateral inferior frontal gyrus, insula, middle cingulate cortex, and inferior parietal lobule when performing response inhibition tasks. These seemingly differential results might also be explained by the differences in the inhibition processes involved.In line with a previous study , the curSeveral neuroimaging studies have contributed greatly to enhancing our knowledge of the neural correlates of subcomponents of inhibitory control or age-related change in the activation in the two subcomponents . HoweverThrough synthesizing data from different subcomponents, we found that brain regions including the inferior frontal gyrus and anterior insula, as well as regions including the middle cingulate cortex and supplementary motor cortex, were consistently activated across all inhibition tasks. This finding may suggest that these brain areas are core inhibitory control regions. Meanwhile, different age-related changes in the activation between the subcomponents of inhibitory control could be observed. Functional reorganization of the aging brain in different inhibitory control tasks showed a complex pattern of increase and decline: the corresponding cognitive inhibition tasks required older adults to increasingly recruit the core inhibitory network and additional inhibitory regions, such as the frontal regions and bilateral insula. However, a contrary pattern of age-related decline in the inhibitory network including prefrontal areas and middle cingulate cortex was shown during the process of response inhibition. The current results suggest that these differences might result from the increasing demands on inhibitory function from cognitive inhibition to response inhibition. Furthermore, age-related increased activation of additional inhibitory networks was limited. When the task demand exceeded the older adults’ capacity, activation in the inhibitory network decreased clearly. These findings are of significance for the understanding of the neuro-developmental mechanisms of inhibitory control and may provide insights into inhibitory control deficits in clinical settings.As mentioned above, common and distinct activation patterns are involved in the processes of proactive and reactive inhibition, and age-related changes in activation patterns in proactive and reactive inhibition have been investigated. Experimental evidence from neuroimaging studies supports a right-lateralized frontoparietal circuit being widely recruited through the reactive inhibition process . In addiWe acknowledge that the current study still has some limitations. First, we note that a potential limitation in meta-analysis methods in general is that any meta-analysis method is prone to publication bias; in this study, we only considered the results available in the published literature and original studies which reported coordinates. Moreover, we could not control the statistical methods used in original articles for thresholding the data. There is an emerging trend to store unthresholded statistical maps, which will allow image-based meta-analyses to be performed in the future studies .The second limitation relates to the bias of employing different tasks for measuring the components of inhibitory control and including studies using a variety of stimulation types. Specifically, our meta-analysis adopted a mixture of inhibitory control tasks as different subcomponents of inhibitory control, such as the Stroop, Simon, and Flanker tasks used to capture cognitive inhibition and the GNG, stop signal task, and antisaccade tasks to capture response inhibition, which consequently increased the heterogeneity of the study designs. Leave-one-out analysis was performed as validation analysis to test homogeneity in cognitive inhibition and response inhibition separately. The results from leave-one-out analysis were consistent with the results of brain activation patterns in each component of inhibitory control from the MKDA analyses and the details are reported in Third, considering that task difficulty and behavioral performance in different inhibition tasks may influence age-related brain activity in different individuals, and not all studies included in the current meta-analysis reported behavioral performance for each participant or task difficulty, we selected a total of 81 studies which reported task performance with successful inhibition in response inhibition tasks. Then, we performed a meta-regression analysis and several contrast analyses separately. The results refer , 5 were Fourth, the findings from this study are of significance for the understanding of the neuro-developmental mechanisms of inhibitory control and may provide insights into cognitive health in older adults. However, cognitive health is affected not only by physiological factors such as age, but also by socio-demographic factors; particularly significant is educational attainment. Understanding the links between education and cognitive health or cognitive aging could improve the cognitive prognoses and offer clues about the mechanisms underlying cognitive decline that can be targeted by interventions. Previous studies found that a better level of education might affect cognitive ability in older adults and attenuate aging-related decline in cognition functions . This maIn this meta-analysis, we examined the neural correlates of subcomponents of inhibitory control and the difference in age-related changes in activation between the subcomponents. Activation of the middle cingulate cortex, supplementary motor area, inferior frontal gyrus, inferior parietal lobule, and anterior insula was common across the different inhibition processes, which revealed that these regions are the core neural system engaged in inhibitory control. On the other hand, differences in the activation patterns of subcomponents of inhibitory control with aging showed a complex pattern in the functional reorganization of the aging brain. Specifically, when performing cognitive inhibition tasks, stronger activation of the core inhibition regions was observed in older adults, whereas activation in prefrontal areas in older adults declined during response inhibition tasks. We summarize that these differences may be driven by the different demands between inhibitory control tasks. Aging individuals recruit additional inhibition-related brain regions when performing an inhibitory control task. However, with an increasing demand of inhibition tasks, limited reallocation of cognitive resources in older adults eventually results in a lower level of the activation of inhibitory brain regions in older adults during inhibitory control processes. These results may further enhance our knowledge of age-related changes in the activation patterns of inhibitory control and may provide insights into inhibitory control deficits in clinical settings.The original contributions presented in the study are included in the article/The study was reviewed and approved by the Institutional Review Board (IRB) of Southern Medical University.JL: conceptualization, data curation, data analysis, writing the manuscript, reviewing, and editing. XS, YW, CW, and RH: writing—reviewing and editing. RZ: conceptualization, supervision, funding acquisition, and writing—reviewing and editing. All authors contributed to the article and approved the submitted version.


QST) was greater than neutral allele frequency differentiation (FST) for many traits, signaling directional selection between pairs of populations. All populations exhibited higher fitness metric values when grown at their native elevation, and Mexican landraces had higher fitness than South American landraces when grown in these Mexican sites. As environmental distance between landraces’ native collection sites and common garden sites increased, fitness values dropped, suggesting landraces are adapted to environmental conditions at their natal sites. Correlations between fitness and anthocyanin pigmentation and macrohair traits were stronger in the highland site than the lowland site, supporting their status as highland‐adaptive. These results give substance to the long‐held presumption of local adaptation of New World maize landraces to elevation and other environmental variables across North and South America.Populations are locally adapted when they exhibit higher fitness than foreign populations in their native habitat. Maize landrace adaptations to highland and lowland conditions are of interest to researchers and breeders. To determine the prevalence and strength of local adaptation in maize landraces, we performed a reciprocal transplant experiment across an elevational gradient in Mexico. We grew 120 landraces, grouped into four populations , in Mexican highland and lowland common gardens and collected phenotypes relevant to fitness and known highland‐adaptive traits such as anthocyanin pigmentation and macrohair density. 67k DArTseq markers were generated from field specimens to allow comparisons between phenotypic patterns and population genetic structure. We found phenotypic patterns consistent with local adaptation, though these patterns differ between the Mexican and South American populations. Quantitative trait differentiation ( Over time, given sufficiently low genetic drift and gene flow, theory predicts that a population will adapt to the selective pressures of its local environment  interaction  is an extensively studied model system of high agronomic , which is adapted to cool, dry highland conditions  in Andean highland landraces  to neutral genetic differentiation between populations (FST) to find traits under directional selection.To investigate the extent and degree of local adaptation between highland and lowland maize landraces, we conducted an elevational reciprocal transplant experiment. To test whether reportedly highland‐adaptive traits (macrohair and anthocyanin pigmentation) are truly adaptive in highland conditions, we calculated their correlation with fitness metrics at both common garden sites and compared them. Landraces’ fitness values were regressed to environmental distance between collection site and common garden site to determine if fitness values diminished when grown in environments more dissimilar from their native location. We also compared quantitative trait differentiation (22.1Accessions are present in the Seeds of Discovery (SeeDs) dataset  such that both landraces of a pair were collected from the same 1‐degree of latitude bin, and all pairwise distances between accessions were greater than 50 km. These 120 samples were split into four populations  with 30 accessions per population. We note that our provisional population designations are designed to reflect continental and elevational distinctions and not necessarily population genetic structure, and that we use the word “Mexican” to refer to the North American populations despite the fact that two of the accessions are from Guatemala. Passport data for the 120 landrace accessions are available in Table The two common garden sites that comprise this reciprocal transplant are the Winter Services nursery site near Puerto Vallarta in the Pacific coastal lowlands (elevation 54 m) of Mexico (hereafter “Low Site”), and a CIMMYT field site near the town of Metepec in the highlands (elevation 2852 m) of the Mexican Central Plateau (hereafter “High Site”). Seed lines were regenerated at the field site in which they would be planted for one generation prior to the experiment to reduce seed storage and maternal effects. Best local practices for irrigation, fertilizer, and pest/weed control were used at both sites. The High Site field experiment was conducted in the summer of 2016. The Low Site field experiment was conducted in the winter of 2016, but virus damage led us to repeat the field experiment at the same site in the winter of 2017. Certain traits were collected from both years of the Low Site. A map of the field sites and geographical origin of each accession and boxplots summarizing the elevation, temperature, and precipitation distributions of these four populations are presented in Figure Each field was arranged in a complete block design with two blocks of 120 rows of 15 seeds of a landrace accession. Landraces from latitudinal pairs were planted in adjacent rows.2.2Phenotypes Table  were colPrimary ears from tagged plants from the high site and the 2016 low site were returned to the lab to be photographed and processed for analysis. Total ear weight, ear length, ear diameter, and number of kernels per row were measured.mexicana). For these reasons, the “solid” pattern may have a stronger association with highland adaptation, and other patterns may represent stress responses to other biotic and/or abiotic factors. Plants were given the categorical qualitative label of either “banded,” “spotted,” “uniform,” or “no pattern” (either no pigment present or irregular pigment pattern). Plants with patterns of “banded” or “spotted” were binned into a “spot” group. Plants with pigment patterns “solid” and “no pattern” were binned into the group “solid.” When a plant exhibited multiple patterns, the highest‐priority category was selected . Macrohair density on the second leaf sheath from the top of the plant was visually scored on a scale of 0–4. Pubescence along the leaf sheath and pubescence restricted to the sheath margin may be under different genetic control and may play different roles in highland adaptation. Therefore, plants were grouped by macrohair trait pattern (leaf sheath vs. leaf sheath margin).Methods for field visual assessment of anthocyanin pigmentation and macrohair were derived with modification from Lauter et al. . PigmentTwo adjusted fitness metrics were computed from the combination of several fitness traits  and conducted admixture analysis. To estimate admixture coefficients from the genotypic data, we used sparse non‐negative matrix factorization  and traits previously identified and frequently reported as highland adaptive Doebley, . FITplan2.3.3We used a linear mixed‐effects model , CONTINENT (Mexico or South America), ELEVATION (High or Low), all interaction combinations therein, BLOCK nested in GARDEN, and calls as random effects with random intercept accession LATITUDE and LATITUDE/GARDEN interaction. The significance of specific treatment effects was evaluated using the lmerTest , between highland and lowland populations from the same continent within each field site (to quantify highland‐lowland adaptation), and between Mexican and South American populations from the same elevation within each field site (to quantify adaptation to continent‐specific factors).We compared each population's phenotypes between field sites (to quantify 2.3.4QST) was contrasted to the distribution of FST for neutral genetic markers  resolution global GeoTiff files downloaded from WorldClim 2.1 . A negative environmental distance value signifies that the environmental value at the landrace's origin location was lower than that of the common garden site. We then regressed vegetative fitness (FITplantveg) against environmental distance with a linear model (FITplantveg ~ DISTANCE) for each environmental variable. To remove the effect of unequal mean fitness between common garden sites, we used the residuals of this linear model . Next, to test if fitness residuals decreased with increasing (more positive or more negative) environmental distances, fitness residuals were fit with a quadratic model (e ~ DISTANCE +DISTANCE2). The relationship between the fitness residuals and the quadratic coefficient is quantified with a t‐value with an associated p‐value to denote the probability of no relationship. A significant p‐value therefore indicates that the fitness residuals follow a quadratic (parabolic) trend more closely than would be expected by chance. The proportion of fitness residual variance explained by the quadratic model is expressed with R2.In keeping with methods employed by Gates et al. , we regr33.1K = 3 ancestral populations . Admixture coefficients for both K values are plotted across geographic space to demonstrate their distributions  were used to perform PCA. The first two components distinguish individuals from the High Site from both plantings of the Low Site Figure a. The twGarden‐specific Pearson correlations of phenotypic traits were calculated and plotted Figure . Black s3.33.3.1δ13C (hereafter −δ13C), pigment traits, and macrohair traits vary between both common gardens  is strongly negatively correlated with solid‐pattern anthocyanin pigmentation intensity (P_INTsolid) and extent (P_EXTsolid) and leaf sheath macrohair density (M_DENsolid). In the High Site, however, these correlations become strongly positive, suggesting that these traits are more advantageous in the High Site than the Low Site. A similar (but weaker) pattern is seen with fitness correlations with spot‐pattern anthocyanin pigmentation intensity (P_INTspot) and extent (P_EXTspot) and leaf margin macrohair density (M_DENmarg). This suggests that expression of the alternate patterns of these traits is advantageous in the High Site, but less so than for the solid‐pattern traits.δ13C can be thought of as roughly analogous to water use efficiency (WUE). This trait is more correlated with fitness in the High Site than in the Low Site, suggesting that WUE is more advantageous in the highland environment. −δ13C has no significant correlations with anthocyanin pigmentation intensity or extent, regardless of pattern or garden site, nor with leaf margin macrohair density, but it does correlate positively with leaf sheath macrohair density in both sites . This may suggest that leaf sheath macrohair density may contribute towards WUE.−3.3.2G × E) interaction. When local populations have fitness trait values higher than the fitness trait values of non‐local populations, resulting in crossed reaction norms, this is known as local adaptation.Reaction norms describe phenotypic trait values of genotypes  at different environments (common garden sites). Nonparallel reaction norms indicate that populations respond to environments differently, a pattern known as genotype‐by‐environment  and vegetative fitness  than low populations. In the Low Site, Low populations had higher vegetative fitness than High populations , though differences in agronomic fitness were less clear . In all but one contrast, Mex populations had higher fitness than SA populations from the same elevation, though the significance of these differences is generally less than those of High/Low population contrasts. Agronomic fitness was higher in Mex High than in SA High in the High Site , and vegetative plant fitness was higher in Mex High than in SA High in the Low Site . However, vegetative plant fitness was lower in Mex Low than in SA Low  at the Low Site.Reaction norms for all traits are available in Figure t‐ratio = 7.039, p < 0.0001). Plant biomass and yield trait values were predicted to be higher in the Low Site. For comparison, plant height . This fitness difference is likely due to the impact of virus damage in the Low Site significantly depressing ear weight , which are a component in the adjusted agronomic fitness variable.Contrary to expectations, agronomic plant fitness was higher in the High Site than the Low Site . Though all populations showed similar patterns, SA took longer to flower than Mex , and Low took longer than High . Anthesis‐silking interval .Flowering took longer in the High Site  and in the High populations . While SA Low, SA High, and Mex High did not vary significantly for δ13C, SA High showed a distinct pattern of high δ13C in the Low Site, similar to both Low populations, and low δ13C in the High Site, similar to Mex High.C Figure  values wt‐ratio = 4.769, p < 0.0001) and extent . High populations had higher intensity  and extent  than Low populations. Mex High and Mex Low had more similar values of anthocyanin intensity and extent, but SA High had much higher values of each than SA Low .The High Site was characterized by increased values of solid‐pattern anthocyanin intensity  and SA High .None of the populations varied significantly in leaf sheath macrohair density  had significantly high QST values.Four sets of comparisons were carried out: High vs. Low Figure , Mex vs.3.3.4y = 0 indicate decreasing fitness with increasing environmental distance. Variance in the fitness residuals explained by the quadratic model is quantified as R2, and p‐values denote the probability that t‐values of the quadratic coefficient are equal to zero .The residuals of linear regressions of fitness values to environmental distances  were tested for goodness‐of‐fit to a quadratic model Figure . Residuap < 0.0005) and annual mean temperature (p < 0.0005), but no significant trend is found for annual precipitation (p = 0.07). Significant decreases in fitness with increasing environmental distance were also found for the environmental variables isothermality (p < 0.005), max temperature of the warmest month (p < 0.0005), min temperature of the coldest month (p < 0.05), and mean temperature of the wettest (p < 0.0005), driest (p < 0.005), and warmest (p < 0.0005) quarters. Conversely, significant increases in fitness were found with greater distance in precipitation of the driest month (p < 0.0005) and quarter (p < 0.0005). All twenty plots are available in Figure This model finds that fitness decreases with greater distance of elevation  in up to four ways: plasticity, evolution, gene flow, or extinction . This is in contrast to the diverse traditional agronomic practices utilized at smallholder farms across Mexico in which landrace diversity is maintained. This disparity between native habitat conditions and experimental common garden conditions may have reduced the observable signal of local adaptation to mitigated selection pressures. For example, common garden sites were well‐irrigated, releasing crops from reliance on precipitation events, which may explain why plant fitness decreased relatively little across most precipitation‐related bioclimatic variables in the environmental distance regression analysis. However, other environmental pressures  are less likely to have been affected.5in situ conservation status of landraces are complex and dynamic, though locally adapted and evolving populations are more resilient and less likely to be supplanted by modern varieties (Perales et al., These results demonstrate that maize landraces from across the Americas are locally adapted to elevation and temperature. Landraces adapted to diverse environmental conditions are an invaluable resource for breeding efforts that rely on fewer costly and ecologically harmful inputs (Dwivedi et al., The authors declare no conflict of interest.Supplementary MaterialClick here for additional data file.


Sustainment refers to continued intervention delivery over time, while continuing to produce intended outcomes, often with ongoing adaptations, which are purposeful changes to the design or delivery of an intervention to improve its fit or effectiveness. The Hispanic Kidney Transplant Program (HKTP), a complex, culturally competent intervention, was implemented in two transplant programs to reduce disparities in Hispanic/Latinx living donor kidney transplant rates. This study longitudinally examined the influence of adaptations on HKTP sustainment.Qualitative interviews, learning collaborative calls, and telephone meetings with physicians, administrators, and staff (n = 55) were conducted over three years of implementation to identify HKTP adaptations. The Framework for Reporting Adaptations and Modifications-Expanded was used to classify adaptation types and frequency, which were compared across sites over time.Across sites, more adaptations were made in the first year (n = 47), then fell and plateaued in the two remaining years (n = 35). Adaptations at Site-A were consistent across years , while Site-B made considerably fewer adaptations after the first year . Both sites proportionally made mostly skipping (32%), adding (20%), tweaking (20%), and substituting (16%) adaptation types. Skipping- and substituting-type adaptations were made due to institutional structural characteristics and lack of available resources, respectively. However, Site-A’s greater proportion of skipping-type adaptations was attributed to greater system complexity, and Site-B’s greater proportion of adding-type adaptation was attributed to the egalitarian team-based culture.Our findings can help prepare implementers to expect certain context-specific adaptations and preemptively avoid those that hinder sustainment. Organizations are commonly unable to maintain implementation of evidence-based interventions (EBIs) over time –3. SustaExamining sustainment can help predict and increase the likelihood of long-term EBI delivery ,10,11. FWhile there are a variety of study designs for sustainment research, scholars recommend assessment over multiple time points throughout a multi-year study to identify potential changes to the intervention that may affect sustainment ,5,19. SuThe Northwestern Medicine™ Hispanic Kidney Transplant Program (HKTP) was established in December 2006 to provide culturally competent and linguistically congruent care to Hispanic/Latinx patients initiating evaluation for kidney transplantation, with the intent of increasing living kidney donation rates . Living HKTP was implemented at two transplant programs and evaluated for effectiveness and implementation fidelity. While most complex interventions occur for one or two years , our intThe Framework for Reporting Adaptations and Modifications-Expanded (FRAME)  guided tWe conducted a type II hybrid effectiveness-implementation study design  to assesHKTP was implemented at two kidney transplant programs: Site-A, located in the southern region of the USA, and Site-B, located in the southwest region. Both sites were selected because they served large Hispanic populations, perform more than 50 LDKTs per year, and have a Hispanic bilingual transplant physician. Two matched control sites were used for comparison.Eligible participants were stakeholders directly involved in HKTP implementation and included transplant physicians , administrators , and clinical and research staff . Site PIs notified and requested stakeholders to participate in data collection activities via email, phone, and/or in-person. Stakeholders did not have a relationship with the co-PIs  prior to study commencement. Co-PIs presented reasons for performing the research with site PIs prior to grant submission and to all stakeholders at the initial site visit.As a multi-level intervention, HKTP is comprised of multiple components and strategies, as shown elsewhere . HKTP prWe used several implementation strategies including learning collaboratives, in-service presentations within each site, marketing events, and data monitoring. The research team held quarterly “Learning Collaboratives” involving stakeholders from both sites to design solutions (including intervention adaptations) to barriers to implementing HKTP . OrganizWe also monitored sites’ progress in establishing HKTP during the pre-implementation period by providing a monthly timeline that compared progress made at each site. Using green, yellow, and red colored indicators of site progress on each implementation step, the timeline was intended to be informative and foster motivation through competition. This approach was discontinued several months after sites began implementing because it was designed to foster program launch and not sustainment.In the primary outcomes paper for this study , we founTo assess HKTP implementation fidelity, research staff documented the a) number of in-service and marketing materials and events used to promote HKTP, b) number of dialysis centers visited and number of hours spent performing outreach, c) bilingual and bicultural status of outreach staff, d) audio-recorded quarterly phone calls with patients scheduling their transplant evaluation visit, e) audio-recorded quarterly HKTP education sessions to document the core content areas covered, f) number of education sessions held and the type of clinician delivering the sessions, g) number of potential recipients and family members attending education sessions, h) whether each potential recipient received a call from a physician 6–8 weeks after the education session to complete transplant evaluation, and i) number of patients who were sent 90-day reminder letters to complete transplant evaluation.Qualitative data were collected during annual site visits in 2017, 2018, and 2019. Study co-PIs  conducted the visits, which involved one-on-one interviews and group discussions with transplant stakeholders to identify barriers and facilitators to HKTP implementation, assess intervention delivery, and troubleshoot ways to facilitate HKTP implementation.www.cfirguide.org). Interview questions included the following: “What kinds of changes have you had to make to your outreach plan to fit with your institutional setting/city/demographics?”, “What kind of changes do you think that you will (still) need to make to the implementation so it will work more effectively in your setting?”, “What kind of data is your organization collecting on the HKTP in how well it’s doing or working?”, and “How hard is it going to be to sustain the HKTP?”. The co-PIs led in-person group discussions to clarify the study protocol, assess progress on intervention implementation, and brainstorm ways to accommodate the intervention.Co-PI EJG conducted in-depth, semi-structured interviews with stakeholders to assess perceptions of organizational culture, attitudes about the implementation complexity, and perceived barriers and facilitators to implementing HKTP components using the CFIR Interview Guide , all transcripts were recoded. Discrepancies between coders were resolved through group discussions. Second, two research staff members independently coded the same transcript for adaptations using the FRAME, identifying the type, instigator, and reason for the adaptation [Descriptive statistics were used to calculate frequencies of adaptations by study site, demographics, adaptation type, instigator, and reason. Analyses were conducted with the Statistical Packages for Social Sciences (SPSS) version 26.Fifty-five stakeholders  participated in one or more of the following research activities across all three years: site visit interview (n = 48), group discussion (n = 18), and/or learning collaborative discussion (n = 22)  and Site-B n = 152)  than Site-B . Site-A closely adhered to the protocol each year of the intervention period . Site-B adhered to the protocol the first two years of the HKTP intervention, but adherence decreased in 2019 .The HKTP protocol requested that all education sessions be delivered by a bilingual, bicultural physician. Site-A reported a greater number and proportion of HKTP education sessions delivered by a bilingual, bicultural physician  than Site-B . Over time, all HKTP education sessions were delivered by a bilingual, bicultural physician at Site-A , while Site-B had a lower proportion .For HKTP to be sustainable, sites must continue to recruit new potential recipients through outreach efforts at dialysis centers, schedule potential HKTP recipients, and conduct culturally competent education sessions. They must also maintain a bicultural/bilingual team and the availability of interpreters or interpreter services. The implementation strategies used in this study also suggest that ongoing training, in-service presentations to local transplant stakeholders, marketing campaigns, ongoing data monitoring for quality assurance, and learning collaboratives might be necessary, but the pre-post non-randomized study design did not allow formal testing .During the pre-implementation period, one 4-hour learning collaborative was held by telephone, and one 1½ day in-person retreat, which entailed discussion to: clarify the intervention protocol, brainstorm approaches to align the intervention with institutional context, train providers through role-playing sessions, and review progress made. During the implementation period, twelve 1-hour telephone meetings were held from 2017–2019 (range: 3–5 per year).Across all years, Site-A hosted more in-service presentations than Site-B (n = 6 versus n = 3). Both sites reported a drop in in-service presentations in 2018 and an increase in 2019 .Across all years, Site-A hosted more marketing events targeting healthcare providers at other institutions than Site-B (n = 23 versus n = 1). Both sites hosted the most events in 2017, which dropped and remained constant in subsequent years .Across all years, Site-A hosted more marketing events targeting patients and family members than Site-B (n = 36 versus n = 3). Both sites hosted most events in 2017, which dropped in subsequent years .Sites aimed to complete 832 h of outreach at dialysis centers per year for a total of 2,496 h during the study period, as per the protocol. Overall, Site-A dedicated more hours and completed a greater proportion of the target goal  than Site-B  . Over time, both sites increased adherence after the first year . At Site-A, the increase coincided with an increased number of potential recipients attending HKTP education sessions. By contrast, despite the increase in adherence over time, Site-B experienced an 8% decrease in attendance in 2018, which may be a result of its decreased outreach efforts. In 2019, Site-B reported its highest adherence to scheduler scripts which coincided with its highest number of potential HKTP recipients. Overall, sites’ adherence to the scheduler scripts resulted in comparable HKTP attendance numbers.Although stakeholders (site PIs) were encouraged to monitor their site data at the study onset, they indicated during site visit interviews that they did not collect or monitor the study-specific data. Stakeholders reported that they lacked awareness of processes for tracking participants involved in the study at Site-A and that tracking participants would have required additional time to manually prepare the list of known participants at Site-B.Across sites, more adaptations were made in the first year 2017: n = 47) and then declined and plateaued over the two remaining years   Fig. b. Both sTM . At Site-A, stakeholders added information to education slides and included town hall meetings to introduce HKTP to potential patients and increase outreach efforts. Site-B included Spanish-speaking transplant professionals  at education sessions to answer questions from Spanish-speaking patients. Further, Site-B created flyers to inform potential HKTP patients at dialysis centers of upcoming outreach sessions and provided telephone assistance to potential living donors when completing the English Breeze. In 2018, Site-A’s previous additions to improve outreach efforts and education sessions continued. By contrast, in 2018, Site-B discontinued its effort to enhance outreach by announcing upcoming dialysis clinic visits through flyers and stopped assisting Spanish-speaking potential living donors to complete the Breeze but continued to have transplant professionals in attendance at education sessions. In 2019, Site-A continued and increased its efforts to improve outreach by adding a “mini-automatic enrollment” procedure to expedite the scheduling of potential HKTP patients.Overall, Site-A made fewer adding-type adaptations than Site-B (Site-A: n = 10 Site-B: n = 13) Fig. c. AddingSite-B made more adding-type adaptations than Site-A, likely because it made more efforts to improve patient engagement  and to assist Spanish speakers in the first year. However, Site-B discontinued 2017 additions to improve outreach  and to assist Spanish-speaking potential living donors, which resulted in a decrease of adding-type adaptations in 2018. By contrast, Site-A continued 2017 additions made to improve outreach efforts, which increased over time. Both sites made adding-type adaptations to address patient needs. Site-A made additions to its outreach efforts to provide accessible information to its Spanish-Speaking patients, while Site-B made additions to increase patient engagement during education sessions and to provide patient support.Over time, both sites made a comparable number of tweaking-type adaptations   Fig. e. Site-AWhile a bilingual/bicultural outreach staff was hired in 2018 at Site-A, the English-speaking outreach staff continued to do outreach. While the English-speaking outreach staff was involved in outreach at dialysis facilities (directed toward facility staff) in all 3 years, the Spanish-speaking outreach staff led patient-directed outreach efforts. Further, the English-speaking staff was accompanied by a Spanish-speaking research staff to help interpret. To improve communication with Spanish-speaking patients, Site-A relied on bilingual research and outreach staff to act as interpreters because there were not enough available interpreters from 2017 to 2018. While Site-B also relied on Spanish-speaking staff members to serve as interpreters, Site-B also relied on Spanish-speaking staff to conduct education and wrap-up sessions because there were not enough available Spanish-speaking physicians throughout the three years of implementation. Site-B made more substituting-type adaptations in 2019 than previous years because there were less Spanish-speaking staff available to assist with scheduling and clinical staff follow-ups and thus relied on a Spanish-speaking research staff.Both sites made substituting-type adaptations because of lack of available resources . Site-B made more substituting-type adaptations than Site-A because it had fewer available Spanish-speaking staff. While Site-B made a relatively consistent number in 2017 and 2018, it increased the number of substitutions made in 2019 because it needed more Spanish-speaking staff to conduct patient scheduling and clinical staff follow-ups which resulted in a Spanish-speaking research staff fulfilling those roles.While the conceptualization of sustainment continues to evolve, most frameworks and models include multiple dimensions thought to be related to, or necessary for, ongoing intervention delivery over multiple years ,10,15. OTM, and this study represented the first attempt to scale up the intervention to other systems.Both study sites made a number of adaptations of different types to HKTP over time. Adaptations of the adding type tended to increase over time in attempts to increase the effectiveness of the intervention. Substituting and delay/skipping-type adaptations decreased over time suggesting a potential need earlier in implementation to prune or de-implement HKTP components that were ineffective or misaligned with the context of the delivery sites. Relatively speaking, Site-B made fewer adaptations early in the implementation, which might have led to poorer fidelity and the need for more adaptations in the third year to increase effectiveness. This degree of adaptations might be expected given that HKTP was developed at Northwestern MedicineNotable intervention adaptation differences emerged between the sites. Site-A, which had higher implementation fidelity than Site-B, made fewer adaptations across all years of implementation. Further, tweaking or substituting types of adaptations were more likely to increase over time, as occurred at Site-B. While adaptation is expected when new interventions are implemented in a particular setting , this fiThe use of the learning collaborative strategy was hypothesized to help ensure adaptations were both fidelity-consistent and would increase the implementation and effectiveness of HKTP through cross-site learning between Sites A and B and Northwestern University, where the HKTP was developed and first implemented. While this seems to have worked well for Site-A, it was not sufficient to overcome contextual barriers in Site-B. Evidence of the effectiveness of learning collaboratives for implementation has been mixed, in large part due to the high degree of protocol variability –41. ThisDespite encouragement to use data monitor strategies, both sites indicated not doing so. Similarly, a review of healthcare organizations implementation of culturally competent interventions found that relatively few studies implemented audit or quality improvement approaches of the intervention . Had sitAlthough sustainment has become recognized as an essential implementation outcome , there mA strength of this study is a longitudinal and ongoing analysis of adaptations to a complex, culturally competent intervention using the FRAME over a three-year period across diverse healthcare organizations. Limitations include reliance on participant self-reports, which may not reflect actual behaviors. Social desirability bias may have affected descriptions of adaptations. However, data triangulation through stakeholder interviews and weekly phone calls with research staff served to clarify and confirm adaptations. Future research could conduct observational evaluations of adaptations, but this is often infeasible due to cost and the nature of the intervention. The two-site design limits our ability to draw conclusions regarding the effects of specific strategies on intervention adaptations and sustainment more broadly. Future research should examine the extent to which adaptations beget other adaptations. Doing so would likely necessitate a more frequent evaluation that could capture the dynamics of adaptation, as well as the use of other implementation strategies, using tools such as the Longitudinal Implementation Strategy Tracking System ,45. LastOur findings illuminate factors that challenge the sustainment of complex interventions and underscore the importance of ongoing assessment of adaptations concerning their impact on target outcomes. Further, certain contextual determinants challenge the sustainment of complex interventions that cannot be overcome solely through adapting the intervention. Chasing fit with context by adapting the intervention led to low-fidelity implementation in one site, and certain adaptations had a clear adverse effect on intervention delivery. For example, lack of time and available Spanish-speaking staff led to adaptations, which resulted in outreach not being performed at target levels.Systematic reviews show that culturally competent care interventions are effective in improving patient, provider, access, and organizational outcomes ,46,47. FPractically, our findings can help prepare implementers to expect certain context-dependent adaptations to preemptively avoid those that reduce fidelity and effectiveness and to focus on those that support sustainment. The manner through which such decisions for adaptations are made remains a question for future research but our findings suggest the potential for learning collaboratives to play a role in these processes.