This critical PhD review paper examines existing scholarship on ethical leadership in sport. Following a general trend in business ethics and related fields, ethical leadership has gained considerable research attention in sport over the last decades. Within this growing body of literature, ethical leadership is often presented as part of the desired strategic response of sport organizations to tackle the so-called dark side of sport . However, this critical PhD review paper argues that the current body of literature on ethical leadership in sport has matured along two strongly related yet quite isolated lines of inquiry: a normative  and a descriptive  line. While the normative line of inquiry focuses on what ethical leadership in sport should look like based on moral reasoning, the descriptive line examines how ethical leadership in sport is perceived in practice and how it relates to certain antecedents and outcomes. As both lines offer complementary insights, we advocate future research to bridge this gap to come to an improved understanding of ethical leadership in sport. To this aim, we propose a broad stakeholder perspective on ethical leadership in sport, in which necessary attention is given to how all involved stakeholders make sense of ethical leadership as a socially constructed and context-dependent phenomenon. Leadership continues to be one of the most studied social phenomena. Although many definitions exist, leadership can be understood as a process or relationship between a leader and follower(s)  or stakeholder(s) , aiming to accomplish shared goals . Within Sport is a social context in which the ethical dimension of leadership is amply illustrated. Leaders in sport, such as coaches, managers, and board members have a strong impact on the people they are working with . Moreover, certain characteristics of competitive sport, such as a focus on performing and excellence, and the presence of often high levels of emotional involvement and pressure, add to an environment in which many different types of ethical challenges occur . These eis and should look like , based on moral reasoning. Descriptive studies emphasize how ethical leadership is perceived in practice , based on empirical study designs. Whereas both views on ethical leadership are considered “complementary sides of the same coin”  in the international sporting world indicate a lack of ethical leadership, as well as a paucity of concrete efforts to enable and stimulate ethical leadership in sport . A potenAttempting to integrate the normative and descriptive lines of ethical leadership research by means of a more comprehensive approach is not completely novel. However, existing studies in this area have led to little follow-up research and limited utilization in practice . This laNormative inquiry into ethical leadership has strong historical roots, which go back as far as renowned ancient philosophers such as Plato and Aristoteles . Ever siSeveral scholars have drawn attention to the relevance and importance of ethical leadership in sport from a normative point of view . This atshould be promoted by leaders to actually be ethical leaders, depends on the unique context at hand and on matching the personal values and preferences of both sides of the leadership relationship  are based on moral reasoning and philosophical inquiry and emphasize that ethical leadership entails the pedagogical promotion of certain values, such as respect, honesty, and fair play. However, it is still unclear whether these (and other) values should be seen as universal and generally applicable . Althougtionship . In othetionship  , mechanisms , and consequences  of ethical leadership . Emphasimoral person , and acting as a (b) moral manager , and (c) a moral entrepreneur   . Offerinllenges) . Hence, llenges) .loophole ethics in sport  (spirit of sport) and can only be achieved when formal policies are translated into actual practices by different levels of leadership within sport organizations  point of view. Part of the explanation for this “delay” in comparison to other fields might reside in sport’s historical preoccupation with (both regulatory and prescriptive) rules . In manyallowed) . After aizations .Today, empirical, descriptive studies on ethical leadership in sport continue to be limited in number and scope . For instance, Cotrufo  has showThese studies based on North American samples have been supplemented with work on European sport over the past few years. More precisely, Constandt and colleagues  have shoIn most of these studies, ethical leadership in sport has been analysed as an individually perceived phenomenon of which the meaning resides “in the moral eye of the beholder” . ParticuThe normative and the descriptive lines of ethical leadership inquiry have both been the subject of considerable critique. Among other critiques, scholars point out that existing descriptive ethical leadership inquiry is conceptually unclear and incomplete , bears limited explanatory power, focuses predominantly on Western cultures [for a few exceptions, see e.g., Considering these critiques, future ethical leadership research should move away from the strict division between normative and descriptive studies, but also from the artificial demarcation between classical and contemporary approaches . In esseA stakeholder perspective on ethical leadership is promising to bridge this ethical leadership research gap in sport see  and beyofollower-centric perspective  instead of a leader-centric approach of leadership   . More preaders?)  has showobserver-centric perspective has been proposed .Nevertheless, as some people who are confronted with leadership are either non-receptive or not the actual target for its influence – and are thus not actual “followers” but rather “observers” – an proposed . An obseThis stakeholder perspective should be broad, ideally including everyone who impacts or is impacted by the organizational sport setting(s) under study . MoreoveSuch stakeholder perspective not only honours the active nature of ethical leadership as a relational phenomenon that is not merely implemented in a top-down way, but it also re-integrates the perspective of the leaders themselves in ethical leadership research . AcknowlThis PhD critical review paper argues that there are two main ways to implement a stakeholder perspective on ethical leadership in sport: (a) by conducting and intensifying research in each of the sketched pillars , and (b) by integrating these three pillars in thorough quantitative and (single and multiple) case study research that aims to compare and contrast findings. Additionally, a more diverse set of stakeholders  and sport settings should be considered, while a broader range of methods is required to enhance our understanding of ethical leadership in sport. Finally, these two lines of suggested research should both dedicate sufficient attention to non-empirical, philosophical insights which help to enhance our understanding of ethical leadership based on sound reasoning . ExistinThe importance of a stakeholder perspective on ethical leadership in sport has been highlighted in a study focusing on the extent to which fans care about ethical leadership in professional football . HoweverFurthermore, forthcoming scholarship on ethical leadership in sport should broaden its scope to more diverse settings. Currently, both normative and descriptive insights in ethical leadership are quite limited to intercollegiate athletics in North America and football (soccer) in Europe. To expedite comparisons, other sports and regions should be explored to examine whether context-dependent differences are really present. In other words, how much common ground  is present about ethical leadership in sport? Additionally, we encourage future work to pay attention to the extent of stakeholder group homogeneity vs. heterogeneity  and to the role of trust and values. When assessing ethical leadership, it is particularly interesting to examine whether stakeholders are actually rating their leaders’ ethical leadership or rather the extent in which they actually like, trust, and/or share the values of their leaders .While broadening the scope of ethical leadership in sport research to more diverse settings, attention could be paid to more practice-oriented research questions and to the practical implications of the study’s findings. Studies guided by such research questions as “How could ethical leadership be increased among coaches?” and “How can coaches be ethical yet demanding in elite sport contexts, and what are the underlying mechanisms?” could help to stress the practical relevance of ethical leadership in sport scholarship in a clearer way. Moreover, such research would support the evidence-based development of specific valorization tools , aimed at stimulating ethical leadership in sport practices.In terms of methods, future work is encouraged to strengthen the current dominant yet limited quantitative ethical leadership measurement scales. After all, these generic scales hold inherent biases that measure not only the behaviours that people observe in leaders, but also the respondents’ own prior expectations, ideals, and assumptions of ethical leadership, as well as their general trust in their leader . In lighIn addition to developing and implementing these scales on ethical leadership (in sport), the use of qualitative methods that enable more fine-grained work on ethical leadership is amply needed to examine (a) what is actually understood by ethical leadership in different settings and by different stakeholders, (b) how these understandings influence stakeholders’ actions, and (c) what the desired and supported comprehension of ethical leadership is in a given context . EvidentA broader range of methods is thus required to respect the complex nature of ethical leadership in sport. The multiple interactions between different stakeholders, both on and of the sport field, should thereby be taken into consideration. For example, (a) participatory observation in sport organizations, (b) social network analysis (SNA), (c) and novel methods such as smartphone apps could be specific applications of future ethical leadership research. Participatory observation and smartphone apps facilitate the collection and analysis of real time and recurrent responses when it comes to certain sport contexts . Such apps might thus support the measurement of the evolution of ethical leadership over time, analysing the (un)stability of ethical leadership as a construct. Furthermore, SNA could help to shed light on the role of power distributions and underlying ties between stakeholders . SNA thuAs a unique leisure time activity and branch of the entertainment industry, sport is often offering a stage for people to showcase both the best and worst kinds of human behaviours. While sport is believed to stimulate health and social cohesion and to bring joy, numerous indications of different ethical issues are surrounding sport’s manifestations. In this light, ethical leadership is considered to be part of the desired approach within sport organizations to mitigate this tension. Nonetheless, the scope of existing scholarship on ethical leadership in sport is not yet that broad, leaving debates on two important and context-dependent questions largely unsettled: (a) how should ethical leadership look like ?, and (b) how is ethical leadership understood in practice ? Despite their interplay, both research questions are currently mainly assessed in certain isolation of each other. This PhD critical review paper therefore advocates forthcoming studies to integrate both questions by means of a broad stakeholder perspective. Such stakeholder perspective would help to learn how all people involved in sport  under scrutiny) help to make sense of ethical leadership in sport. Moreover, such perspective would also help to guide sport organizations’ actions to successfully overcome the ethical challenges they are facing.


This paper presents an active wide-baseline triple-camera measurement system designed especially for 3D modeling in general outdoor environments, as well as a novel parallel surface refinement algorithm within the multi-view stereo (MVS) framework. Firstly, the pre-processing module converts the synchronized raw triple images from one single-shot acquisition of our setup to aligned RGB-Depth frames, which are then used for camera pose estimation using iterative closest point (ICP) and RANSAC perspective-n-point (PnP) approaches. Afterwards, an efficient dense reconstruction method, mostly implemented on the GPU in a grid manner, takes the raw depth data as input and optimizes the per-pixel depth values based on the multi-view photographic evidence, surface curvature and depth priors. Through a basic fusion scheme, an accurate and complete 3D model can be obtained from these enhanced depth maps. For a comprehensive test, the proposed MVS implementation is evaluated on benchmark and synthetic datasets, and a real-world reconstruction experiment is also conducted using our measurement system in an outdoor scenario. The results demonstrate that (1) our MVS method achieves very competitive performance in terms of modeling accuracy, surface completeness and noise reduction, given an input coarse geometry; and (2) despite some limitations, our triple-camera setup in combination with the proposed reconstruction routine, can be applied to some practical 3D modeling tasks operated in outdoor environments where conventional stereo or depth senors would normally suffer. Accurate 3D reconstruction is in high demand for a wide variety of tasks such as digital documentation, reverse engineering and industrial inspection. The traditional modeling approaches are mainly categorized into binocular stereo, structured light sensing, and time-of-flight (ToF) measurement. High-end ToF laser scanning systems and structured light sensors have been widely deployed for industrial applications where high modeling precision needs to be guaranteed. Although most laser scanners are capable of directly delivering dense point clouds with a high accuracy and can be applied in outdoor environments, they are normally expensive, time-consuming for data acquisition, and require an additional registration process to add texture information. Similar to laser scanners, industrial structured light sensors  can produce accurate and traceable 3D coordinates as well as high resolution polygon meshes for surface inspection, 3D printing, etc. However, such systems are also costly and measurements are mostly operated in a controlled indoor environment.With the development of computer vision and semiconductor technology, consumer grade depth sensors based on structured light and ToF techniques have become available, such as the structured light based Kinect v1 and ToF based Kinect v2. The biggest advantage of these commodity sensors is that they are able to capture the color and aligned depth data per pixel at a real-time frame rate, which makes them even more popular than those high-precision but costly and cumbersome scanning systems in those applications (like robotic navigation and human-machine interaction ) where data acquisition rate is more important than data quality. Even though their application for dense mapping and 3D modeling can be found in a vast literature, e.g., ,5,6, theSince most depth sensors additionally provide color images at a much higher resolution than that of depth images, researchers thereby have proposed various approaches to enhance the depth measurements by leveraging visual cues in color images. One straightforward idea is to raise the low-resolution depth images to the high resolution of the color image through joint bilateral upsampling and its variants , on basiRegarding stereo techniques, traditional binocular stereo vision is typically referred to as a passive stereo system composed of two cameras, which estimates the pixel depth by matching and triangulating correspondences across two views. Basic stereo setup can be built on a small budget, and compared with other techniques its data acquisition is much faster and more convenient. The downsides are relatively low depth quality and heavy dependence on texture information due to the matching process. To overcome these limitations, active stereo systems have been proposed to improve the modeling accuracy and completeness by enriching textures in the scenes using an external projection system. Similar to its structured light and ToF counterparts, compact commodity RGB-D cameras based on active stereo vision are developed, such as Intel RealSense D435 composed of a pair of IR cameras, an infrared projector as well as a color camera, enabling real-time acquisition of color and depth data at a moderate resolution but suffering from limited triangulation accuracy due to the short baseline. Although there exist wide-baseline active stereo systems (like GOM ARAMIS 3D Camera series) specially designed for high-precision industrial inspection, most of them are not suitable for outdoor 3D modeling tasks either.Most modeling processes using active stereo systems are operated in a traditional range scanning manner, where segments of point cloud are individually retrieved from static stereo images at every acquisition and are further merged into a dense cloud via geometric registration ,12. For In this paper, we propose a novel multi-view dense reconstruction system that is capable of achieving detailed and complete 3D modeling of objects even in general outdoor scenarios. Specifically, the main contributions of our work are (1) an active triple-camera measurement setup  that enables the synchronized acquisition of depth data as well as the original texture information of objects, and (2) a highly parallel surface refinement algorithm that improves coarse depth quality on the basis of multi-view photographic information, surface curvature, and depth priors. The use of stereo depth in our system implicitly recovers the metric scale of objects that cannot be obtained from other pure image-based MVS methods.This paper is arranged as follows. In In this section, we firstly give an overview of our triple-camera measurement system, and then describe how to perform synchronized image acquisition using this system.As shown in In our experiment we use a laptop to communicate with the mini-PC through the local wireless network, thereby controlling the image acquisition of the sensors. The complete workflow is depicted in The main modules of our proposed dense reconstruction pipeline are detailed in this section. At first we briefly introduce the triple-camera calibration along with the preparation work for raw images. Afterwards, the utilized pose estimation approach that sequentially combines multi-way iterative closest point (ICP) registration  and RANSSince our system bases on active stereo rather than structured light technique utilizing camera-projector correspondences, we only need to calibrate camera intrinsic parameters along with the rigid transformations between left-right cameras for stereo depth estimation and left-color cameras for the alignment of depth and color frames. For such a wide baseline setup, the camera intrinsics are at first independently calibrated using the standard chessboard method , and aftIn order to obtain aligned depth and color frames, a set of operations are executed on raw image pairs, as depicted in In a standard MVS framework, accurate pose estimation is of great importance to the dense reconstruction process, which requires relative transformations to compute and aggregate photo costs across neighboring views for depth optimization in the reference view. In the context of RGB-D sensors, ICP along with its variants ,21 that With regard to the specific implementation, the multiway ICP registration approach in  is utililocal patch-based optimization and parallel patch-wise refinement. As a surface patch is the basic unit being processed by our algorithm, the respective patch parametrization methods . Furthermore, i, Our implementation is built on the framework proposed by Goesele et al.  that for used in , the opts, i.e.,θ*:=argmilocal methods suffer from outliers and generally fail to recover smooth geometric surfaces. As an alternative, global methods aims to directly seek a continuous smooth model by jointly maximizing photo consistency measures and smoothness terms assuming that the scene geometry can be well modeled by smooth curved surface as shown in Despite their high computation efficiency, Schwarz Alternating Procedure, where every patch is locally optimized in one thread block and interacts with neighbor patches through boundary conditions. The depth estimates of an additional two-pixel wide boundary are required to compute depth derivatives as well as to impose constraints on the patch optimization n et al.  as our prated in ,32. Giverdinates (6)clinearizing the non-linear optimization problem by computing the residuals and Jacobians for Equation  using on(2)Solving this linear system in parallel using the conjugate gradient (CG) method that can be efficiently implemented within one thread block , the initial depth map and confidence map of the target view as well as the co-visibility map derived by checking the geometric consistency between initial depths to the global memory of GPU. Afterwards, a set of thread blocks are launched to execute the patch-wise optimization. Except for the read-write operations before and after optimization that needs to exchange data with global memory, the shared memory along with registers in the thread block are exploited for most computations, which is much faster than global memory access. In the specific implementation we perform 15 Schwarz iterations in total, and in each iteration all the sub-divided patches are optimized using the Gauss-Newton solver on the GPU. And the optimization process for one patch includes two main steps:In the end, a depth filtering process ,33 is apIn this section we test the proposed parallel MVS algorithm on benchmark data as well our own synthetic dataset, and afterwards demonstrate the complete 3D modeling pipeline  with the designed triple-camera measurement setup in a general outdoor scenario. The reconstruction results are compared with three other representative libraries in MVS community: OpenMVS  based onOur work (as well as SMVS) are implemented within the framework of OpenMVE, and adopt the same basic data structures and file formats as OpenMVE. For the convenience and consistency in subsequent comparison, we transplant the original implementation of OpenMVS (only the core dense reconstruction module) to the framework of OpenMVE as well, and no obvious difference in reconstruction quality is observed during our simulations. Another benefit for such a transplantation is that some parameters  related to the reconstruction process can be unified and the same post procedures such as depthmap filtering and meshing, are applied for these evaluated approaches. Note that our parallel refinement algorithm is executed on an input coarse geometry, and for the fairness an interface function is programmed for other three methods to seed the reconstruction process from an external input 3D model rather than their respective original initialization. All evaluated libraries are executed on a PC with an Intel Core i5-6600K CPU with 3.5 GHz (16 GB Ram) and an Nvidia GeForce GTX 1080 GPU. We empirically select the parameters in the implementation as follows: Relief dataset provided by Zollhoefer et al. [We start with the r et al. , where cFountain-P11 and Herz-Jesu-P8) are used. For computation efficiency and memory issue, the original high-resolution images are downsampled by half to 1536 × 1024 for dense reconstruction. To present quantitative analysis, two outdoor benchmark datasets  with groCaesar sculpture along with its reference geometry  in recoEquation ) for itsThe presented results from quantitative and qualitative evaluations on benchmark and synthetic datasets demonstrates that given a coarse geometry our proposed MVS reconstruction method achieves better overall performance than other representative counterparts , in terms of accuracy, completeness and smoothness. The reconstructed models of these evaluated methods agree with their respective characteristics well: Local approaches produce noisy surfaces and outliers in weakly-textured regions as parameters of each pixel are independently estimated. On the other hand, global methods are capable of delivering continuous and smooth geometry by introducing regularization terms but easily get stuck in local optima , due to their large parameter vectors and the strong non-convexity of the underlying optimization problem. Besides, the selection of the regularization weight is usually tricky for such global methods to reach a good balance between detail recovery and surface smoothness. In contrast, our approach divides the original optimization problem  into a set of sub-problems defined over subdivided square patches in the image domain, thereby reducing the complexity and parameter dimension of sub-tasks effectively and facilitating the parallel implementation of the Gauss-Newton solver on a GPU. Although this optimization strategy is theoretically sub-optimal, impressive results can still be achieved after a small number of iterations, because of its better convergence characteristics compared to conventional global optimization, as well as the usage of additional depth prior constraints.Our experiment verifies the applicability of the designed triple-camera system to 3D digitization of real-world objects in general outdoor scenarios, in combination with the proposed reconstruction pipeline. Although active measurement techniques have been developed for several decades, efficient and high-quality modeling still remains a challenging task. The recently popular RGB-D sensors, like Kinect and RealSense cameras, suffer from the interference of ambient lighting in depth measurements and require a very short acquisition range to obtain sufficient spatial resolution for the object in color images due to their large FOV settings, which is not always available in practical cases because of the equipped platform or the location of targets. And the industrial optical scanning systems  are mostly deployed in very high-end indoor applications. From the experiment it can be seen that despite of the use of the wide stereo baseline and active projection, raw stereo depth data from single acquisition still has a relatively poor quality due to degradation in image quality and long working distance. Therefore, the camera poses estimated by running ICP on stereo depth data show apparent misalignment that needs to be mitigated using the RANSAC PnP approach, and the local optimization  should fThere are a few limitations for our system. On the hardware side, although our projector provides a much higher output power than those integrated projectors in commodity sensors, it is still not suitable for applications operated in strong environment lighting conditions  that would make our active system degrade into a purely passive stereo setup. On the software side, a good initial geometry still plays an important role in our proposed algorithms, and in sharp depth discontinuities distortions and artifacts might arise and cannot be easily fixed during the optimization.Since our measurement setup is designed to be equipped on a flight platform for aerial data acquisition, the hand-held experiment is the first step to test the performance of the proposed system for outdoor reconstruction, and in future work we would mount the setup on a hexacopter and capture images in a aerial manner, as shown in In this paper we present a triple-camera measurement system as well as the specially designed MVS reconstruction routine, able to achieve detailed and complete modeling even in an uncontrolled outdoor environment. Our hardware is composed mainly of an active stereo setup for depth acquisition, one color camera equipped with an optical filter for texture capture and a mini-PC that communicates with a client laptop and controls the data acquisition process. In order to yield high-quality results, a novel reconstruction routine is proposed to fully exploit the aligned depth and color frames converted from raw image pairs. The raw depth data from static stereo is first utilized for obtaining metric-scale camera poses and then taken as input by our MVS reconstruction modules. We evaluate our approach on benchmark and synthetic data comprehensively. The results demonstrate that the proposed parallel refinement algorithm performs better compared to other conventional methods in terms of noise reduction and surface accuracy. Finally, an outdoor reconstruction experiment is conducted using our setup in a hand-held manner, detailing the proposed pipeline from data acquisition to pose estimation to dense reconstruction, and proving that our system can be applicable to practical modeling tasks. Despite of some limitations as discussed in


Numerous studies have documented the detrimental impact of age-based stereotype threat (ABST) on older adults' cognitive performance and especially on veridical memory. However, far fewer studies have investigated the impact of ABST on older adults' memory distortion. Here, we review the subset of research examining memory distortion and provide evidence for the role of stereotype threat as a powerful socio-emotional factor that impacts age-related susceptibility to memory distortion. In this review we define memory distortion as errors in memory that are associated with gist-based errors or source misattributions. Whereas, some of the reviewed experiments support the conclusion that ABST should be considered in the context of age-related differences in memory distortion, others reported little or no impact of stereotype threat. These discrepancies suggest that the role of ABST, and socio-emotional processes generally, in age-related changes in memory distortion are less clear. In this review, we argue that ABST does play an important role in age-related changes in memory distortion. We present evidence suggesting that discrepancies in the reviewed literature may be reconciled when evaluated in the context of the leading theories about stereotype threat: the Executive Resource Depletion hypothesis and the Regulatory Focus theory. We also discuss how differences in methodology and participant characteristics can account for a priori contradictory results in the literature. Finally, we propose some recommendations for researchers and practitioners when assessing memory in older adults. Traditionally, age-related influences on cognition have been considered from the cognitive and cognitive-neuroscientific perspective. However, more recently, researchers have begun to also consider the influences of socio-emotional factors as they impact age-related cognitive change. For example, it is now clear that aging changes life goals, inducing a positivity bias that influences memory and decision making  or aging in combination with stereotype threat and memory, episodic memory, or false memory. After identifying articles that fit these criteria, we also reviewed the references from each article to determine whether additional articles were appropriate. For the purposes of the present review, we chose from these articles those that featured one or more dependent variables that measured memory distortion. This process yielded five articles (six experiments) that used either the DRM paradigm  and the eyewitness-memory paradigms (Section 3 Older Adults and Eyewitness Memory). Then we discuss the underlying mechanisms that have been proposed to account for memory distortion in the two paradigms that have been used, and highlight how stereotype-threat effects in older adults may interact with these proposed mechanisms . We also review moderating factors that have been shown to influence stereotype susceptibility in older adults and discuss how consideration of these factors helps account for discrepancies in the results from experiments on the topic . As a byproduct of synthesizing the research on the topic, this review will present a path forward in reconciling the inconsistencies in this literature and understanding the complex relationship between stereotype threat and memory distortion in older adults.In the DRM paradigm, participants are presented with associated words  and then perform a free recall or Y/N recognition test of memory. The typical finding is that people recall and/or recognize related but unstudied lure words  as having been previously presented Deese, . Older aItem-specific processing involves the encoding of information that serves to individuate one item from another. This kind of processing focuses on the differences among items within a list and fosters accurate discrimination between studied items and test lures. In contrast, relational processing promotes the extraction of similarities across items. When engaging in relational processing, the learner often seeks to extract a shared cue that may be used to cluster individual items . Research suggests that age-related increased misinformation susceptibility may result because older adults are less likely than younger adults to rely on effortful source monitoring that is necessary for accurate retrieval . In Study 2, when encouraged to engage in retrieval monitoring, older adults in the High threat group did not differ from older adults in the Low threat group. Further, on a final source discrimination task, older adults in the High threat group were more accurate than those in the Low threat group.In Study 1, where retrieval monitoring was unnecessary for test accuracy, older adults in the High threat group were less accurate than older adults in the Low threat group. Importantly, the decrease in accuracy in the High threat group was directly related to errors of omission. That is, older adults in the High threat induction group were more likely to withhold responses than those in the control group. On the Operation Span test, ABST resulted in numerically lower performance; however, the interaction did not reach the level of standard statistical significance  provide initial evidence of the important role of socio-emotional factors in age-related susceptibility to false memories. That is, facing a situation where negative age-related stereotypes are salient may have resulted in a stress response that had downstream consequences on memory. We argue that the socio-emotional impact on false memory susceptibility is relevant in understanding the mechanism that may underlie age-related changes in memory distortion. Specifically, socio-emotional processes may independently impact and/or directly interact with neurological changes in medial temporal lobes and/or the prefrontal cortex to increase or decrease memory distortion. That said, the six experiments discussed thus far present a puzzling picture regarding the impact of ABST on memory distortion. Though perplexing when taken at face value, we argue than when cognitive and motivational processes underlying ABST are considered along with methodological and participant-level differences, some clarity is gained and a path forward is uncovered.False memories in the DRM paradigm and decreased accuracy in the misinformation paradigm as a result of ABST have been considered within the context of the Executive Resource Depletion (ERD) account . This possibility nicely fits the apparently contradictory results obtained on the DRM paradigm by Thomas and Dubois  and WongIn the eyewitness memory paradigm, Thomas et al.'s  results When considering the discrepancies in the research on stereotype threat and memory distortion in older adults, there are additional methodological factors beyond the regulatory fit of the experiment that must be considered. As Special attention must be paid to the methods by which researchers induce stereotype threat in older adults, as researchers employ a wide range of threat-induction procedures. Threat is sometimes induced using explicit methods such as those employed by Thomas and Dubois  and someBlatant manipulations are used in most research investigating the impact of ABST on older adults. These inductions present factual statements that inform older participants about their inferiority in memory/cognitive abilities and clearly define the task as a measure of memory/cognitive capacity. These inductions rely on salient cues, so that participants are aware of the stigma and the fact that their performance could validate the stereotype about their group. This kind of induction affects older adults' performance expectations but likely does not directly influence the threat caused by age-based stereotypes. For example, studies using blatant inductions informed participants about recent findings showing age-related decrements in memory performance  had a greater impact on older adult memory and motor-task performance as compared to blatant manipulations (d = 0.16). The authors suggested that subtle manipulations may have a greater impact because they cause uncertainty about the presence of a threat. This ambiguity may increase distracting thoughts and tax cognitive resources required for successful performance on difficult tasks  than blatant inductions (d = 0.06). However, a stronger effect of blatant (d = 0.26) over subtle (d = 0.23) manipulations was found on episodic memory. This surprising finding should be interpreted with caution because of the small number of studies on which it relies (three studies), but also because each of the three studies rely on different episodic memory tasks . Using a subtle stereotype threat induction, Kang and Chasteen (d = 0.68), but not on cued-recall or recognition. This finding is consistent with the general pattern that threatened or stigmatized individuals are at a higher risk of experiencing performance decrements on difficult tests because these tasks create greater physiological stress responses . In the six studies examining the impact of ABST on memory distortion, we should note some variation in task demands associated with Y/N recognition tests, forced-choice recognition tests, and cued-recall tests  as compared to their older counterparts  and consider statistical approaches, perhaps involving linear mixed modeling, to account for this variability.The studies examining ABST on memory distortion in older adults provide evidence that socio-emotional factors may, at least in part, influence the cognitive processes that underlie memory performance. We suggest that ABST may result in behavioral changes as measured by response output  independent of variability in neural-network recruitment and age-related neurological decline. That said, the relationship between ABST and neural compensation and coping is understudied and would provide much needed insight to understanding the contribution neural and socio-emotional factors that may underlie ABST broadly, and ABST in memory distortion specifically. More precisely, the concept of Cognitive Reserve (CR) postulates that individual differences in the cognitive processes or neural networks underlying task performance allows for variability and individual differences in both age-related cognitive decline and compensation and coping in the context of brain damage Stern, . The exaIn addition to providing practical advice for future research, our analysis of the literature on ABST and older adult memory distortion sheds light on real-world considerations for older adult memory. The studies discussed here suggest that ABST can leave older adults more vulnerable to memory distortion, but perhaps only under conditions in which there is a mismatch between their regulatory state and the type of memory task they must complete. For instance, in the case of an older adult who is insecure about her memory and must go before a court as an eyewitness, it could be helpful to frame the recall task to fit with the prevention focus she is likely experiencing. Instructing her to be careful to only report details that she is certain of (prevention focus) might result in better memory performance than instructing her to report as many details as she can remember (promotion focus). Additionally, in scenarios like this, it is important to consider whether the individual characteristics of the eyewitness may leave her more vulnerable to experiencing subtle ABST. A witness who is retired, under the age of 70, and/or highly educated may be more susceptible to stereotype threat, making it even more important to consider the framing of the questions that are asked of her on the witness stand. Of course, future research is needed to determine if the results observed in laboratory research extend to situations like this.Project initiation and primary drafting of the manuscript were done by MM and AT. All authors contributed to manuscript writing, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We contend that by understanding the influenza imprinting event in the context of the infant immune system, we will be able to design more effective influenza vaccines for both infants and adults. Working through the lens of imprinting, using infant influenza animal models such as mice and ferrets which have proven useful for infant immunity studies, we will gain a better understanding of imprinting and its implications regarding vaccine design. This review examines literature regarding infant immune and respiratory development, current vaccine strategies, and highlights the importance of research into the imprinting event in infant animal models to develop more effective and protective vaccines for all including young children.Influenza virus infection causes severe respiratory illness in people worldwide, disproportionately affecting infants. The immature respiratory tract coupled with the developing immune system, and lack of previous exposure to the virus is thought to synergistically play a role in the increased disease severity in younger age groups. No influenza vaccines are available for those under six months, although maternal influenza immunization is recommended. In children aged six months to two years, vaccine immunogenicity is dampened compared to older children and adults. Unlike older children and adults, the infant immune system has fewer antigen-presenting cells and soluble immune factors. Paradoxically, we know that a person’s first infection with the influenza virus during infancy or childhood leads to the establishment of life-long immunity toward that particular virus strain. This is called  Influenza virus is a negative-sense RNA virus and a major burden on global health . InfluenThere infant immune system differs from older children and adults. These differences include variant levels of soluble immune factors ,9, lowerInfluenza viruses mutate rapidly over time leading to new seasonal virus strains that can evade pre-existing immunity, the antigenics in the annual influenza vaccine are updated annually. There are several vaccine platforms currently available and approved for use including inactivated (IIV), live attenuated (LAIV), recombinant, and adjuvanted vaccines . Only IIimprinting event [One’s first exposure to influenza virus, whether that be by infection or vaccination, is a significant event which we refer to as the ng event . In partng event . More woResearchers have used several infant animal models to study the infant immune response to influenza virus infection, including mice and ferrets. A literature review of infant mice studies has shown decreased T cell immune responses in infant animals ,18, but Below, we review the literature surrounding infant immune imprinting in the context of influenza vaccination. We will first discuss influenza virology, clinical outcomes, and vaccine platforms. We will then discuss how this pertains to infant infection and vaccination. Finally, we will end with a discussion of possible animal models for further investigation of infant influenza virus immunity and vaccination.Orthomyxoviridae family [Influenza viruses are negative-sense RNA viruses belonging to the e family . As showe family , and onle family . To datee family , with the family . The HA e family . Due to e family , unique The pathology caused by seasonal influenza virus infection is primarily localized to the respiratory tract, where the virus infects respiratory epithelial cells. Damage to the respiratory tract is mainly caused by the host inflammatory response to the virus Symptoms of infection can range from mild upper respiratory symptoms to lower respiratory tract involvement manifested by bronchitis, bronchiolitis, and/or complicated pneumonia . ClinicaTM pediatric which has MF59 as an adjuvant is approved for use in children [Although annual influenza vaccination is not implemented in the majority of countries across the world, it is recommended in many high income countries as the most important means to prevent infection by emerging seasonal influenza strains  and has children .In order to elicit the best immune response at vaccination, we need to consider how the influenza virus first imprints the immune system, how memory is established, and subsequently how the imprinted immune system is recalled over a lifetime. Evidence suggests that due to the continued presence of influenza virus strain specific antibodies, memory B cells produced during early exposures to the influenza virus still circulate in adult life . The conimprinting event [Our group refers to the first exposure to influenza virus and the resulting development of initial influenza immune memory as the ng event  which wang event . Since eng event ,49. Moreng event . Howeverng event .In the seminal imprinting study by Gostic and colleagues in 2016, the HA stalk imprinting hypothesis was put forth. This hypothesis specifically contended that cross-protection could occur if individuals were imprinted with an influenza virus containing an HA protein belonging to the same HA group as a subsequent infecting strain . For exaTaken together, these descriptive studies show that influenza outcome as well as vaccine effectiveness may be inferred by analyzing what influenza strain was circulating during an individual’s birth year . AlthougTo understand the imprinting event and how it can be applied to optimize infant influenza vaccination, we must first consider the unique features of the early immune system. These features, along with the still-developing respiratory tract, provide the physiological context in which the imprinting event occurs. The greatest challenge facing the neonatal immune system is the transition from the relatively sterile intrauterine environment to a world of tremendous antigenic variation. During this transition, infants have two seemingly contradictory challenges: they must learn to co-exist with commensal microbes, but also learn to eliminate invasive pathogens . NeonateEarly immunity against specific antigens is partially conferred by maternal immunoglobulins (Ig). During the third trimester of pregnancy, significant amounts of maternal IgG are actively transported across the placenta . This prThere are some major similarities and differences between adult and infant innate immune system components. In response to infection, neonates can produce interleukin (IL)-6 at the same or greater levels compared to adults ,65. DuriAs early as 14-weeks gestation, mature B and T cells with a remarkable range of antigenic diversity are already circulating, although there is relatively little antigen present . InfantsInfants were once believed to be immunodeficient because of limited production of IL-2; however, the distinction between Th1 and Th2 T helper cell subsets showed that infant immune responses simply have increased Th2 lineage cells . This prInfant B cell responses are considered to be deficient compared to older children and adults—they do not respond fully to T cell-independent antigens until about two years of age . MutatedIdeally better understanding of infant immune responses to vaccination compared to those of adults could lead to the development of improved infant-specific vaccines.As previously stated, maternal influenza vaccination is shown to decrease the risk of influenza infection in infants up to 6-months post-partum, and protection does not seem to differ significantly with the timing of maternal vaccination . At birtTM pediatric has been shown to increase vaccine responses in children [Most influenza vaccines elicit suboptimal responses in young children. IIV and subunit vaccines have limited efficacy in infants . Antigenchildren . Additiochildren . This machildren . More woVaccination in infants does not elicit the same level of protective immune response as vaccination in adults. It will be important to consider possible mechanistic differences that lead to the different vaccination response, and to do so, proper animal models for infant immune studies must be established.Experimental animal studies have been the cornerstone for biological discoveries. We have limited ability to conduct ethical and controlled experiments in humans, and even less ability in infant humans. The respiratory tract and the immune system of infants are significantly different from those of the adults; these differences are the probable causes of variable responses during infection and vaccination . To explWhile the use of infant animals for influenza virus infection and vaccination research has not been standardized, mouse models are the main experimental animal for other immune studies. Mice are preferred due to their small size, relatively low main maintenance cost, and ability to reproduce quickly . The gesWith this in consideration, the use of neonatal and infant mice has been instrumental in learning about the infant immune responses post influenza virus infection. Firstly, results have suggested that neonatal/infant mice are able to clear low levels of viral infection by immune responses regulated differently than compared to adult mice. Specifically, γδ T cells have been shown to protect neonatal mice against mortality following influenza virus infection . In one In addition to the above work, studies have shown that neonates have an increased ability to develop inducible Bronchus Associated Lymphoid Tissue (iBALT) within the lungs . iBALT iLooking at these studies together, there is accumulating evidence to suggest that there is decreased activity, recruitment, and memory establishment of T lymphocytes in infants following influenza virus infection in the mouse model. These studies show how the infant regulates the immune response to prevent an overactive filtration of T cells into the delicate immature lung. We first recognize from this review of the literature that there are few studies investigating the humoral response and antibody evolution following influenza virus infection in the infant mouse model. Furthermore, we see a trend of decreased T cell immune responses as expected from what is understood of the Th2 polarization of the infant immune system. It is also evident that there is decreased recruitment of T cells into the alveolar space, which may be a clue to the establishment of influenza imprinting.The ferret model has also been used to investigate age-related host response and disease severity to influenza virus infection both for the old  and younA study by Collie and colleagues found that seasonal influenza virus infection in newborn ferrets with a recombinant H3N2 virus strain led to mortality, significant viral replication within the respiratory tract, and evidence of severe respiratory pathology including collapsed alveolar spaces, necrotizing bronchiolitis, and death . In a foNon-human primates (NHPs) have been effective models of influenza virus infection and transmission for over a century . SeveralRhesus macaques (RMs) may be an effective model of infant immunity, as their immune ontogeny throughout fetal development and following birth is incredibly similar to that of human infants . HoweverDespite these important similarities between the RM and human infant, macaques are generally not optimal models of human influenza virus infection . Where fWhen considering vaccination studies, some investigations have applied non-human primate models to study influenza virus infection and vaccination strategies in infants. For example, a study by Kim and colleagues using 4–6-day-old African green monkeys (AGMs) showed that vaccines containing flagellin, a TLR5 agonist, enhanced IgG responses at following vaccination boost and challenge . AnotherThe purpose of this section was to highlight the importance of using appropriate animal models for influenza virus infection studies. After reviewing studies conducted in both infant mice, ferrets, and non-human primates, it is clear that these models are able to provide valuable information regarding the infant immune system, but more development needs to be done. We need an infant animal model that shares the unique immune features of a human infant in order to understand the influenza virus imprinting event so we can design vaccines that better cater to the infant immune response.In this review of the infant immune system and influenza, we understand that there are unique features of immune regulation and pathogen response in infants; that influenza infection during early life can lead to life-long immunity (imprinting), and that the influenza vaccine is poorly immunogenic in the younger age groups. Synthesizing these bits of knowledge, we ask two questions: (1) Can understanding the infant immune interaction with the influenza virus identify mechanisms that lead to immune imprinting and broader immune responses toward influenza viral antigens? and (2) Can we utilize imprinting knowledge to develop better influenza virus vaccines? When considering our first question, there has been much effort placed into how broadly reactive immune responses can be employed for universal influenza vaccine development . SpecifiWe note that these strategies are mostly concentrated on the virus while there have been fewer studies focusing on manipulating the immune system for broader responses . UnderstWhen considering our second question—Can we utilize imprinting knowledge to develop better influenza virus vaccines?—we must first recognize that there are two major issues with in respect to influenza vaccines. This first is that infants have decreased immune responses to influenza vaccine immunizations. The second is that the current seasonal vaccine is directed toward specific antigens of circulating viruses which necessitates vaccine updating each year. In this review we wanted to determine if understanding infant immunity and influenza virus infection could offer any insight for future vaccine design. The addition of adjuvants to the current vaccine formulations has been successful in clinical trials of MF-59-adjuvanted influenza vaccine. As well, we know that infants have decreased toll-like receptors (TLRs) which may significantly affect the stimulation of inflammation for antigen up-take at vaccination. It is possible that tailoring adjuvants toward the unique expression pattern of TLRs during infancy and childhood may be an effective strategy for increasing immunization effectiveness specifically of influenza vaccines. Moreover, using vaccines that can elicit iBALT or possibly NALT  in infants and adults may be an effective strategy for the development of a local and possible broader immune response. Considering this, work is needed to determine if local immune structures such as iBALT and NALT can induce broader responses. However, since we do know that the LAIV is more effective in young children, investigation into the memory induction after LAIV vaccination may give insight into the use of LAIV as an imprinting vaccine. With regard to adult vaccination strategies, identifying the mechanisms that the infant immune system uses to decrease somatic hypermutation and increase B cell memory induction may provide clues to how we can stimulate these pathways during adult vaccination for a broader and more long-lived immune response at influenza vaccination. Moving forward, comprehensive studies of influenza vaccination in infancy and adulthood in both preclinical animal models should examine the type of antigen, adjuvants, route of vaccination, vaccination schedule , and host age that maximizes the specificity and long-lived memory of the immune response.Infant immune systems and respiratory tracts differ significantly from those of adults. Infants and young children have increased rates of influenza virus infection, hospitalization, and mortality compared to older persons. Due to some of these immune differences and insufficient data on infant influenza vaccination, currently available vaccines cannot be used in infants less than 6 months, and others used in older infants result in dampened immune responses in infants, providing inadequate protection to future influenza virus infection. We note the importance of the imprinting event and how this significant event can shape the immune response to future infections. Currently there is no standardized animal model for infant influenza and immune research. Both mice and ferrets have been used in these previous studies. There are some gaps as these preclinical studies primarily examine cell-mediated immunity rather than humoral immunity and many of the studies are focused on infection rather than vaccination in infants. In order to move forward, studies investigating infant immune response to vaccination should be conducted in infant animal models of appropriate age as well as in humans. Understanding how vaccination can serve as the imprinting event will inform the development of more efficacious vaccines and better infant vaccination policies. This is necessary work if we wish to keep infants as safe as possible during seasonal influenza epidemics and may also provide the keys to developing a broadly reactive and long-lived universal influenza vaccine that will continue to provide protection into adulthood.


This Research Topic comprises ten articles describing different approaches to study the regulation or maturation of bone marrow adiposity. The conversion of the “red” hematopoietic bone marrow to a “yellow” fatty one is a long-known phenomenon that has been referred to by many names. Bone Marrow Adipocytes (BMAds) have also been revealed as puzzling yet intriguing cells, which could provide exciting novel insights into the pathophysiology and treatment of aging, osteoporosis, anorexia nervosa, obesity and diabetes, aplastic anemia, multiple myeloma, leukemia, bone metastases, and many other clinical conditions. Thus, it is no wonder that enthusiasm surrounding Bone Marrow Adiposity (BMA) research has accelerated in recent years, especially since techniques for the isolation and study of BMAds have become increasingly refined and established . BMAS is an open society with many investigators from diverse fields who have been gathering in working groups to share protocols and experience. Two of those working groups have important publications in this Research Topic , which are sure to provide a foundation with a high impact on BMA research in the future. Other BMAS working groups are now finalizing additional position papers (e.g. for Biobanking), which will provide further important resources for future BMA research.BMAS was founded in 2017 to consolidate the growing scientific community interested in BMA, after the success of meetings organized since 2015. This young society brings together physicians and scientists working on rheumatology and bone biology, oncology, hematology, medical imaging, endocrinology, and metabolic perturbations, for which BMA research provides a new scientific direction. So far there have been five meetings with an excellent standard of keynote lectures and research presentations, in combination with interactive discussions in working groups. Reports from the third and the fourth meetings are presented in this Research Topic . Indeed, BMA can be measured through histomorphometry, computed tomography (CT), and Magnetic Resonance Imaging (MRI), a diversity of techniques that has also led to a confusing heterogeneity. Recommendations of specific terms, abbreviations, and units have thus been discussed and compiled to propose a standardized nomenclature to be adopted by the BMA research community. As observed in the field of bone histomorphometry following the first consensus publication in 1987 . This paper already has received many readings and downloads online, demonstrating that uniformity in methods has become indispensable to boost BMA research not only in quantity but also in quality. Based on the review of the literature and on expert opinions, specific gold-standard methodologies are discussed regarding 1) histomorphometry of BMAds, 2) ex vivo BMA imaging using µCT following the staining with osmium tetroxide or other contrast-enhancing agents, 3) in vivo BMA imaging using MRI techniques in clinical studies, 4) cell isolation, culture, differentiation, and in vitro modulation of primary BMAd and BM stromal cell precursors, 5) lineage tracing and in vivo BMA modulation, and 6) BMA biobanking. Importantly, this second publication highlights the requirements for consensual annotations and standardization in techniques (choice of referent and condition) and provides guidelines for a detailed description of critical experimental parameters to minimize variability and to improve the comparability between studies. Emerging techniques are also described, which may soon come to complement or substitute the gold standards. One of these techniques is histomorphometry by unbiased semi-automatic image analysis; this is thoroughly described in this Research Topic by Tratwal et al. in an original research paper on MarrowQuant, a new image analysis plug-in. Other relevant technical strategies have also been developed and are described in the other associated articles.Another critical need related to methodological standards has also led to a second position paper  properties and BMAT development in rodents and patients with skeletal complications (Costa and Reagan). In doing so, they propose new strategies in conjunction with radiotherapy. The central nervous system is a key mediator of adipose tissue function through sympathetic adrenergic neurons. Wee et al. investigate whether central autonomic pathways are also involved in BMAT regulation using viral transneuronal tract tracing in two mouse strains . After quantifying the local sympathetic adrenergic innervation, they establish that BMAT shares common central neuroanatomic pathways, notably with peripheral adipose tissue, which paves the way for future studies on BMAT functional regulation. An interesting additional hypothesis is that temperature also regulates BMAT through the sympathetic nervous system. Turner et al. report the effects of propranolol in mice housed at 22°C or thermoneutrality to highlight that β-adrenergic receptor signaling contributes to regulating BMAT levels and metabolism without critically impacting on the premature cancellous bone loss observed at room temperature . Chronic hyperglycemia has also been revealed as a promoting factor for adipogenesis within the bone marrow. Rharass and Lucas further investigate the impact of low and high glucose levels on human SSC-derived BMAds and their non-lipid-laden-cell counterparts (Rharass and Lucas). They demonstrate that high glucose concentrations drive only mature BMAds toward an altered phenotype through a rise in reactive oxygen species (ROS) generation. Finally, Dalla Valle et al. evaluate in this Research Topic the handling of free fatty acid (FFA) desaturation in human SSCs to prevent saturated FFA-induced lipotoxicity . Using pharmacological agents to modulate LXR activity, they provide evidence for a protective role of the desaturase enzyme Stearoyl-CoA 9-Desaturase (SCD)1 in human SSC viability during saturated FFA exposure.Many scientists aimed to answer the urgent questions on how BMA is regulated. Several papers in this Research Topic address this subject. A well-known stimulus for BMA accretion is irradiation. It is therefore highly relevant that Most of the research in this Research Topic focuses on the regulation of BMAT and the differentiation routes of SSCs. Elucidation of these entangled pathways is crucial for targeting SSCs or BMAds for the treatment of osteoporosis or other metabolic (bone) diseases. For this ambition, we also need to clarify how BMAds regulate bone cells such as osteoblasts and osteoclasts. Unravelling the cross talk between BMAds and bone cells is crucial not only to target BMAds for improved bone health, but also if we are to uncover other mechanisms important in local and systemic metabolism.NB and SL wrote the manuscript. CR corrected and approved the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Anopheles mosquitoes according to where people spend their time were first developed over half a century ago. However, crude indoor and outdoor biting rates are still commonly interpreted as indicative of human-vector contact patterns without any adjustment for human behaviour or the personal protection effects of ITNs.Effective targeting and evaluation of interventions that protect against adult malaria vectors requires an understanding of how gaps in personal protection arise. An improved understanding of human and mosquito behaviour, and how they overlap in time and space, is critical to estimating the impact of insecticide-treated nets (ITNs) and determining when and where supplemental personal protection tools are needed. Methods for weighting estimates of human exposure to biting A small number of human behavioural variables capturing the distribution of human populations indoors and outdoors, whether they are awake or asleep, and if and when they use an ITN over the course of the night, can enable a more accurate representation of human biting exposure patterns. However, to date no clear guidance is available on what data should be collected, what indicators should be reported, or how they should be calculated. This article presents an integrated perspective on relevant indicators of human-vector interactions, the critical entomological and human behavioural data elements required to quantify human-vector interactions, and recommendations for collecting and analysing such data.If collected and used consistently, this information can contribute to an improved understanding of how malaria transmission persists in the context of current intervention tools, how exposure patterns may change as new vector control tools are introduced, and the potential impact and limitations of these tools. This article is intended to consolidate understanding around work on this topic to date and provide a consistent framework for building upon it. Additional work is needed to address remaining questions, including further development and validation of methods for entomological and human behavioural data collection and analysis. Insecticide-treated nets (ITNs) have accounted for an estimated two-thirds of malaria cases prevented in the past decade . HoweverQuantifying and characterizing gaps in personal protection against mosquitoes, defined as the proportional reduction of biting exposure an individual experiences as a direct result of personal use of a protection measure, requires information on the behaviours of vectors and humans, as well as when and where they intersect. Methods for factoring spatiotemporal interactions between vectors and humans into biting exposure estimates were developed as early as the late 1960s and early 1970s –7. A numA review of published literature between 2000 and 2017 identified fewer than a dozen studies in sub-Saharan Africa that integrated entomological and human behavioural data to enable more meaningful interpretation , 12. LikCrucially, calculation methods for weighting exposure estimates according to human location can alter interpretations when compared to those suggested by entomological observations alone –16. For Despite their utility, such quantitative indicators of when and where interactions between humans and vectors occur remain under-utilized, and no clear guidance is available on what data should be collected, what indicators should be reported, or how they should be calculated. Further, what little methodological literature exists is somewhat scattered, with inconsistent definitions and notation in different reports at different development stages of the methodology .Anopheles such efficient malaria vectors also render them vulnerable to population control with insecticidal personal protection measures like ITNs  go to sleep yesterday?During what time period did [name] wake up today?Did [name] sleep indoors or outdoors last night?If [name] slept indoors, during what time period did [name] finally go indoors for the evening last night?If [name] slept indoors, during what time period did [name] first go outdoors for the day this morning?These questions can be asked in addition to standard survey questions on ITN use described in the current Roll Back Malaria Household Survey Indicators for Malaria Control. Defined categorical options should be offered as answers. For time-related questions 1, 2, 4 and 5, options are hour-long time periods starting every hour e.g. 18:00 to 19:00, 19:00 to 20:00 etc.The variability and reliability of these estimates should be presented using the 95% confidence interval calculated from data sets of adequate sample size, containing multiple observations of human and vector behaviour through space and time. It is possible to estimate sample sizes of proportions by classifying human behaviour or mosquito behaviour into categories. When considering the toolbox of vector control interventions that are currently available, appropriate classifications for human behaviour may be categorised as (1) indoors asleep, (2) indoors awake or (3) outdoors. Similarly, after estimating average bedtime as a cut off, vector mosquitoes may be classified by the proportion of bites that occur (1) indoors before bed, (2) indoors after bed (3) outdoors. While this is a simplification, it is adequate to allow the calculation of minimum sample sizes to precisely detect a specified difference at either the individual (household), or village (cluster) level provided some information on the variability in human and vector behaviour is available a priori to account for differences between villages . Other mAn. arabiensis. With increasing resistance to pyrethroids reported among malaria vectors throughout sub-Saharan Africa, continued indoor biting despite high coverage of ITNs may indicate a need to distribute piperonyl butoxide (PBO) or next generation nets. Likewise, monitoring would provide insights into to whether the proportion of exposure to vector bites occurring outdoors is stable or changing over time, as even small increases in outdoor exposure have the potential to impact transmission dynamics [Ongoing transmission of malaria is a direct result of the overlap between human and vector behaviours, and intervention access and use. It is essential to look at these pieces together for a more complete picture of malaria exposure. This information can inform selection of appropriate vector control tools for implementation in a particular scenario, guide prioritization of interventions in resource-constrained environments, and allows for monitoring of temporal changes in performance of interventions that may be influenced by human and/or vector behaviour. For example, given the Kenya example illustrated in Figs. dynamics . In otheLongitudinal data across seasons can highlight the impact of seasonal variation in vector and/or human behavioural data. For example, in some contexts, people may spend more time outside when the weather is hot, compared to when the weather is cool or rainy , 70. OutThe approach presented in this paper provides improved estimates of biting risk by accounting for the availability of human hosts indoors and outdoors as well as the protection provided by an ITN or other personal protection measures. Beyond biting risk, there are wide-ranging applications for this approach. The key parameter values estimated by considering human-vector interaction can be used as input values and/or to validate host-vector interaction-based models, with the potential to improve their prediction accuracy , 73–76. Previous work has highlighted the importance of heterogeneity in entomological inoculation rates for malaria transmission  as well Further, while the approach presented here is useful for measuring patterns of human exposure to malaria vectors, complementary qualitative data is needed to characterize relevant nighttime activities, sleeping patterns, and intervention use in greater depth, to better understand groups that may be at higher risk, as well as to identify barriers and facilitators to malaria prevention in different contexts , 70, 82.Collecting and integrating a minimum set of human behavioural data elements–the proportion of the human population indoors, asleep, and using an ITN throughout the night–with hourly indoor and outdoor mosquito biting rates can provide a more accurate measure of when and where people are at risk and how best to protect them. This information can help to guide National Malaria Control Programmes in deploying interventions targeting specific vector and human behaviours and inform target product profiles for new tools . If collAdditional file 1: Figure S1a. Directly measured biting rate and human location. Figure S1b and S2a Behavior-adjusted biting rate for an unprotected individual. Figure S2b Behavior-adjusted biting rate for an ITN user. Figure S2c Population-wide mean exposure to vector bites.


Although significant hurdles remain before these findings can be translated into vaccines and other protective strategies, they should lend optimism to the prospect that neonatal and even fetal vaccination is achievable. Next steps toward this goal should include efforts to define the conditions for optimal stimulation of infant immune responses, including antigen timing, dose, and route of delivery, as well as antigen presentation pathways and co-stimulatory requirements. A better understanding of these factors will enable optimal deployment of vaccines against malaria and other pathogens to protect infants during their period of greatest vulnerability.Childhood vaccines have been the cornerstone tool of public health over the past century. A major barrier to neonatal vaccination is the “immaturity” of the infant immune system and the inefficiency of conventional vaccine approaches at inducing immunity at birth. While much of the literature on fetal and neonatal immunity has focused on the early life propensity toward immune tolerance, recent studies indicate that the fetus is more immunologically capable than previously thought, and can, in some circumstances, mount adaptive B and T cell responses to perinatal pathogens  The human infant has long been considered immunologically immature, or deficient, when judged against the yardstick of the adult immune system. Indeed, the fetus and newborn are vulnerable to severe disease and high morbidity from numerous pathogens that cause only mild disease in older hosts. It had previously been believed, based largely on extrapolation from mouse models of immune development, that the tolerogenic intrauterine environment is incompatible with the priming of fetal T cells or results in marked polarization of CD4 T cells toward a Th2 response over a Th1 response. However, it is now appreciated that human fetal immune development differs quite markedly from that of the mouse. Neonatal mice are profoundly immunodeficient—indeed, migration of murine T cells from the thymus begins only after birth. In contrast, during human gestation, T cells appear in the fetal liver at week 10 and T cell zones can be seen in the spleen during week 18 .in utero, and findings from this model bear relevance to other parasitic pathogens. Annually, more than 125 million pregnancies occur in areas where malaria is endemic  have been detected in the cord blood of malaria-exposed infants as early as 22 weeks gestation  or from a tolerogenic cytokine environment. A better understanding of the conditions  that foster the priming and development of functionally competent pathogen-specific T cells (while avoiding induction of pathogen tolerance) could be of fundamental importance for efforts to develop vaccines that are optimally immunogenic in infancy.Together, these data indicate that the essential machinery for generation of robust T and B cell responses to pathogen-derived antigens is present during fetal life. They further suggest that the mechanisms that curb T cell inflammation The maternal and fetal blood supply are separated by a single multinucleated cell layer termed the syncytiotrophoblast. Once malaria antigens or immune complexes cross the syncytiotrophoblast barrier, it is not clear where, how, and by “whom”  they are taken up, processed, and presented to lymphocytes . This isIn adults, myeloid-lineage cells such as dendritic cells (DCs) and monocytes play a principal role in antigen presentation, although activated CD4 T and B cells also upregulate HLA-DR and can present antigen –28. In tex vivo human placental perfusion model, upon transplacental transfer immune-complexed MSP-1 was observed in the fetal villous stroma where it predominantly co-localized with fetal endothelial cells, not Hofbauer cells  exhibit robust antigen presentation capabilities upon activation  in the fetal and infant immune response to malaria has received little research attention. Fetal NK cells that develop early in gestation can respond robustly to antibody mediated and cytokine-induced stimulation, but respond weakly to HLA-devoid cells and are more susceptible to TGF-β mediated suppression . At birtnfection . In lighnfection , these fDuring gestation, maternal antibodies are transferred across the placenta to the fetus via an active transport mechanism mediated by FcRn, the neonatal Fc receptor. FcRn is expressed on syncytiotrophoblast cells beginning at approximately 13 weeks gestation , and selMaternally derived antibodies are essential for infant protection from some pathogens that are commonly encountered during infancy. In the case of malaria, the importance of this passive maternal antibody transfer is not clear. It has been widely promulgated that transplacental transfer of antimalarial antibodies is responsible for the relatively low incidence of symptomatic malaria during the first 6 months of life. Yet, a thorough review of this literature found scant evidence to support a protective role in infancy, concluding instead that malaria-specific IgG in cord blood merely serves as a biomarker of maternal exposure . It shouIgG subclass and glycosylation can both greatly influence the efficiency of transplacental antibody transfer by FcRn . The oveex vivo placental perfusion model (In addition to conferring passive immunity, maternofetal antibody transfer may play a role in conveying pathogens and pathogen-derived antigens to the fetus in the form of antigen-antibody complexes. While some malaria antigens may breach the maternofetal barrier due to focal denudement of the syncytiotrophoblast cell layer, the more common route of transfer is likely via FcRn-mediated active transport of antigen-antibody complexes , 36, as on model –68. HencThe ultimate goal of better understanding the components of the fetal, neonatal and pregnant immune systems is to enable the translation of this knowledge to vaccine development. Late stage trials are underway for vaccines to prevent placental malaria by inducing maternal antibodies against VAR2CSA, a pregnancy-specific adhesion ligand that is thought to be an important mediator of placental adherence . The goain utero raises the additional question of whether active immunization of the fetus may indeed be possible. Such a strategy would be dependent upon delivery of antigen to the fetus in a context that favors priming of antigen-specific fetal T and/or B cells. The demonstration that fetal B and T cells are primed naturally in response to placental malaria in some infants (in utero vaccination may seem like a far horizon, these observations provide proof of concept that induction of protective immunity prior to birth may be possible. However, efforts toward fetal immunization would need to address the potential for induction of pathogen-specific tolerance in utero, which has been reported in some malaria-exposed infants (Mounting evidence that adaptive T and B cell responses can be primed  infants , 8 shoul infants . While i infants , 80.in utero, providing grounds for optimism that they may respond to vaccination. In order to harness this intrinsic capability to engender durable antigen-specific memory in neonates, we will need to refine our understanding of which APCs are most able to prime fetal and neonatal immune responses and which adjuvants are best able to target and stimulate these APCs.As pregnancy progresses, the fetal immune system gradually evolves from one that is skewed toward tolerance to one that is poised to fight foreign pathogens. The research agenda for translating recent advances in our understanding of fetal and neonatal immunology into vaccines that are safe and immunogenic when administered in early infancy is now coming into focus. Understanding how to best prime adaptive immune responses in the neonate is critical, due to both the increased susceptibility of newborns to infectious diseases and to the increased healthcare contact of this vulnerable population at the time of birth. This will be particularly important in the context of malaria vaccines, as the vast majority of malaria deaths occur in children under the age of five. Recent evidence from studies of infants exposed to perinatal pathogens indicates that fetal B and T cells can be primed and differentiate into effector cells PC, LF, and MF wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.