There are many different factors involved in how and why people develop problems with video game playing. One such set of factors concerns the structural characteristics of video games . Much of the research examining the structural characteristics of video games was initially based on research and theorizing from the gambling studies field. The present review briefly overviews the key papers in the field to date.The paper examines a number of areas including (i) similarities in structural characteristics of gambling and video gaming, (ii) structural characteristics in video games, (iii) narrative and flow in video games, (iv) structural characteristic taxonomies for video games, and (v) video game structural characteristics and game design ethics. Many of the studies carried out to date are small-scale, and comprise self-selected convenience samples .Based on the small amount of empirical data, it appears that structural features that take a long time to achieve in-game are the ones most associated with problematic video game play . The study of video games from a structural characteristic perspective is of benefit to many different stakeholders including academic researchers, video game players, and video game designers, as well as those interested in prevention and policymaking by making the games more socially responsible. It is important that researchers understand and recognize the psycho-social effects and impacts that the structural characteristics of video games can have on players, both positive and negative. Problematic video game playing is multifaceted rather than a unitary phenomenon. Consequently, many factors may come into play in various ways and at different levels of analysis . Put very simply, there are many different factors involved in how and why people develop problems with video game playing. Central to this view is that no single level of analysis is considered sufficient to explain either the etiology or the maintenance of video game playing behavior. This perspective asserts that all research is context-bound and should be analyzed from a biopsychosocial perspective . One setMuch of the theoretical and empirical work on structural characteristics in video games has borrowed concepts and terminology from the gambling studies field. Work in the 1990s by Griffiths , 3 demonA number of authors have noted the structural, behavioral, and psychological similarities between specific forms of gambling games  and video games , 11•, 12World of Warcraft (WoW) players (described as “heavy users”), Karlsen reported that near misses and entrapment were present in WoW  and influenced by other elements such as social engagement and competition (elements that might have a strong effect on propensity to play excessively).In the gambling studies field, there are now dozens of published experiments that have manipulated various structural characteristics and demonstrated that such features can prolong gambling compared to games without such features. This includes many experiments demonstrating that “near misses” can increase arousal levels and facilitate repeated gambling –26, as wGriffiths and Wood  in a revSound Graphics .Background and setting .Duration of game .Rate of play .Advancement rate .Humor .Control options .Game dynamics .Winning and losing features .Character development .Brand assurance .Multiplayer features .The first paper to empirically examine multiple structural characteristics in video game playing was by Wood, Griffiths, Chappell and Davies •. In a sWood et al. • reporteOther studies have reported that specific structural characteristic in-game can motivate video game play. For instance, an experiment by Chumbley and Griffiths  assessedAnother study that examined a single gaming structural characteristic was by Qin and colleagues  who deveinteractive than other media, a video game designer can hide part of the story, encouraging the player to explore the game world. Two main aspects define interactivity. The first is that the story is shaped both by the gamer’s way to interact with the game’s character(s) and by how they choose to overcome the difficulties. The second mainly concerns Massively Multiplayer Online Role-Playing Games (MMORPGS), and relates to the way players interact with each other in-game. The uncertainty  causes players to move swiftly into the narrative and helps them to more fully understand it. Another important point in the video game narrative is its game structure which, according to the conflict-driven model analysis [Given that video games are more analysis , is compembedded narrative and emergent narrative. The first is the core narrative that exists in the game without the player intervention. The second is constructed via the player’s interaction with the game. Majewski [According to Salen and Zimmerman , there aMajewski  asserts antecedents , experience , and effects . With respect to the playing of video games, flow refers to the intense enjoyment of immersion while gaming [Chen, Wigand, and Nilan  claim the gaming . Conseque gaming . Becausee gaming .Curiosity: Arousal of senses and cognition and attraction to explore game narrative.Concentration: Ability to concentrate long-term on the game narrative.Challenge and skills: Some relative difficulty in the game narrative for players and corresponding players’ skills.Control: Ability to exercise a sense of control over game narrative.Comprehension: Understanding the structure and content of the storyline.Empathy: Mentally entering into the imaginary game world while playing the game.Familiarity: Being familiar with the game story.The study by Qin et al.  exploredThe authors recommend their instrument be used by any researchers exploring the relationship between narrative and immersion, although the applicability in terms of problematic gaming was not mentioned at all in the study.n = 110) were asked questions assessing video game addiction , the exon Scale •, flow , and haon Scale ). Findinon Scale ) did notLaffan Greaney, Barton, and Kaye • noted tThe authors reported that flow correlated significantly with the social features, reward features, punishment features, and presentation features although only the punishment features  and presentation features  significantly predicted flow level after carrying out a hierarchical multiple regression. Flow was most likely to occur when the gamers rated presentation and punishment as important in gameplay. This appears to make sense because the player must encounter some difficulties (via punishment features) and be immersed in the game (via presentation features) to experience flow. General happiness only weakly predicted flow. The authors concluded that presentation and punishment features facilitated flow experiences because the punishment aspects of video game playing may be contributory factors to the difficulty of playing and the amount of effort needed for a state of flow to be reached.social features), (b) gamers’ roles in influencing in-game outcomes (manipulation and control features), (c) gamers’ roles in character creation and interactive storytelling (narrative and identity features), (d) ways in which gamers win and lose in-game (reward and punishment features), and (e) auditory and visual presentation of video games (presentation features)  of using a game controller. The most highly rated structural features by problem gamers were earning points, managing in-game resources, mastering the video game, and getting 100% in-game. The commonality among these features is that they are those that take up far more playing time than other structural features. Using a multiple regression statistical analysis, it was also demonstrated that specific types of structural characteristic appeared to be better predictors of problematic gaming than factors such as age, gender, and the time spent gaming weekly. The study by Hull et al.  outlinedcasual gamers , (ii) social gamers , (iii) solo limited gamers , (iv) solo control/identity gamers , (v) story-driven solo gamers , and (vi) hardcore online gamers . The study also found that the in-game sound effects and graphics facilitated a more immersive and realistic context for the video game’s rewards and storytelling design. Almost all gamers (apart from the solo control/identity gamers) highlighted the necessity for realistic graphics and high-quality sound.Using a different methodological approach, Westwood and Griffiths • developfantasy, challenge, narrative, expression, discovery, fellowship, sensation, and submission). The DPA taxonomy was developed to describe the design for serious video games and added other categories to the MDA taxonomy including learning, competition, altruism, and physical activity. Although both of these taxonomies concern video game design, neither features what would classically be seen as featuring structural characteristics and neither has been empirically investigated.Other taxonomies of video game design have been developed including the “Mechanics, Dynamics and Affect” (MDA ) taxonom3D graphics, realistic graphics, collect things, search for hidden things, explore things, fantasy world, play with friends, single player, more than one player, other gender, other race, other species, challenging obstacles, difficult to master, display skills in public, high core, and play online). More specifically, they examined the relationship between structural characteristics and personality by assessing 15 sub-traits of the Five Factor Model using 60 items from the International Personality Item Pool-Neuroticism, Extraversion, and Openness ; exploration, referring to the enjoyment of exploring, collecting, and finding hidden items (12%); fidelity, referring to the realism of the game (9%); companionship, referring to the pleasure of playing with friends or in multiplayer environments (9%); challenge, referring to mastery and overcoming obstacles (8%); and competition, referring to displaying one’s skills and competing with others (7%).They surveyed 293 participants . Two sets of analyses were conducted: firstly, a factor analysis to determine the factors concerning game design, and secondly a cluster analysis to explore associations between video game structural characteristics and personality. The factor analyses on game characteristics yielded six factors explaining 58% of the video game preference variance. These were subsequently labeled Dutiful companions: Comprising 21% of the participants and playing for an average 1 h per week. Of these, 27% preferred playing alone, 44% with one other, and 27% with more than one other.Extraverted fidelitist companions: Comprising 19% of the participants and playing for an average 2.4 h per week. Of these, 26% preferred playing alone, 18% with one other, and 53% with more than one other.Imaginative fidelitist explorers: Comprising 17% of the participants and playing for an average 3.6 h per week. Of these, 29% preferred playing alone, 31% with one other, and 35% with more than one other.Conscientious companions: Comprising 16% of the participants and playing on average 1.34 h per week. Of these, 19% preferred playing alone, 46% with one other, and 35% with more than one other.Introverted challenge-seeking fidelitists: Comprising 15% of the participants and playing on average 1.39 h per week. Of these, 47% preferred playing alone, 33% with one other, and 19% with more than one other.Calm challenge-seeking companions: Comprising 12% of the participants and playing on average for 1.37 h per week. Of these, 16% preferred playing alone, 9% with one other, and 72% with more than one other.The cluster analyses used the six factors above and 15 personality traits  to create a typology of six sub-groups of player. The optimal solution contained six clusters:When comparing the six factors with the MDA  and DPE Starcraft II, a short game can last less than 10 min, while others can last much longer such as Age of the Empire 2).When discussing taxonomies of structural characteristics, it is also worth noting that there are of course different genres of online games such as Massively Multiplayer Online Role Playing Games (MMORPGs), First-Person Shooter (FPS) games, Multiplayer Online Battle Arena (MOBA) games, and Real-Time Strategy (RTS) games. However, these online game genres are not structural characteristics because structural characteristics are the elements and components of the video games and not the games themselves. For instance, in the gambling studies field, genres equivalent to RTS or MOBA games might be games like online poker or blackjack whereas MMORPGS might have more in common with online bingo because of the highly social elements of the games. Games in both the gambling and video game fields comprise different genres but the genres themselves are not structural characteristics and should not be thought of as such. However, while most research examining problematic gaming has tended to focus on MMORPGs, there is a growing body of research that has compared different genres of online games –67, reseMore recently, Klemm and Pieters • examineHowever, as a number of authors have pointed out, structural characteristics and individual characteristics can impact on each other. Griffiths , 3 notedKlemm and Pieters also note that when game developers create software for a video game, they will “impose” a behavior to the user either consciously  or unconsciously . They claim that coding to modify a video game player’s behavior is common in MMORPGs . To help overcome problematic play, they assert that game designers should incorporate “technological mediation” . The purpose of such mediation is not to force players to adopt a particular behavior but to make them “choose” a more constructive behavior rather than a more “destructive” one. The authors claim that such mediations could work via emotions on three different levels  but focus their analysis on the behavioral level and examine the “function and use of a product” as they believe that this is the most crucial aspect in gaining insight into the development of problematic gaming.Klemm and Pieters claim that several game mechanics trigger player emotions, and thus impact on their subsequent behavior (mainly resulting in the continuance of playing within session). One game mechanic included in all MMORPGs is the reward system involving the use of operant conditioning that leads to repetitive play because the player cannot predict when the next reward  will be provided within-game. Another game mechanic used in video games to enhance time spent in-game is the social interactions. MMORPGs are designed to make it very hard—if not impossible—in some games to advance in-game alone. Basically, individuals have to form strategic partnerships and work as a team to advance and that some quests within the game can take hours at a time. One person leaving the game—even if they have been playing together for hours—can lead to failure for the whole group in-game. Players become socially obliged to play even if they do not want to or do not really have the time to play.coercive , persuasive , seductive , and decisive . The authors claim that the game mechanics of MMORPGs mechanics are mostly seductive, although some players may be aware of such mechanics, shifting such mechanics to being persuasive . Such mechanics do not have to be negative, as some MMORPGs include game mechanics reducing the time spent in a single session . However, many games require daily log-ins to the game to gain experience bonuses).Klemm and Pieters evaluated the ethics of video game design mechanics utilizing Tromp et al.’s  model ofThe authors also offer several ways to improve the game mechanics in a way that would lead to less problematic use. For example, more transparent fixed chances to get an item would allow the players to know how long they may need to play before getting an item, thus preventing some from engaging in a long activity. They also propose a linear leveling system where it would take as much time to get between levels 1 and 10, as between 40 and 50. Some countries  have introduced “fatigue systems” for minors who after 3 h of gaming, start to punish the individual if they continue the play the game  .Such examples have a purpose to remove game mechanics that may lead to addictive use, but Klemm and Pieters highlight other game mechanics that promote a healthier use of video games. For example, the awarding of badges, rewards, or bonus experience for players not connecting more than 20 h per week. Furthermore, displaying the time spent on the game clearly to players would help them realize when they have been playing for too long, helping them to reduce the length of future sessions. Such recommendations also echo the thoughts of other scholars , 73 who Compared to other areas such as those examining the psychological and biological underpinnings of problematic and addictive video game play, far less research has examined from a structural characteristic perspective. This is also mirrored in other similar areas (such as the research investigating problematic and addictive gambling) but even when compared to other similar areas, there is still far less empirical evidence in the gaming studies field. Eclectic and multitheoretical approaches are needed if we are to understand the relationship between structural characteristics and video game addiction. Based on the evidence to date, the research appears to demonstrate that some structural characteristics of video games at the very least have a contributory role in the acquisition, development, and maintenance of problematic and addictive video game playing. Clearly more research is needed to establish which structural features appear to be most associated with problematic gaming but it appears that features that take a long time to achieve in-game are (unsurprisingly) the ones rated highly by problem players .There is clearly robust theory underpinning why some structural characteristics contribute to addictive video game playing. For instance, operant conditioning helps explain why gamers experiencing problems highly rate structural features such as experience points, rapid loading times, meta-game rewards, and collecting rare in-game items. Many of these rewards operate on variable reinforcement schedules, known to facilitate a repetitive response patterns to stimuli over time and which are often resistant to behavioral extinction. However, there are many structural characteristics where operant conditioning theory is less able to explain the rewards gained by players when interacting with a video game .Given the recent emergence of research in this particular area, it is unsurprising that many of the studies carried out to date are small-scale, comprise self-selected convenience samples, and are tentative in their conclusions. Most of the research in the area has utilized self-report survey studies or non-ecologically valid laboratory experiments. Future studies should perhaps explore the nature and experience of structural characteristics while gamers are actually playing in their normal gaming context, rather than via retrospective self-report surveys or playing games for unnatural restricted periods in laboratory experiments. One way forward in the field would be for gaming operators to provide access to real-time behavioral tracking data of players so that researchers can conduct secondary analysis of player behavior in relation to specific in-game structural characteristics. This has already started to happen in the gambling studies field with analyses of the impact of structural and situational characteristics on the behavior of slot machine players , 78.The further study of video games from a structural characteristic perspective is of benefit to many different stakeholders. This includes (i) academic researchers who can further understand and integrate a structural perspective into the biopsychosocial model of addiction and apply this knowledge to assist problematic games and help develop effective prevention and intervention programs and strategies, (b) video game players, who can be further educated concerning potentially harmful structural features which may help prevent problematic play, and (c) video game designers, who can then develop video games to include more appealing and rewarding features that promote long-term consumer loyalty without exploiting players. Other stakeholders that may benefit are policymakers and those interested in prevention who could apply some of the findings outlined into their own policies and programs. Video game technologies are ever evolving and becoming increasingly varied and interwoven into contemporary society. Therefore, it is important that researchers understand and recognize the psycho-social effects and impacts that the structural characteristics of video games can have on players, both positive and negative.


Coleoid cephalopods  are renowned for their elaborate body patterning capabilities, which are employed for camouflage or communication. The specific chromatic appearance of a cephalopod, at any given moment, is a direct result of the combined action of their intradermal pigmented chromatophore organs and reflecting cells. Therefore, a lot can be learned about the cephalopod coloration system by video recording and analyzing the activation of individual chromatophores in time. The fact that adult cephalopods have small chromatophores, up to several hundred thousand in number, makes measurement and analysis over several seconds a difficult task. However, current advancements in videography enable high-resolution and high framerate recording, which can be used to record chromatophore activity in more detail and accuracy in both space and time domains. In turn, the additional pixel information and extra frames per video from such recordings result in large video files of several gigabytes, even when the recording spans only few minutes. We created a software plugin, “SpotMetrics,” that can automatically analyze high resolution, high framerate video of chromatophore organ activation in time. This image analysis software can track hundreds of individual chromatophores over several hundred frames to provide measurements of size and color. This software may also be used to measure differences in chromatophore activation during different behaviors which will contribute to our understanding of the cephalopod sensorimotor integration system. In addition, this software can potentially be utilized to detect numbers of round objects and size changes in time, such as eye pupil size or number of bacteria in a sample. Thus, we are making this software plugin freely available as open-source because we believe it will be of benefit to other colleagues both in the cephalopod biology field and also within other disciplines. Cephalopods are renowned for their rapid body pattern change capabilities utilized in camouflage or communication  for information processing, and a muscular skin for generating patterns  resolutions and at a high frame rates. Current HD commercial cameras (and even some smartphone devices) can record videos at 1,280 × 720, 1,920 × 1,080, and 2,560 × 1,440 pixel resolutions. These cameras can also record footage at 60, 120, and 240 frames per second (FPS) in NTSC format. More expensive camcorders can record at even higher resolutions (Ultra HD) and higher frame rates.Recording at higher resolutions helps improve data acquisition, as each chromatophore is represented by more pixels and has more detail compared to lower resolutions. A higher framerate of acquisition has a shorter interval between consecutive frames and collects more images of chromatophores per second. The amount of detail per image and the rate of continuation between frames become extremely important for the task of detecting, tracking, and measuring individual chromatophores. This enables researchers to study specifics of the chromatophore sensorimotor system as a whole  in a living animal. Therefore, higher quality video acquisition improves data collection and makes data analysis more manageable.However, because of the additional information being stored per frame, and with more frames being recorded per second, the size of HD videos at high frame rates climbs to several GB per minute of recording. This is an important point because a larger video file will require additional processing time and computing resources which may disrupt or end altogether the normal software analysis process.The following steps are necessary to extract chromatophore activity data from a series of images: (1) detect individual chromatophores and remove unnecessary background information, (2) track each chromatophore in time and space  and, (3) measure chromatophore surface area and color. One of the main issues with analyzing individual chromatophore data has to do with the large number of objects of interest to be measured. Depending on cephalopod species and magnification level used for video recording, the observer may be looking at a few individual chromatophores on a newly hatched animal or up to a few hundred to thousands in an adult animal. Manual processing of all the chromatophores becomes extremely cumbersome, if not impossible. Therefore, an automatic system of detecting, numbering, and tracking each chromatophore (both in space and time) becomes essential for such analysis.There have been a few published studies in the cephalopod biology field which mention use of image analysis tools to measure individual chromatophore activity from video recordings  is used to import and read video files (.avi format) of chromatophores or other objects of interest to be analyzed.TrackMate (http://imagej.net/TrackMate) detects and tracks every spot for the entire length of the video. Also, TrackMate keeps a record of every spot's X, Y coordinates from every frame for later reference. Lastly, it allows users to filter out spots that are of no interest.Particle Analyzer  analyzes and keeps track of the Regions of Interest (ROIs) in each frame and measures the area of each spot.Measure Color (author: George El Haddad) is a simple algorithm that retrieves the central X, Y coordinate of each spot (with the help of TrackMate) and return the Red, Green, and Blue (RGB) values for the spot.Apache POI (https://poi.apache.org/) is a fast and highly scalable library used to export data to a Microsoft Excel file (.xlsx). It is capable of generating large Excel files, depending on the amount of data to be exported.The following steps outline the procedure used by SpotMetrics to filter images and enhance chromatophore detection, tracking, and measurement.Program processes the imported video by converting all frames to 8-bit gray scale.Uses Fiji's Auto Threshold on every frame (method = “Default”) to remove background and keep spots (chromatophores) for further analysis.Image processing and background subtraction:Analyze objects in image to identify/detect spots in each frame.Based on user settings (spot size), filters out spots that do not fit in selected category.Each spot is identified by a unique number.Track spots of interest over the length of video to collect data on size and color.Spot detection and tracking:First spreadsheet lists the surface area (in pixels squared) of each spot per each frame.Second spreadsheet lists the RGB values of each spot per each frame.The program will generate an Excel file containing two spreadsheets with size and color measurements for further analysis:Data output.For first-time users, we recommend to run the program using the default options initially and to adjust settings for subsequent analyses based on results.1. Run Fiji .Note on video file format compatibility: The user must first convert all video files to be used with SpotMetrics into the.avi format. This is a requirement of the AVI_Reader library that is used here to import video files: “4. The user has the option to crop part of the video at this point by using the Fiji available editing tools.Keep the default settings for the initial run. The default settings will be “subtract background: 50” and “dark background” unchecked. Threshold method will be set to “default.”5. Click on the “Processing” tab to set video processing options Figure .Keep thAll measurements are in pixels, so set the “blob diameter” to a value close to each spot. For example, the default blob diameter is set to “10” pixels.The “blob threshold” value. Any chromatophore smaller than this diameter will not be tracked. Thus, if the user is only interested on larger spots, then a lot of the smaller ones can be filtered out using this setting.Linking max distance set to “15”Gap closing max distance set to “15”Gap closing max frame gap set to “2”Initial spot filter value set to “0”For the remaining options, we recommend leaving the default values as is:6. Click on the “Tracking” tab to set the spot tracking options Figure .All meaSet the square area of the particle to detect (this is in pixels squared).Set the circularity of the particle being detected where 1.0 is a perfect circle.7. Click on the “Analysis” tab to set particle analysis options Figure .Set the8. Set the initial ROI offset for each spot that the particle analyzer will scan inside of. This is the initial box that will be drawn around each spot; the particle analyzer will scan inside this box so this has to be more or less accurate. If not, it can be tweaked later.9. Click “Start” to initiate analysis.Once the program has analyzed the video and measured spot properties, the user can run diagnostic tests to see how many spots have missing data and apply edits to fix the issues.When analysis is done and the spots are listed in a tree menu: Figures , 8.This instructs the plugin to perform a particle analysis based on the “Particle Analyzer” options under the “Analysis” tab.In the tree menu, right click on any track and select menu item “Diagnose All Tracks”Number of spots per track.Number of tracks with missing spots.The “scan results” report indicates:From this point in analysis, the user can manually edit each track that has missing spot measurements in specific frames.The ROI around the spot will turn from magenta to blue to indicate it is being edited.Click the “Next” button to scan frames forward to find the spot that is not being detected by the particle analyzer.Normally the issue is that the spot touches the ROI boundary, either because the is ROI is too small or slightly offset.Adjust the blue ROI with the mouse so that it properly encapsulates the spot and has at least a one-pixel gap between.Click “Update ROI.”Continue until all frames are accounted for then close the “Edit Track” pop-up window.1. Right click and select menu item “Edit Track”Make sure that all the spots are properly detected and there is no missing information from any frames.2. Right click and select menu item “Analyze—Show Results.”Also, the user can delete any track from the tree menu:3. Right click and select menu item “Delete Track.”4. Click the “Export Excel” button and choose a directory and filename to save the chromatophore data in an Excel sheet. You can create graphs to visually inspect the chromatophore activity Figure .5. Click on the “Export Overlay” button to render a new video in which each tracked spot is shown with its outline as an overlay Figure . Each spSpotMetrics makes heavy use of CPU and RAM resources which are reallocated to speed up the analysis. The processing time of SpotMetrics is estimated by the number of chromatophores/spots that are detected within a given video file. If the plugin has to analyze 100,000 spots, the processing time will be significantly longer than analyzing 1,000 spots. We highly recommend using a PC with a modern processor to run this plugin. In addition, users should avoid having other utilities run in the background while SpotMetrics is processing data.The success of this plugin depends heavily on the image quality of the imported video files. For example, chromatophores/spots that appear out-of-focus/blurry will be more difficult to be detected and tracked by the plugin. In turn, the plugin will extract less information from such videos compared to recordings in which chromatophores/spots appear in more detail Figure .In addition, shaky footage, or lots of movement of chromatophores in the video can decrease the efficiency of detection and tracking over time. If the chromatophores/spots are displaced in the 2D domain rapidly, then the program will have difficulty tracking them for the entirety of the video. However, this can be corrected, up to a point, by applying a stabilization tool over the original video, using popular video editing software such as Sony Vegas Pro or Adobe After Effects. Nevertheless, we advise to proceed with caution whenever using video effects in this manner as to avoid modifying the recorded video in ways which may alter the image and add artifacts.Cephalopod chromatophores are stacked in a vertical hierarchy (see section Effectors). Depending on the species, the top layer consists of either the largest chromatophore type (such as in some octopus species) or the smallest (such as in some squid species). The specific chromatophore arrangement becomes important when considering SpotMetrics detects and tracks objects within a 2D image; if two objects in a 3D environment are situated in such a way that the larger object is directly above a smaller object, then when converting the image to 2D, the larger object will appear to cover the one below when viewed from a top-down perspective. In this case, the smaller object below is not available for observation and thus SpotMetrics will not detect it.When examining cephalopod body patterning, if a video sequence consists of fully expanded chromatophores within the top layer of Octopus skin, and given this type of chromatophores is the largest, then the smaller chromatophores below could be completely covered and hidden from observation from a top-down perspective. In this example, SpotMetrics would not be able to detect the hidden chromatophores, and would instead detect, track, and measure only the top layer of chromatophores. Therefore, to prevent this ommission when studying the chromatophore activity from a top-down perspective, it's vital to consider this fact to choose an appropriate choice of cephalopod species to study.SpotMetrics' value as a research tool comes in the form of automation and simplification for the researcher. This plugin would take several days' worth of manual processing down to an hour with just a few clicks in a user-friendly graphical environment. It does so by utilizing the power of existing algorithms, tools, and libraries provided by the scientific imaging open-source community and combining them for the use of tracking and analyzing spots.Without a plugin such as SpotMetrics, a researcher would have to use a different plugin for each of the following steps: (1) to filter video data based on the contrast of the image and to remove unnecessary background information, (2) to identify and use the right method to detect spots in a video, (3) track spots over a duration of time and through space, (4) to analyze the spots that have been tracked for their color properties, (5) to analyze spots for surface area changes, and (6) to extract and collect the data from each individual tool and consolidate them into an organized spreadsheet ready for statistical analyses of results. Undertaking each of the above steps manually is technically possible. However, in this scenario, the researcher would have to spend a considerable amount of time on research, and trial-and-error process, in getting the output from each plugin to be formatted appropriately to be used as input for the next step. SpotMetrics automates all the above processes, saving the researcher valuable time which would have otherwise been spent on researching and troubleshooting each method.SpotMetrics can be used in a variety of image analysis procedures with the goal of detecting, tracking, and measuring circular objects over a period of time. This plugin was developed with the primary goal to contribute to existing studies on sensorimotor integration control of the chromatophore system in cephalopods. We believe this tool will be helpful to researchers who wish to examine chromatophore activity as a response to sensory stimulation to better understand the underlying mechanisms of both sensors and effectors. For example, SpotMetrics can be used to measure chromatophore responses when animals are tested behaviorally under different chemical agents, presented with different background information, or presented with a potential predator, prey, mate, or competitor.Similar to cephalopod biology studies, SpotMetrics can be of benefit to researchers who study chromatophore and melanophore systems in fish and reptiles. Lastly, this software can potentially be utilized to detect numbers of round objects and size changes in time, such as pupil dilation studies or number of bacteria in a sample.We are making SpotMetrics freely available under the GPL license. The source code will be made available on the GitHub repository which will enable easier access to the latest update of the program. We'd like to extend an invitation to interested parties who may want to collaborate on improving this plugin by adding customized features and expanding the scope of the software in analyzing experimental data.The animals used in the present study were squid. There was no requirement for this study to be approved by an ethical committee since at the time this study took place  the Institutional Animal Care and Use Committee (IACUC) protocols were not issued for invertebrate research in the USA. Nevertheless, we took every precaution to ensure the animals were under the least amount of stress possible and were not harmed in this study. Furthermore, the animals were allowed to acclimate when transported from housing to the experimental rig and vice versa. The study was observational and the animals were not subjected to any invasive methods.SH contributed to the conception and design of the work. SH contributed to the drafting the manuscript. SH gave final approval for this version to be published. SH agrees to be accountable of all aspects of work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GE contributed to the software development presented in this paper. GE contributed to revising the manuscript. GE gave final approval for this version to be published. GE agrees to be accountable of all aspects of work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The study was supported by a doctoral student research grant from the Graduate Center of the City University of New York to SH.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JJC and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


As one of the most important applications in peer-to-peer (P2P) networks, the video-on-demand (VoD) system freely supports video cassette recorder (VCR) operation for users. However, the users may experience significant playback delay after frequent VCR operations in the VoD system, which will affect the quality of experience (QoE) of the users. Hence, selecting an appropriate data-prefetching strategy to support better VCR operation is an important approach to improve the QoE. This paper proposes a data-prefetching strategy (DSA) to determine the most suitable anchor interval by considering the playback delay and positioning satisfaction. According to the DSA, we use the multiple-attribute decision-making (MADM) theory to model the selection of intervals of prefetching data blocks  and the technique for ordering preference by similarity to an ideal solution (TOPSIS) algorithm to solve the MADM. The simulation results show that the DSA strategy obtains higher positioning satisfaction than the existing schemes, which is approximately 60% higher than the anchor points, popular parts of video, and user interests (API)-based method. Moreover, with the increase in network bandwidth, the DSA strategy can minimize the playback delay after VCR operation using relative few extra bandwidths. In recent years, with the rapid development of internet and multimedia technology, increasingly more users have gained access to high-speed internet, and the service of online video-on-demand (VoD)  has beenCompared with the live video system, a significant feature of the VoD system is that it can support the users to perform video cassette recorder (VCR) operations   theory . Based oThe remainder of the paper is structured as follows. The model of the P2P-based VoD system is described in Before stating the research of the data-prefetching strategy, it is necessary to introduce the P2P-based VoD system. This system is an overlay network  built beAs illustrated in When a CN goes online, it must first register with the TS. After the registration is successful, the servable video list of this region is sent to this CN by the TS. The users can select the video that interests them from the video list. After receiving the user’s selection, the CN must determine the download order of the video segments according to the segment selection algorithm. Then, the CN requests the servable peers from the TS and sorts the servable nodes. After selecting the most suitable node as the content provider, the CN can download video segments in order. It is notably important to improve the user’s viewing experience by determining a suitable order to download the video segments, which we will introduce in detail in the following chapters.The segment-downloading sequence affects the viewing experience of the user in the P2P-based VoD system. Therefore, many segment selection strategies were proposed. To support the particularity of the VCR operation in the P2P-based VoD system, data-prefetching strategies were introduced as a specific segment selection strategy, i.e., downloading the data before the current playing point in advance, which is designed to reduce the playback delay after VCR operations. The most mature data-prefetching strategy is the anchor point strategy . When thFirst, we discuss the anchor duration. Each anchor must be a block that can be independently played. Based on the content fragmentation strategy in the P2P-based VoD system in Second, to study the anchor interval, we must consider two factors: playback delay and positioning satisfaction.The playback delay is the time the CN takes to resume playing the video after a VCR operation, as illustrated in When the anchor duration is fixed, if the anchor interval increases, the anchors that are perfected with identical residual download bandwidths will have a wider distribution in the video. When the user randomly jumps to a certain point using a VCR operation, the probability that the anchor near the point that has been downloaded increases, and the probability that the user experiences a delay decreases. Therefore, the average playback delay decreases.We simulated the VCR behavior of a VoD system. The fast-forward and -backward operations compose a notably small percentage (approximately 1%) of the user’s actual operations. As mentioned in ,16, mostThe length of each jump in the VCR operation complies with Weibull distribution , and theAfter the video was played for 1 min, the user randomly performed 20 VCR operations; then, the average playback delay was recorded. As shown in When the user performs a VCR operation, he/she hopes that the player resumes playing the video exactly from the designated point. As mentioned in the anchor-prefetching strategy, the actual playback point of the player does not exactly coincide with the designated point by the user. Thus, the concept of positioning satisfaction is generated.As shown in Satisfaction is a fuzzy concept of people psychology, so we use the membership function of fuzzy mathematics to define the positioning satisfaction. We define that the positioning satisfaction is 1 if the time gap of the actual playback point and the designated point is less than 5 s, and a greater difference implies lower positioning satisfaction. The positioning satisfaction with time gap is calculated according to Equation (2):We have studied how the anchor interval affects the positioning satisfaction using simulations. Since the user more likely jumps forward for a VCR operation ,19. We mIt is not acceptable for the user to experience a long playback delay when they perform a VCR operation, i.e., a shorter playback delay corresponds to a better user experience. According to the analysis in The positioning satisfaction reflects the difference between the actual playback point and the designated point. A smaller difference indicates higher satisfaction of the user. According to the analysis in Therefore, the playback delay and positioning satisfaction are two conflicting factors.As analyzed, the playback delay is a cost factor, and the positioning satisfaction is a benefit factor. Based on the two types of factors, we present the anchor optimization selection strategy DSA. This paper aims at selecting the most suitable scheme from the limited number of optional anchor interval schemes. Hence, it is a typical MADM problem.S+) and negative ideal solution (S−). The basic principle of TOPSIS is using the distance from each candidate to S+ and S− as the criterion to rank the candidates. According to the ranking, we can select the most suitable candidate. The detailed steps of the TOPSIS method are summarized as follows:As one of the most widely used method to solve the MADM problem, the TOPSIS method  proposesStep 1. Construct the normalized decision matrix AFirst, it is important to construct the original decision matrix before the normalization, and the decision matrix V with m candidates and n factors is shown in Equation (3):j-th factor value of the i-th scheme. To eliminate the difference of these two factors, the decision matrix must be normalized. For the benefit factor and cost factor, the normalization method is shown in Equations (4) and (5), respectively.In this paper, the decision matrix V consists of 20 optional schemes and 2 factors.Then, the normalized decision matrix A is obtained:Step 2. Calculate the weight of each factorThe entropy weight is calculated as follows:j:In Equation (7), In Equation (8), Step 3. Construct the evaluation matrix based on the entropy weight:Step 4. Determine the ideal and negative ideal schemesS+ and negative ideal scheme This step determines the ideal scheme Step 5. Calculate the distance of each scheme from the ideal and negative ideal schemesStep 6. Calculate the distance of each scheme from the ideal and negative ideal schemesStep 7. Sort the candidate schemes according to.In this study, we propose 20 optional anchor interval schemes, and the length of the interval is 0.5–10 min with uniform increments. The TOPSIS method is used to comprehensively evaluate the 20 schemes, and the priority order of the candidate schemes is shown in In the TOPSIS method, each factor value of the ideal solution is the optimal value of all candidates. In other words, the ideal solution has the smallest playback delay and highest positioning satisfaction among all candidate schemes. Therefore, the ideal solution can achieve the best viewing experience. Each factor value of the negative ideal solution is the worst value of all candidates. The negative ideal solution will ideally result in the worst viewing experience. In fact, the ideal solution and negative ideal solution do not exist in the proposed candidates. The best candidate has the farthest distance from the negative ideal solution and the shortest distance from the ideal solution. Therefore, the best candidate has the highest viewing experience among all candidates.To verify the rationality of the proposed strategy in this paper, we compared it with the most mature anchor strategy, whose anchor interval is 5 min , and theWe implemented the P2P-based VoD system and data-prefetching algorithm using Java. In the comparative experiment, we simulated the VCR operation process when the user watches a video in a P2P-based VoD system, and the test video bit rate is 600 kbps. After the video was played for 1 min, the user randomly performed 5 times VCR operations every 15 s.In a P2P-based VoD system, the data-prefetching strategy is proposed to minimize the latency that the user must wait after the VCR operation. Therefore, the playback delay is one of the most important indicators to evaluate the validity of a data-prefetching strategy. For identical network bandwidths, a smaller delay indicates a better data-prefetching strategy.As shown in The VoD system enables the users to perform VCR operations and quickly search for interesting content. The users hope that the player resumes playing the video exactly from their designated point after the VCR operation. Positioning satisfaction is the indicator to evaluate the proximity of the designated point and the actual playback point.As shown in The peers in the P2P-based VoD system require auxiliary information to prefetch data, and the bandwidth consumed by the auxiliary information is the extra bandwidth. To prefetch data for the peers using the anchor-prefetching strategy or the DSA strategy, two extra fields must be added to the index file: the anchor length and the list of starting segment numbers for each anchor. When a peer begins watching an on-demand video, the index file from the server or peers must first be obtained and locally saved. Then, the peer requests the segments according to the index file and the user’s playing request. Therefore, to implement these prefetching strategies, one peer must only transmit two additional fields.However, the API strategy prefetches both anchors and popular segments. To achieve this prefetching strategy, adding the two fields of the anchor length and starting segment number for each anchor to the index file is not sufficient, as previously mentioned. To acquire the popular segments of the current system, the server must perceive which segment of the video is currently played by each online peer. To satisfy this requirement, two information fields (the video ID and currently played video segment) should be added to the heartbeat packet, which is periodically sent by peers. The heartbeat packet is a collection of real-time basic information of the peers that must be periodically uploaded to the tracker server (TS) by online peers. The server manages the peers through the heartbeat packet information. A peer sends a heartbeat packet every 30 s by default.When an online peer watches a 60 min video, we assume that the user watches the video for a total of 30 min over a series of VCR operations. The extra bandwidth required for the three strategies is shown in In the API strategy, the peer’s playing information must be added to the periodically sent heartbeat packet, which consumes 20–30 times more bandwidth than the other two strategies. However, the anchor-prefetching strategy and proposed DSA strategy in this paper consume notably little extra bandwidth for each video, which is within the acceptable range.When tens of thousands of online peers watch thousands of on-demand videos in the P2P-based VoD system, the extra bandwidth consumed by the API sharply increases compared to the other two strategies. In other words, the implementation of the API causes a significant system burden. Therefore, the API has poor practicality.In this paper, the optimal data-prefetching scheme is derived using the TOPSIS algorithm based on the MADM theory: the DSA strategy. In order to determine the most suitable data prefetching strategy, we considered factors of different type which can influence user’s viewing experience, such as playback delay and positioning satisfaction. The experiment demonstrates that the proposed DSA strategy in this paper improves the positioning satisfaction by approximately 60% relative to the API strategy. Moreover, the DSA strategy can ensure that the delay performance is relatively good. In addition, the delay performance increases the fastest with the increase in network bandwidth, compared with the other two strategies, and achieving this strategy requires less extra bandwidth. Therefore, the proposed DSA strategy in this paper has the best performance based on the comprehensive evaluation in these three strategies, and it can enable users to obtain a better viewing experience. Also, this paper has presented a model to determine the most suitable prefetching data strategy based on different factors. The model has good extensibility, and can be extended from two factors to multiple factors. This model can also be applied to the segment selection algorithm to determine the downloading order of different types of segments.Due to the limited conditions, the experiments were evaluated by simulations with Java. Hence, some future work is still needed. The performance of the DSA strategy needs to be validated in real experimental environments.


To evaluate the effect of histological chorioamnionitis (HCA) with a negative amniotic fluid (AF) culture on adverse pregnancy and neonatal outcomes and inflammatory status in the AF compartment in women with preterm labor or preterm premature rupture of membranes (PPROM).This is a retrospective cohort study of 153 women diagnosed as having a preterm labor or PPROM (20–34 weeks) who delivered singleton gestations within 48 hours of amniocentesis. AF obtained through amniocentesis was cultured, and interleukin (IL)-6, IL-8, and metalloproteinase-9 (MMP-9) levels were determined. The placentas were examined histologically.The prevalence of HCA with negative AF culture was 23.5% (36/153). The women with HCA but with a negative AF culture (group 2) and those with a positive AF culture (group 3) had a significantly lower mean gestational age at amniocentesis and delivery than those with a negative AF culture and without HCA (group 1). Women in group 3 had the highest levels of AF IL-6, IL-8, and MMP-9, followed by those in group 2, and those in group 1. Composite neonatal morbidity was significantly higher in groups 2 and 3 than in group 1, but this was no longer significant after adjusting for confounders caused mainly by the impact of gestational age.In the women who delivered preterm neonates, HCA with a negative AF culture was associated with increased risks of preterm birth, intense intra-amniotic inflammatory response, and prematurity-associated composite neonatal morbidity, and its risks are similar to the risk posed by positive AF culture. Histologic chorioamnionitis (HCA) complicates as many as 30–80% of preterm births with preterm labor or premature rupture of membranes (PPROM), and has been shown to be a risk factor of adverse maternal and neonatal outcomes, including earlier gestational age at delivery and neonatal brain and lung injuries –4. MoreoMost of the previous studies that demonstrated a strong association between HCA and documented poor neonatal and pregnancy outcomes included mixed cases of HCA with and HCA without MIAC , 4, 7, 8This is a retrospective cohort study conducted at Seoul National University Bundang Hospital  from June 2004 to August 2013. The study population consisted of consecutive women diagnosed as having either preterm labor and intact membranes or PPROM who underwent transabdominal amniocentesis. The patients were retrospectively identified by searching our perinatal database according to the following criteria: (1) singleton gestation; (2) amniocentesis performed; (3) delivery at a gestational age between 20+0 and 34+6 weeks; (4) delivery within 48 hours of amniocentesis; and (5) histopathological examination of the placenta. The exclusion criteria were as follows: (1) multiple gestations; (2) a time interval of >48 hours from amniocentesis to delivery ; and (3) major congenital anomalies. The data of 58 patients were previously reported in a previous retrospective study that evaluated the predictive value of intra-amniotic and serum markers for inflammatory lesions of preterm placenta . The diaIn women who were admitted under the diagnosis of either preterm labor or PPROM, and delivered a preterm neonate at our institution, amniocentesis for the assessment of microbiological and inflammatory statuses of the amniotic cavity was recommended. In addition, placentas were routinely sent for histopathological examination. Based on the results of the placental histological examination and AF culture, the subjects were divided into 3 patient groups as follows: (1) no placental inflammation with a negative AF culture result , (2) placental chorioamnionitis with a negative AF culture result , and a positive AF culture result .Mycoplasma hominis and Ureaplasma species), according to previously described methods [g and 4°C for 10 minutes. The supernatant was aliquoted and stored at −70°C until assayed. The samples were not subjected to freeze-thaw cycles before assay. The levels of interleukin (IL)-6, IL-8, and metalloproteinase-9 (MMP-9) in stored AF were measured by using an enzyme-linked immunosorbent assay human DuoSet Kit . The ranges of the IL-6, IL-8, and MMP-9 standard curves were 7.8–600, 31.2–2000, and 31.2–2000 pg/ml, respectively. All the samples were assayed in duplicate. The intra- and inter-assay coefficients of variation were each <10%. The AF culture results and WBC counts, but not AF IL-6, IL-8, and MMP-9 levels, were available to the managing obstetricians and neonatologists. Immediately after amniocentesis, WBC count and C-reactive protein (CRP) level in maternal blood were measured, and details of these measurements were previously described [AF was aseptically obtained by performing abdominal amniocentesis under sonographic guidance. AF was analyzed for white blood cell (WBC) counts and cultured for aerobic and anaerobic bacteria, as well as genital mycoplasmas . Multivariable logistic regression analysis was used to examine the relationship between the HCA with a negative AF culture, neonatal outcome, and inflammatory status in AF after adjusting for compounding factors . All statistical analyses were performed by using SPSS version 20.0 for Windows , and P values of <0.05 were considered statistically significant except in the pairwise comparison.Continuous data are presented as mean ± standard deviation (SD); and dichotomous data, as frequency and associated percentage. Shapiro-Wilk and Kolmogorov-Smirnov tests were used to evaluate whether the data are normally distributed. As the continuous data were not normally distributed, non-parametric tests were used for the analyses. The Kruskal-Wallis test was used to test for comparison of continuous data among 3 groups. Multiple comparisons between the groups were performed by using the Mann-Whitey Ureaplasma urealyticum (n = 38), Mycoplasma hominis (n = 30), Streptococcus viridans (n = 5), Streptococcus agalactiae (n = 2), Staphylococcus aureus (n = 2), Staphylococcus mitis (n = 1), Staphylococcus oralis (n = 1), Escherichia coli (n = 1), Lactobacillus species (n = 1), unidentified gram-positive cocci (n = 3), unidentified gram-negative rod (n = 1), and unidentified gram-positive rod (n = 1). Polymicrobial invasion was present in 31 cases . HCA was present in 36% (36/100) of cases with a negative AF culture and in 75% (40/53) of those with a positive AF culture.During the study period, 159 consecutive women with preterm labor (n = 83) and PPROM (n = 76) who met the inclusion criteria were identified. Of the 159 women, 5 had no available AF samples for retrospective analysis of IL-6, IL-8, and MMP-9 levels and one had no available placental pathological report. Thus, 153 women (95%) were included in the final analysis. Among the 153 women, 50% (76/153) had HCA and 20% (31/153) had funisitis. The prevalence of a positive AF culture was 35% (53/153). Of the 53 women with a positive AF culture, 13 (25%) had no evidence of HCA, of whom 12 had PPROM and one had preterm labor. The microorganisms that were isolated from the amniotic cavity included Measures of neonatal outcomes for the 3 groups based on the results of the placental histological examination and AF culture are shown in We show that (1) among women who delivered preterm neonates owing to preterm labor or PPROM, the prevalence of HCA with a negative AF culture was 23% and that (2) similar to pregnant women with positive AF cultures, women with HCA with a negative AF culture are at increased risk of clinical presentation of symptoms and delivery at earlier gestational ages, intra-amniotic inflammation, and prematurity-associated composite neonatal morbidity. These findings underscore the role of HCA, regardless of AF culture results, as a major risk factor of preterm birth and adverse perinatal outcome, and the need to develop novel rapid biomarkers with greater sensitivity, especially noninvasive ones, for detecting early HCA in the preterm setting.In regard to HCA and MIAC in women who delivered preterm neonates, the prevalence, inverse correlation with gestational age at presentation and birth, and the relationship with adverse outcome are in line with the observations previously reported by our group and other groups , 12, 15.Several investigators have reported that the incidence of intra-amniotic inflammation (as assessed by a mass-restricted score or glucose level) was significantly higher in patients with HCA than in those without HCA, all of whom delivered within 48 hours of amniocentesis , 18. In In the literature, although inconsistent, data suggest that HCA may be a risk factor of preterm birth, and neonatal morbidity and mortality, including early onset neonatal sepsis, BPD, IVH, PVL, and cerebral palsy , 4, 6. HThe present study has several limitations. First, the study was of retrospective nature, potentially leading to selection bias, although most data were collected prospectively. Second, the study population consisted of a heterogeneous status of fetal membranes, including intact or rupture membranes. However, our results remain valid because we derived our results from a multivariable analysis, adjusting for this confounder. Third, the present study used neither placental culture, including the space between chorioamniotic membranes, nor molecular technique  to detect microbes or their DNA in AF. Therefore, we could not specifically explain the causes of HCA with negative AF culture. The strength of our study is the relatively large sample size, yielding clear results, given the low frequency of delivery within 48 hours of amniocentesis. Furthermore, it is the first study to examine the effects of HCA with negative AF culture on maternal and neonatal outcomes, and inflammatory status of the AF.Our study shows that among the women who delivered preterm neonates, HCA with a negative AF culture was associated with increased risks of preterm birth, intense intra-amniotic inflammatory response, and prematurity-associated composite neonatal morbidity. These risks are similar to the risk posed by positive AF culture. Further studies with large sample sizes are needed to assess the possible effect of HCA per se on the long-term outcomes  of premature, particularly extremely premature, infants.S1 File(SAV)Click here for additional data file.


Routinely collected health data (RCD) are increasingly used for randomized controlled trials (RCTs). This can provide three major benefits: increasing value through better feasibility , expanding the research agenda , and offering novel design and data collection options . However, numerous hurdles and barriers must be considered pertaining to regulatory, ethical, and data aspects, as well as the costs of setting up the RCD infrastructure. Methodological considerations may be different from those in traditional RCTs: RCD are often collected by individuals not involved in the study and who are therefore blinded to the allocation of trial participants. Another consideration is that RCD trials may lead to greater misclassification biases or dilution effects, although these may be offset by randomization and larger sample sizes. Finally, valuable insights into external validity may be provided when using RCD because it allows pragmatic trials to be performed.We provide an overview of the promises, challenges, and potential barriers, methodological implications, and research needs regarding RCD for RCTs.RCD have substantial potential for improving the conduct and reducing the costs of RCTs, but a multidisciplinary approach is essential to address emerging practical barriers and methodological implications.Future research should be directed toward such issues and specifically focus on data quality validation, alternative research designs and how they affect outcome assessment, and aspects of reporting and transparency. Routinely collected health data (RCD), such as electronic health records (EHRs), registries, or administrative claims data, are useful for randomized controlled trials (RCTs), especially those whose aim is pragmatic. RCTs embedded in routine data collection might be the next disruptive clinical research technology . HoweverRCTs are often very expensive. Some trials are stopped early because of failure to recruit; some fail to generate useful evidence for clinical practice; and in some, the results are not disseminated at all. Various limitations of RCTs are used as arguments to support observational “real-world” RCD studies , 10. We RCDs may make RCTs easier and more feasible by reducing costs, time, and other resources. This might mean larger RCTs for the same cost or RCTs in research areas where high costs and insufficient funding previously precluded their conduct. Finally, even when cost and resource limitations do not exist, RCD may foster novel research activities, such as the use of registries for rapid, consecutive trial enrollment , 4.www.registerforshare.org) that can be linked to EHRs also support pretrial identification of potentially eligible participants. Even more widely available than registries, health insurance databases provide an extensive sampling frame for patient recruitment, as well as a wealth of outcome data [Effective recruitment is necessary for a successful trial . Targeteome data .All or some outcome data could be taken from RCD, reducing the need for cumbersome follow-up visits, bespoke data collection, costly monitoring, and audits. Building new infrastructures outside standard healthcare, training research staff, or purchasing additional equipment are avoided. This may accelerate trial setup, provide faster results, and also reduce trial costs significantly. Site monitoring accounts for 9–14% of total trial costs . In addiResearch questions not otherwise amenable to trials  might be answerable with RCD. For example, local and national registers of people with myotonic dystrophy played an important role in the successful recruitment strategy of the OPTIMISTIC trial .Using RCD may help to address some traditional imbalances in the evidence landscape and reduce traditional research agenda biases. Treatments that are typically not championed by commercial interests, such as exercise or physical therapy, speech therapy, psychotherapy, or surgeries, are less supported by randomized evidence than drugs or devices. Any cost reduction could facilitate trials for interventions that typically strongly depend on public funding structures and noncommercial research support. By saving resources elsewhere, RCD-based trial research may broaden therapeutic options or even reveal better treatments.For drug therapies, the use of RCD may allow independent realization of notoriously lacking head-to-head comparisons and evaluation of “blockbuster drugs” in pragmatic megatrials . Those dWhereas many outcomes that are traditionally of interest in clinical research, including biomarkers and patient-reported outcomes, are not included in most RCD sources, RCD typically include outcomes that are not included in many traditional RCTs . Implementing RCTs at the point of care, with randomization occurring directly in EHR platforms, might lead to RCTs having more generalizable results that assess more patient-relevant and clinically relevant outcomes , 20, 21.Instead of inviting a patient for a repeated measurement or calling his/her healthcare provider for the patient’s clinical information, the researcher can access the RCD database and extract it autonomously, which avoids disrupting the usual care environment and without coming to the attention of the patient or care provider or requiring additional work from either. By reducing the need to affect the flow of routine care and the need to contact patients and care providers, such as by artificial blinding and outcome assessment procedures, observer bias  is minimized. This may be especially true for behavioral interventions .Administrative databases offer a wider array of variables of interest to use in an RCT, including social factors, unemployment or disability status, or healthcare use. For example, an insurance claims database could be queried automatically at admission to identify individuals frequently visiting an emergency department to target them for a discharge-planning intervention.Retrospectively linking RCT databases with RCD supports data collection after regulatory approval is given for a drug or device. For example, data from large approval trials could be linked with cancer registries for evaluation of postapproval safety concerns, or very long-term trial outcomes could be collected from registries, as was done in the West of Scotland Coronary Prevention Study .Greater use of RCD in RCTs is challenging. When using RCD to overcome some of the limitations of traditional RCTs, several additional barriers may occur and can be classified into four principal domains: data, regulatory and ethical aspects, costs, and novelty Table .Table 2BEven when the RCD necessary to answer a research question is available, it may be difficult to locate and access. The data owner may not be easy to contact, may not be willing to provide or share the data, or may not be able to provide it in a form that one may need to conduct an RCT, such as aggregated data being offered when individual patient data are what is needed.The datasets may be very large, requiring a substantial information technology (IT) system, including human resources, hardware, and software to sort through and organize the data in such a way that it can then be analyzed. Connecting or linking to a research database with a system that is either continuously collecting the data (such as an EHR) or to another database (such as insurance claims database) requires significant planning and software development.A few RCD variables and some RCD source types may be more accurate and better validated than others. Each variable for each source has variability in its accuracy that makes it difficult to make a general accuracy judgment. Hence, different EHRs or registries may have different data quality , but the major obstacle remains the variability within the same source , 7. HoweAll in all, each research question, or even each outcome estimate, should be carefully examined, paired with the specific RCD source and variables used, to establish whether such elements were appropriate and what degree of confidence can be placed in such outcome assessments. A population registry based on a unique identifier that every individual receives at birth and has been established for many years with considerable resources for quality assurance  is likeCore ethical principles for clinical research include informed consent, independent ethics review, confidentiality, or risk management . Although the principles themselves remain the same, differences exist in the way in which they can and should be applied in research with RCD. Some ethical issues, such as confidentiality, can become more significant, whereas others, such as consent and audit, might be simplified. In particular, when variations of usual care are explored, privacy-related issues typically dominate ethical assessments. Recent guidelines  and repoTemplates for broad consent texts have already been developed and implemented for research with human biospecimens and might be applied in a modified and simplified version for research with RCD , 34. ConWhen using high-dimension datasets, effective anonymization is often quite difficult . With a At a policy level, public and patient involvement builds another cornerstone for long-term public trust in research with RCD, especially when such research includes consent waivers or broad consent , 36. PubSetting up infrastructures to implement use of RCD for clinical research may be associated with enormous overhead costs. Specific investments may be needed before starting such research. Although the costs related to maintaining the RCD source  may not rely on the researcher, this should be considered in institutions where both clinical practice and research take place, such as in university hospitals. It may become common practice to charge for the release of RCD once it becomes more widely used. Alternative models involving supported access to RCD are also possible; Scotland’s electronic Data Research and Innovation Service provides access and support and publishes charging structures . Even ifThe novelty of using RCD for trials may itself be a barrier. Established structures, such as templates for ethical approval or grant proposals, are often not yet designed to apply to this kind of research.Guidelines for use and handling of RCD often stem from nonexperimental research with other foci. For example, on one hand, the most widely used reporting guideline for this type of data was developed for observational RCD analyses , but thFurthermore, the novelty of the technology itself will require additional training and data science staff necessary to implement RCD-RCTs embedded in routine care. Although RCD-RCTs may reduce the costs associated with training research staff for patient recruitment or outcome ascertainment, any savings may be offset by new expenses for training those who generate and collect the RCD so that the data can be used for research and for training researchers to prepare, manage, and analyze this data within a clinical trial framework.In addition to general barriers to using RCD in clinical trial research, novel methodological problems and potential biases may be introduced. However, use of RCD may also reduce and preemptively avoid some internal validity biases and provide valuable insights into external validity by showing potential differences between included patients and/or nonincluded but eligible individuals.RCD-based research obviously requires reasonable data quality, but this holds for both randomized and observational research using RCD. Data quality issues, including misclassifications, are much less of a problem with randomization, however, because this typically rules out the possibility that the explored intervention is related to data quality. This is in sharp contrast to observational studies, where determination of exposures may actually be strongly associated with data quality and increase risks of misclassification and detection biases. However, even in a trial, it may be problematic when the measurement of outcomes is associated with the allocated intervention. Bias might occur, for example, when one study intervention leads to more contact with healthcare professionals who collect the routine outcome data in a different way . Possible solutions include standardized documentation of core outcomes  and training of healthcare professionals to perform standardized data entry. Efforts at standardization may escalate cost, however, and diminish the advantages related to the ease and low cost of using the RCD.Not only quality but also timeliness deserves attention, because timely assessment of safety issues may be challenging when a specific adverse event data collection mechanism is not in place as in traditional RCTs . BecauseHowever, outcome data collection in RCD-RCTs may have advantages because it is often formally blinded, as in any traditional trial, with blinded endpoint assessment. Then, and when outcome data collection is standardized and unrelated to the intervention, any misclassification would be completely at random and only introducing noise and decreasing precision of outcome estimates.Dilution of effects due to imprecision and misclassification may gain particular importance for noninferiority questions or evaluation of some adverse events, which may be less adequately addressed with RCD of uncertain data quality. One potential solution is to increase sample size to account for the increased noise that RCD brings. In principle, at least, easy provision of larger sample sizes is one of the key advantages of RCD-RCTs, so making this a routine requirement ought not to be a substantive barrier.Data completeness of RCD-RCTs is not necessarily a problem; actually, sometimes it is quite the opposite, with levels of completeness that are rare in traditional trials. For example, the TASTE trial  , embeddeCareful evaluation of data accuracy, including validation and clarification of algorithms, appears to be one of the most important issues. Other important questions may be asked. Are outcome estimates different when measured in RCD-RCTs compared with RCTs with traditional active data collection? If so, are they source-specific, or do they depend on the type of outcome? How can users of trial research determine if the data are sufficiently accurate? A central register listing routine datasets available for trial research, including information on data quality and validity, would be helpful. A general standardization of routine data collection to ensure that it is useful not only for patient care and administration but also for research would be desirable. Employment of electronic algorithms that could be used to automatically perform validation checks  might also be helpful .Other questions that require exploration are related to patient recruitment and consent. Does pragmatism affect the estimates of treatment effects? Are different consent models needed? Are Zelen trials done without obtaining consent from each and every participant, giving results similar to those of other trials that require consent from everyone? And how can randomization become a standard usual care procedure despite short appointments and constrained resources in clinical care?Development of guidelines for review, conduct, and reporting of trials using RCD may be helpful. Systematic reviewers, health technology assessors, and regulators and other users of this research may need novel tools and some training to assess the quality and risk of bias of such evidence.RCD have substantial potential for improving the conduct and reducing the costs of RCTs. Future research should specifically focus on data quality validation, alternative research designs and how they affect outcome assessment, and aspects of reporting and transparency.Many of these issues will require multidisciplinary research efforts and a large international research initiative on RCD for RCTs. This will allow researchers to exchange, collaborate, and learn but would require support by some structured funding and resources. Overall, better understanding of how to make the best use of RCD for RCTs is needed.


This paper reports the dynamical analysis of the business cycles of 12 (developed and developing) countries over the last 56 years by applying computational techniques used for tackling complex systems. They reveal long-term convergence and country-level interconnections because of close contagion effects caused by bilateral networking exposure. Interconnectivity determines the magnitude of cross-border impacts. Local features and shock propagation complexity also may be true engines for local configuration of cycles. The algorithmic modeling proves to represent a solid approach to study the complex dynamics involved in the world economies. Classic models describe natural and artificial systems using the formalism of mathematics and physics. In the last decades emerged the alternative of computational modeling, particularly in cases where the complexity, or the type, of the phenomena involved makes it difficult to adopt standard methodologies. We find examples of such modeling exercises in several disciplines such as engineering, biology, geophysics, finance and economy, just to name a few , 2. ModeBaxter and Kouparitsas  begin thInterconnectedness matters, as the theory of optimum currency areas demonstrates . NeverthCountries having the most similar sector structure in their economies will also have the most similar business cycle behavior . KydlandKose et al. –33 reminUnemployment is the most visible and well-known feature of business-cycle busts. Demographic variables have been less considered in the literature, but they deserve to be included, because social exclusion increases death rates in business-cycle crises, and poor pre-natal nutrition during periods of downturn can thereby cancel out some collective achievements regarding welfare and life expectancy at birth. Life expectancy is a reasonable reflection of a country’s overall welfare, which itself reflects the soundness of the local economic environment. Demographic variables also emerge as a good proxy for business cycles, because migration is the consequence of attraction or repulsion of the labor force in job markets , especially in a context of free labor movements and low information and transportation costs. Life expectancy and birth rates are nodes of stylized vulnerabilities, because of the impact of busts on demography and their dampening effect on migration.per capita, thereby avoiding the risk of scale bias in the conclusions.The literature above disregards these issues. Because national economies vary tremendously in size, the current research also includes GDP per capita growth rates, which is appropriate for international comparisons to avoid the problem that scale effects may bias the conclusions on the identification of business-cycles. However, the analysis of one single variable, GDP, is too narrow a perspective to define business-cycles of national economies , where H is the Hausdorff distance . For each determinant, we approximate the 11 country trajectories by means of exponential functions:a and b estimated numerically.We calculate the determinants for each country, Ti,j(t). Some gaps in the curves are due to missing data.For example, a, b) obtained for Ti,j(t), Si,j(t), Zi,j(t) and Wi,j(t) are represented in R2. For Fi,j(t) no reliable data could be found.The locus , the same clusters, Ti,j(t), Zi,j(t) and Wi,j(t) the clustering is not complete. For example, with Ti,j(t) we observe that Switzerland moved from Zi,j(t) we verify that Canada and South Africa swap location. For Wi,j(t) we observe that United Kingdom and South Africa changed cluster, while China is not represented due to insufficient available data.We verify that, for These determinants are relevant and shed light into important aspects. Nevertheless, we can ask if it is possible to take advantage of advanced computational techniques and develop new visualization perspectives and indices. This approach will be discussed in the next sub-section.per capita, xi1,(t), annual exports of goods and services, xi2,(t), and life expectancy at birth, xi3,(t). As before, for reference the USA time series are adopted.We consider below the variables GDP i and j at year t is calculated by two distinct measures, namely the arc-cosine and the Canberra distances  years.For comparison, the distance between country time series istances , definedThe first index αk = {1, 1, 1} and per capita has the effect of enlarging the gap between countries in clusters The variations of the distances R2 ∈  for R2 ∈  for a, b) for the two distances is represented in Figs R2.A good fit for all cases is verified, with the coefficient of determination varying in the interval a, b) locus. Moreover, the general layout of the parameters suggests their representation in a distinct coordinate system. In this line of thought, we represent  in the hyperbolic plane [x, y): x > 0, y > 0} in the first quadrant of the Cartesian plane, u represents the hyperbolic angle to  and v denotes the geometric mean of x and y.Distances ic plane . Given aa, b) for Figs Under a three-variable characterization, some national economies had similar performances, making it difficult to disentangle their individual paths. This means that business-cycle behavior similarities existed among those partners . This result confirms the conclusions on 19 countries, by Negro and Otrok  “the aveper capita performance belongs to Switzerland, Australia, and the North American countries (Canada and USA). The champion of openness is Switzerland. Figures also reveal how difficult it is to disentangle each national profile from the USA case for long. For this reason, Results obtained show that the highest GDP In A first one, the less synchronized with USA, includes China and India, the two great Asian empires and civilizations. However, both have been in a trend of synchronization. The Chinese trend after 1990 in the hyper-globalization period has led the country to levels of distance that are similar to those of the second club of countries.This second club of countries, comprising the South American countries of Mexico and Brazil, and South Africa, strongly synchronized with the USA during the Globalization G2. Having experienced large waves of business-cycle fluctuations that prevented their economies from a clear proximity to the USA in the 1980s and 1990s, they have proceeded to distance levels that are similar to those of the Chinese economy but lower than those of the third club.European partners, Canada, Japan, and Australia always formed the club with greatest co-movement with the USA. They synchronized during G2, and their economies are now closely integrated with the rhythm of the USA economic fluctuations . Among tThese conclusions are historically robust. The American bubble before the 2007 crisis had no parallel in the Chinese economy, as For an overall view, All comments are confirmed in looking at the Canberra distances During G2 it is quite clear that there was a co-movement: confirming Diebold and Rudebusch , Fig 12 This paper proposed a computational approach to the modeling of world economies based on time series. The proximity of standards of living and business cycles to those of the USA were approached using a number of variables for 12 large-economy countries. Several description methods were considered, namely SS representation, HC techniques, and distance based-measures followed by trendline approximation. The behavior of the USA was assumed as the pattern for comparison.The multivariate techniques for computational analysis showed that there is a long-run co-movement of these 11 large economies with the USA’s performance. The cross-state deviations from the USA’s level of activity measured by means of arc-cosine and the Canberra distances reflect historical moments: the Latin America crisis of the 1980s, the European countries’ volatility during Europe’s extension to the East, and the Japanese issues of the 1990s are main regional cyclical problems visible in the results of the modeling procedure.In the new millennium co-movement with the American pattern has increased. China shows the most dissimilar business-cycle behavior, but is also synchronizing with the American business cycles, especially over the last decade and a half.Synchronization may be the result of global power, or perhaps, as some might suggest, mutual influence. Is it instead the case that the USA’s business cycles are converging toward China’s fluctuations? In a word, no. The USA’s 2008 subprime mortgage screen belongs to its pattern in which all other trading partners see their fortunes reflected, including China and the Eurozone countries with their current unemployment crisis.The data available until 2015 may foretell an imminent slower economic growth path for all partners, in a de-globalization process.The mathematical and computational exercises reported in this work also help to disentangle euphoria about globalization by revealing how financially interconnected the world has become in the new millennium, and also how difficult it is to say that the 2008-2015 convergence and synchronization is the turning point for de-globlization. The computational methods reported here are untried, it must also be said, but they yield results that are of interest, align well with the historical record, and bring evidence to the issue of how far USA imbalances can be seen as calling the cadence to which integrated markets march—progressing from independent strides of individuals to ever greater lock-step of a unit.


Laser Assisted in Situ Keratomileusis (LASIK) is a proven treatment method for corneal refractive surgery. Surgically induced higher order optical aberrations were a major reason why the method was only rarely used to treat presbyopia, an age-related near-vision loss. In this study, a novel customization algorithm for designing multifocal ablation patterns, thereby minimizing induced optical aberrations, was used to treat 36 presbyopic subjects. Results showed that most candidates went from poor visual acuity to uncorrected 20/20 vision or better for near (78%), intermediate (92%), and for distance (86%) vision, six months after surgery. All subjects were at 20/25 or better for distance and intermediate vision, and a majority (94%) were also better for near vision. Even though further studies are necessary, our results suggest that the employed methodology is a safe, reliable, and predictable refractive surgical treatment for presbyopia. Laser Assisted in Situ Keratomileusis (LASIK) is proven to be a safe, fast, and reliable procedure for corneal refractive surgery. The procedure comprises three steps: (i) cutting a thin flap on the outer corneal surface, (ii) ablating tissue underneath the flap with an excimer laser, and (iii) putting the flap back into place on the stromal bed. Only a relatively small number of side effects, such as dry-eye, halos, corneal ectasia, and epithelial ingrowth under the flap, have been reported. Modern excimer laser systems have demonstrated their ability and performance in treating various ametropic conditions, such as nearsightedness (myopia), farsightedness (hyperopia), and astigmatism. By 2009, more than 27 million eyes had successfully been treated with LASIK refractive surgery all around the world.Even though various approaches—based on diverse technologies and methodologies—for the treatment of age-related far or nearsightedness have been proposed and documented in literature, effective presbyopia treatment remains a challenge in modern eye care. State-of-the-art treatment involves the implantation of multifocal intraocular lenses ,2, whichIn any such procedure, besides restoring the patients’ vision and ability to see far- as well as near-distance objects, the focus should always be that (i) the treatment is reversible and (ii) that postsurgical enhancement, or touch-up, is always possible. Generally speaking, corneal approaches are the least invasive, and are highly accurate and safe procedures. Furthermore, they omit risks that are inherent to the intraocular procedure. It has previously been reported that multifocal LASIK treatments, sometimes also called presbyLASIK treatments, in the cornea showed good refractive results for near, intermediate, and distance vision in hyperopic presbyopia patients ,9,10. ThThis prospective, single-surgeon study of myopic presbyopia treatments with a multifocal presbyLASIK procedure included 72 eyes of 36 patients. All eyes underwent pre- and postoperative full clinical biomicroscopical examination, Orbscan IIz corneal topography  and Zywave II wavefront aberrometry analysis . Additionally, monocular and binocular uncorrected near (UNVA), intermediate (UIVA), and distance (UDVA) visual acuity were assessed using a LogMAR chart. For all examinations, the eyes had undilated pupils, and were conducted preoperatively, as well as one week, one month, three months, and six months postoperatively.All study subjects underwent Supracor refractive surgery, operated with a 217P Excimer laser . The dominant eye of each individual subject was targeted plano for far vision (0.0 diopters), while the respective non-dominant eye of the same subject was targeted at −0.5 diopters. All LASIK flaps were created with a Ziemer LDV femtosecond laser platform , and had a superior hinge and a thickness of 110 microns. All treatments were planned and executed in two main steps: first, the normal ablation pattern for the myopic condition of the subject’s eyes were applied to the cornea, according to the surgeon’s nomogram, and by targeting the mean refractive spherical equivalent (MRSE) to be optimal for distance vision. Second, the aforementioned 3-mm zone near the addition was applied see  to creatThe treatment planning software of a 217P laser system calculates a multifocal ablation pattern by combining the normal distance vision treatment plan for the ametropic condition of the subject, with a near vision addition in the 3-mm central zone of the treatment see . On one p = 5 × 10−6), intermediate , and distance vision . Furthermore, the visual acuity of all eyes remained stable postoperatively after six months. The excimer laser system applied the planned ablation patterns at a very high precision, as the differences between the targeted and achieved spherical equivalent (SEQ), given in the unit of refractive power—diopters (D), at six months postoperative were −0.01 ± 0.14 D (standard deviation—SD) with an r-square of All 72 surgical procedures were successfully executed, no side effects were detected, and not a single complication occurred during the study period. Measured on the LogMAR scale with respect to preoperative visual acuity , the visual acuity of subjects six months after surgery improved significantly, for near  or better, and about 80% were even at 20/20 (LogMAR ≤ 0.00) or better, again for the whole range of near, intermediate, and distance vision. In contrast to that, multifocal lens implantation results in the literature showed LogMAR 0.09 ± 0.08, LogMAR 0.10 ± 0.11, and LogMAR 0.07 ± 0.05, for near, intermediate, and distance vision . ResultsAs expected, while the dominant eyes in this study generally had higher monocular visual acuity for distance vision, the non-dominant eyes performed better in monocular near vision. Presumably, the brains of the study candidates were capable of blending the two distinct monocular images into a binocular image, electively focusing on near, intermediate, and distant targets. This circumstance is supported by the thoroughly high satisfaction of all of the study patients. Generally speaking, the excimer procedure employed in this study was less invasive compared to other presbyopia methods, such as refractive lens implantation. LASIK is a very well accepted and extensively proven procedure. It features high precision in positioning of the correction, in refractive outcome, as well as in predictability of the result. A key factor for this is the high precision and repeatability of flap quality and thickness . A remaiThe thoroughly positive results with the LASIK-based presbyopia treatment in this study can, at least partially, be attributed to the aspherical customization algorithm. The algorithm utilized the K-readings as well as the conic constant (Q) of the cornea to minimize the induction of adverse optical aberration effects ,10,12. I