Background: Sepsis-induced coagulopathy (SIC) denotes an increased mortality rate and poorer prognosis in septic patients.Objectives: Our study aimed to develop and validate machine-learning models to dynamically predict the risk of SIC in critically ill patients with sepsis.Methods: Machine-learning models were developed and validated based on two public databases named Medical Information Mart for Intensive Care (MIMIC)-IV and the eICU Collaborative Research Database (eICU-CRD). Dynamic prediction of SIC involved an evaluation of the risk of SIC each day after the diagnosis of sepsis using 15 predictive models. The best model was selected based on its accuracy and area under the receiver operating characteristic curve (AUC), followed by fine-grained hyperparameter adjustment using the Bayesian Optimization Algorithm. A compact model was developed, based on 15 features selected according to their importance and clinical availability. These two models were compared with Logistic Regression and SIC scores in terms of SIC prediction.Results: Of 11,362 patients in MIMIC-IV included in the final cohort, a total of 6,744 (59%) patients developed SIC during sepsis. The model named Categorical Boosting (CatBoost) had the greatest AUC in our study . Coagulation profile and renal function indicators were the most important features for predicting SIC. A compact model was developed with an AUC of 0.854 (95% CI: 0.832–0.872), while the AUCs of Logistic Regression and SIC scores were 0.746 (95% CI: 0.735–0.755) and 0.709 (95% CI: 0.687–0.733), respectively. A cohort of 35,252 septic patients in eICU-CRD was analyzed. The AUCs of the full and the compact models in the external validation were 0.842 (95% CI: 0.837–0.846) and 0.803 (95% CI: 0.798–0.809), respectively, which were still larger than those of Logistic Regression  and SIC scores . Prediction results were illustrated by SHapley Additive exPlanations (SHAP) values, which made our models clinically interpretable.Conclusions: We developed two models which were able to dynamically predict the risk of SIC in septic patients better than conventional Logistic Regression and SIC scores. Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains the first leading cause of mortality in critically ill patients , 2. Coag9/L) should be screened, first using SIC diagnostic criteria and then using ISTH DIC diagnostic criteria (Sepsis-induced coagulopathy (SIC) criteria were developed by members of the Scientific and Standardization Committee (SSC) on Disseminated Intravascular Coagulation (DIC) of the International Society of Thrombosis and Haemostasis (ISTH) in 2017  Supplem. The cricriteria . HoweverIn recent years, the emergence of new machine-learning algorithms has enabled us to predict disease events dynamically based on huge and complicated clinical information. Advanced machine-learning models can fit high-order relationships between covariates and outcomes, and therefore, they excel in the analysis of complex signals in data-rich environments –22. The We conducted this retrospective study based on two sizeable critical care databases the Medical Information Mart for Intensive Care (MIMIC)-IV  and the In MIMIC-IV, patients who fulfilled the definition of sepsis between 2008 and 2019 were included. According to the Sepsis-3 criteria, sepsis was defined as a suspected infection combined with an acute increase in Sequential Organ Failure Assessment (SOFA) score ≥ 2 . Hourly Only patients who were older than 18 years and stayed in the ICU for more than 24 h were included. No patients were excluded due to missing values. We made no attempt to estimate the sample size of the study; instead, all eligible patients in MIMIC-IV and eICU-CRD were included to maximize the statistical power of the predictive model.We annotated patients' every day when the sepsis definition was fulfilled with their current coagulation state according to the SIC criteria, as recommended . Specifi2, and temperature), laboratory data , transfusion  and urine output. Comorbidities were also collected based on the recorded International Classification of Diseases (ICD)-9 and ICD-10 codes, including hypertension, diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, myocardial infarction, chronic kidney disease, leukemia, stroke, cancer, and liver disease. Lastly, medications such as heparin, antibiotics and vasopressors, continuous renal replacement therapy (CRRT), and mechanical ventilation (MV) were collected.Clinical and laboratory variables were extracted during sepsis. For some variables with multiple measurements, average values were assessed. For the prediction of SIC, 88 variables were collected , includit-test or rank-sum test for continuous variables, and the Chi-square test or Fisher's exact test for categorical variables, as appropriate.Baseline characteristics on the first sepsis day were compared between SIC and non-SIC groups in MIMIC-IV. Values are presented as the means [standard deviations]  or medians [interquartile ranges]  for continuous variables, and total numbers [percentages] for categorical variables. Comparisons were made using the Student PyCaret Python package (version 1.0.0), an open-sourced, automated machine-learning workflow. The assessment process was performed using 10-fold cross-validation. Accuracy and area under the receiver operating characteristic curve (AUC) were calculated on each fold and pooled to evaluate each model. The algorithm with the highest accuracy and the largest AUC was selected. Then, we performed fine-grained hyperparameter adjustment for the potential model using the Bayesian Optimization Algorithm. This algorithm is an efficient constrained global optimization tool, which was performed using the functions of the bayes_opt Python package (version 1.2.0) (As shown in n 1.2.0) . The optSHapley Additive exPlanations (SHAP) Python package (version 0.32.1), which assessed the importance of each feature using a game-theoretic approach based on the validation set , and As shown in p < 0.001), higher SOFA scores , longer prothrombin time (PT) , less urine output , higher rates of linezolid , vancomycin , CRRT , vasopressors  and MV , and higher 28-day mortality  than the non-SIC group. The length of hospital stay was also longer in the SIC group than in the non-SIC group .Variable values on the first day of sepsis in MIMIC-IV were analyzed; the differences in characteristics were compared . The SICDaily data were extracted, and 16,183 samples for prediction in MIMIC-IV were created. Of these samples, 1,489 were labeled as positive (SIC the next day), 14,694 were labeled as negative (still non-SIC the next day). The prediction performances of the various models are listed in Fifteen iterations of Bayesian optimization were performed. The hyperparameter search domains and final settings are listed in p < 0.001), while Logistic Regression had the poorest generalization ability . The sensitivity and specificity analysis of the four predictive methods is summarized in The results of external validation are shown in Model performance in different patient cohorts in eICU-CRD is shown in The summary plot of SHAP in http://www.aimedicallab.com/tool/aiml-sicrisk.html. The SIC risk in the following day can be assessed by using this tool, and interpretation of the prediction result in the instance level will be shown to the user.A website-based tool was established for clinicians to use the compact model, To the best of our knowledge, this is first attempt to apply machine-learning models for the dynamic prediction of SIC. Our study developed and validated two variants of dynamic machine-learning models, providing an accurate predictive tool for SIC in sepsis patients.In this study, we reconfirmed that coagulopathy worsens the clinical outcomes of septic patients . As showCurrently, there is a lack of reliable tools for the early prediction of coagulopathy in septic patients. Our study demonstrated that the family of gradient boosting algorithms, such as CatBoost, Light Gradient Boosting and Extreme Gradient Boosting, can predict SIC with higher accuracy than others. In short, gradient boosting is a powerful machine-learning technique that iteratively trains a weak classifier  to fit residuals of previous models . CatBoosIn this study, we developed two variants of CatBoost models that can identify patients with a high risk of SIC and provide clinical decision-makers with more information. As shown in In general, based on more valuable variables, models have better discrimination but worse clinical usability. Therefore, in our study, two model variants were developed for different application scenarios. The full model predicted SIC based on 88 clinical variables and achieved the highest AUC in this study. In the external validation, the full model maintained good discrimination with only a slight reduction in AUC. However, it is difficult to collect 88 variables and apply this model. As a result, the full model is recommended in hospitals with a well-designed clinical data system. By contrast, the compact model was trained based on 15 selected variables. Under the condition of ensuring accuracy, it achieved practicality as far as possible. In addition, a website tool was developed to help clinicians use the compact model in clinical practice. By logging on to the website and entering the values of 15 variables, our compact model will give the prediction result, and interpretation of the prediction result will be shown to the user.By interpreting the full model, it was found that many clinical variables can help to indicate the risk of SIC. In this study, coagulopathy profile was found to be the most important variable in predicting SIC followed by renal function indicators (urine output and creatinine). As shown in Several limitations of this study should be considered. Firstly, only septic adults in ICUs were included, whereas hospitalized sepsis cases were not analyzed. In addition, in consideration of the immaturity of the coagulation system in children, especially newborns, more research is needed on SIC in children with sepsis. Secondly, our models screen out patients with a high risk of SIC but do not indicate who will benefit from anticoagulant therapy. It is still up to clinicians to decide whether to administer anticoagulant agents. However, the process from sepsis to severe coagulopathy is a continuous condition arising from a coagulation disorder. Early and accurate prediction of SIC can provide more time for clinicians to adjust treatment strategies, and study the potential effect of anticoagulant therapy in the early stage. Thirdly, this is a retrospective observational study. Missing data and input errors exist, despite the very high quality of the MIMIC-IV and eICU-CRD databases. Therefore, prospective validation is still required in the future. Compared with septic shock, for which advances have been made in recent years, giving rise to significant survival improvements, there is still a long way to go in the diagnosis and management of sepsis-associated coagulopathy.In conclusion, the present study developed two variants of the CatBoost model, which can discriminate septic patients who would and would not develop SIC.https://mimic-iv.mit.edu/; https://eicu-crd.mit.edu/.Publicly available datasets were analyzed in this study. This data can be found here: The study was an analysis of two third-party anonymized publicly available databases with pre-existing institutional review board (IRB) approval.Q-YZ, L-PL, and J-CL: conception and design. RG, G-WT, and ZL: administrative support. Q-YZ: collection and assembly of data. Q-YZ and L-PL: data analysis and interpretation. All authors: manuscript writing and final approval of manuscript.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.


High quality head-mounted display based virtual reality (HMD-VR) has become widely available, spurring greater development of HMD-VR health games. As a behavior change approach, these applications use HMD-VR and game-based formats to support long-term engagement with therapeutic interventions. While the bulk of research to date has primarily focused on the therapeutic efficacy of particular HMD-VR health games, how developers and researchers incorporate best-practices in game design to achieve engaging experiences remains underexplored. This paper presents the findings of a narrative review exploring the trends and future directions of game design for HMD-VR health games.We searched the literature on the intersection between HMD-VR, games, and health in databases including MEDLINE, Embase, CINAHL, PsycINFO, and Compendex. We identified articles describing HMD-VR games designed specifically as health applications from 2015 onwards in English. HMD-VR health games were charted and tabulated according to technology, health context, outcomes, and user engagement in game design.We identified 29 HMD-VR health games from 2015 to 2020, with the majority addressing health contexts related to physical exercise, motor rehabilitation, and pain. These games typically involved obstacle-based challenges and extrinsic reward systems to engage clients in interventions related to physical functioning and pain. Less common were games emphasizing narrative experiences and non-physical exercise interventions. However, discourse regarding game design was diverse and often lacked sufficient detail. Game experience was evaluated using primarily ad-hoc questionnaires. User engagement in the development of HMD-VR health games primarily manifested as user studies.HMD-VR health games are promising tools for engaging clients in highly immersive experiences designed to address diverse health contexts. However, more in-depth and structured attention to how HMD-VR health games are designed as game experiences is needed. Future development of HMD-VR health games may also benefit from greater involvement of end-users in participatory approaches. In recent years, there has been a rapid growth in the reported use of virtual reality (VR) in the treatment of a variety of clinical conditions, such acute and chronic pain management –3, phobiResearch in the 1980′s with early computer graphics explored the potential for computer-generated VR experiences with HMDs. At the time, computer processing power was very limited while HMDs were unreliable and cost tens of thousands of dollars. More recently, commercially available computer and graphics technology has become capable of rendering realistic high resolution 3D imagery in real-time. The current level of technology is far removed from devices we were using in research even five years ago (such as the Oculus Rift Development Kit 2). In 2005, basic cloth simulation was hailed as showpiece technology, whilst modern 3D rendering cards with integrated physics support can simulate individual human hair movement in complex lighting situations. This technological progress has made modern VR devices much more immersive, providing a much better sense of presence for demanding VR gaming users, and more importantly, less prone to technical problems than their early counterparts. Whilst the typical cost of a high-end consumer HMD-VR set-up remains high for individual consumers , this generation of technology has seen substantial use in research settings . MoreoveThe key element in these HMD-VR health applications is the use of immersive media content to engage the users in a stimulating interactive experience, where they feel a sense of presence in a different and novel environment , 15. ThiThe typical content takes the form of either a game or a purposeful, yet non-gaming, first-person virtual experience. A common application of the latter is seen in exposure therapy whereby patients with phobias are presented with the source of their anxiety or fear in a controlled and graded manner in order to help them overcome their distress response . AnotherAnother approach has involved developing games specifically as health applications –33. For Developing games as health applications using HMD-VR requires a broad intersection of theoretical and technical lenses. These include biomedical and psychosocial perspectives on health, computer and engineering technologies, human computer interaction theory, and ultimately game design. Several approaches to game design have been articulated by Salen and Zimmerman , Schell Considering Hunicke and colleague’s Mechanics-Dynamics-Aesthetics (MDA) framework , meaningMoreover, the quality of game design ultimately impacts stakeholder adoption of these games as health technology –41. To tTo explore game design in HMD-VR health games, a literature search focusing on the intersection between HMD-VR, games, and health was undertaken. Bibliographic health databases searched included MEDLINE, Embase, CINAHL, and PsycINFO. The engineering database Compendex with a search restriction to the “health” topic was also used. To narrow VR-related literature to only HMD-VR, the keywords: HMD, head mounted display, and virtual headset were used as search terms. For games, the keywords: game, gaming, and exergame were used. Search results were restricted to the English language. To capture the current generation of HMD-VR we also restricted results to those published from 2015 onwards. All search results arising from the Boolean “AND” of the HMD-VR and games search results were screened. Title and abstract screening included any articles mentioning VR or games in a health context. The full text screening criteria are provided in Table HMD-VR health games were charted and tabulated according to the type of input technology implementation, health context , outcomes used in the evaluation of the game, and user engagement employed during game design, if any. Given the wide range of approaches to game design and reporting, a narrative review appeared the most appropriate approach. Accordingly, we summarized each reviewed game according to the MDA framework and narratively described observed trends. Furthermore, we tabulated outcomes related to evaluation of identified games according to therapeutic outcomes, game experience, technology acceptance, cybersickness, and open feedback. Tabulated results were also integrated into each topic of discussion.The complete search was conducted on March 16, 2020 and identified 140 potentially relevant articles. Deduplication yielded 94 unique articles. Title and abstract screening identified 47 articles related to HMD-VR, games, and health. Upon full-text screening, 30 articles were identified as describing HMD-VR games designed specifically for health contexts –77. One . Other health contexts ranged from addressing sensory disorders [Of the HMD-VR health games reviewed, the most common health contexts included physical exercise, motor rehabilitation, and pain related conditions. Physical exercise games were aimed at both healthy adults and those with various health conditions. For example, Tuveri and colleagues designed Rift-a-bike to engage a general audience in cycling-based exercise  while Eiisorders  to cogniisorders . Overallisorders –80. Howeisorders , 21. Perisorders . In suchVRheab [Conversely, HMD-VR games based on therapies involving physical movement were the dominant trend observed. In this context, the choice of interaction technology is particularly important. While HMD-VR provides the principle means of immersing the user in an environment, the quality of motion tracking determines the perceived realism of a user’s actions impacting the virtual environment . This teVRheab . TherefoHMD-VR health games have relied on the successful commercialization of economical VR headsets with suitable features for entertainment such as high-resolution displays, accessible development tools, and comfort. Moreover, the improved ability to track headsets with six degrees of freedom  allows for more natural and immersive interaction with virtual environments. Compared to traditional 2-dimensional (2D) displays, playing games within the greater immersion of HMD-VR can lead to overall greater satisfaction, with emphasis on engrossment and creative freedom . From thMotion controls allow users to interact with virtual environments using their natural body movements. In combination with HMDs, motion control allows for designing game mechanics that rely more on such natural movements, spatial awareness, and binocular vision e.g. puzzles requiring viewing and manipulating objects from multiple angles . Of the Lumapath said static and clear geometric shapes with high contrast helped them feel grounded, however the HMD’s weight became uncomfortable. Yet, videogame players have also demonstrated a willingness to tolerate such usability disadvantages in exchange for a more immersive experience [Cybersickness remains a persistent challenge in HMD-VR design considerations . Indeed,perience . HoweverHMD-VR health games presented game design with a range of detail Table ; 8 of 29As the majority of HMD-VR health games targeted physical exercise and motor rehabilitation, game design trends tended to follow the mechanics and aesthetics typical of exergames . A commoOnly three games involved narrative as a means of engaging end-users. For example, the upper-limb stroke rehabilitation game, “A Priest in the Air”, sets the player traveling through different countries in an air balloon to reach a king, using arm movements to guide the balloon into point-scoring objects . Other gConversely, a few game designs involved mechanics and dynamics that focused on aesthetics of sense-pleasure, discovery, and narrative. Gobron and colleagues used the mechanics of a robotic-pedal interface as piloting controls for a spacecraft ; in thisOverall, the HMD-VR game design discourse for health application echoes that of game design related to non-immersive VR health applications, where the focus remains on using numerical feedback and reward systems to drive motivation and engagement . For exaWithin the HMD-VR health games literature, there lacks a more thorough discussion of designing the game as a compelling game in-of-itself. From the games industry, one common way of discussing a game is in terms of its core loop: the primary repetitive series of actions that a player takes while interacting with the game . This isBeyond a well-designed core loop, the duration of the whole health game experience should also be explicitly addressed, whether as a course of treatment spanning several sessions or something lasting years. Commercially, some games are designed to be played through once or twice, e.g. puzzle or story-driven games, while most games are designed to be played repeatedly without limit. Given the latter is an implicit objective of most health games as behavior change tools, replayability is a crucial consideration. While the concept of replayability has been touched on , it has Renowned game designer Sid Meier once defined games as a series of interesting decisions . CertainOf the studies reviewed, 24 involved evaluation of HMD-VR health games while five studies were purely descriptive of the technology Table . MoreoveLumapath highlighted a need for more guidance through the game experience to aid usability [While therapeutic outcomes remain the principle indicator of a health technology’s overall usefulness, adoption by users is also crucial in determining the long-term viability of a technology . Adoptiosability . Indeed,sability , 71, 74.Quantitatively, constructs of technology adoption were evaluated in 16 studies primarily using ad-hoc questionnaires. These included constructs such as satisfaction, motivation or willingness to use, or ease of use. Validated measures such as the System Usability Questionnaire  appearedUltimately, the purpose of leveraging a game format is to support sustainable engagement with a therapeutic approach. As such, successful game design inherently supports adoption and serves as a means of behavior change for therapeutic adherence. In this respect, HMD-VR health games have been evaluated by how engaging an experience they are. For 12 games, gameplay experience was evaluated using ad-hoc Likert scale questionnaires, with occasional usage of more formal questionnaires such as the Game Experience Questionnaire  or IgrouIn order to improve the adoption potential of health technologies for patients, there have been increasing calls to incorporate stakeholder engagement throughout the technology development process, with particular emphasis on involving end-users , 43, 113Of the 29 HMD-VR health games reviewed, 4 indicated collaboration with clinicians for designing the game , 65, 74.Lumapath may involve older adults throughout the design process to help address topics such as guidance, input simplicity, or further capitalizing on exploration as the main motivating factor, rather than identifying such considerations in later testing. As such, participatory approaches may support a more democratic method of identifying and valuing person-centered considerations regarding usability, playability, and therapeutic value early and throughout the design process of HMD-VR health games.Engaging end-users through participatory approaches, including the field of co-design, may be particularly beneficial in the context of HMD-VR, as this context relies on more dynamic human–computer interactions with practical issues that can make implementation challenging. More participatory approaches aim to empower stakeholders as equitable partners in designing technology and are characterized by mutual commitment, learning, and alignment with stakeholder values . ParticiOf the studies reviewed, only one described engagement with end-users in the design process beyond a purely informant capacity. Eisapour and colleagues followed a participatory design approach involving both clinician users and end-users with mild cognitive impairment . Their aThe search strategy included articles explicitly using HMD and VR as specific terms. As such, we may not have captured articles using only the general term “virtual reality.” However, we deemed this strategy to have much greater specificity and identifies the most relevant articles with substantive discussion of HMD-VR.While a narrative approach is appropriate for the range of game design descriptions present in the articles reviewed, this approach is more interpretive than systematic or scoping reviews. For example, game design summaries required more interpretation where more design details were missing. As such, the findings of this review should be received accordingly. Nevertheless, the narrative approach allows for greater flexibility in situating the particular characteristics of HMD-VR health games within the nuanced context of health technology and game design.HMD-VR health games is a relatively new and growing field of tools for engaging clients in highly immersive games designed to address health contexts ranging from rehabilitation exercise to pain management to sensory disorders. Our review provides a holistic overview of the prevailing trends in designing HMD-VR health games, including health context, game design, technology implementation and adoption, and user engagement in the development process. Overall, HMD-VR health games typically involve obstacle-based challenges, points, and extrinsic reward systems to engage clients in interventions primarily focusing on health contexts related to physical functioning and pain. The technology used to implement these games reflects this trend, with many using skeletal tracking and stationary cycles. Less common were games with emphasis on narrative experiences and use of hand motion controllers, which may better align with non-physical exercise interventions. However, the extent to which game-based formats (versus non-game formats) or HMD-VR technology is most appropriate for less represented health contexts such as mental health requires more research. Nevertheless, we anticipate further growth in diverse and complementary HMD-VR health games.As HMD-VR technology continues to rapidly evolve, the opportunities and ways in which such games can address health contexts will continue to grow. However, these applications will continue to rely on fundamental principles of game design. Indeed, there is a reciprocal relationship between HMD-VR technology creating new design spaces for games and game design needs advancing HMD-VR technology. Given the complex intersection of this relationship with health needs, the associated game design discourse is often lacking. More in-depth and structured attention to how HMD-VR health games are designed as game experiences is needed. This will support greater understanding of what design strategies are most effective for achieving therapeutic goals, including adherence. Finally, future development HMD-VR health games may benefit from more application of participatory approaches such as co-design, that involve end-users throughout the development process. Successful alignment of these games with end-users’ needs and values ultimately maximizes the impact of health games by facilitating their adoption.Additional file 1: S1. Datasheet.


Life-space and falls efficacy are essential to physical independence and consistently predict disabilities. However, it remains unknown whether the CAPABLE, a disability prevention program, improves life-space and falls efficacy in older adults. We evaluated the effects of a home-based disability prevention program on life-space (N=194) and falls efficacy (N=233) among low-income older adults with restricted daily activities. The CAPABLE intervention consists of up to 6 one-hour home visits with an Occupational Therapist (OT), up to 4 one-hour home visits with a Register Nurse (RN), and up to $1300 worth of home repairs, modifications, and assistive devices with a handyman, during four months. Life-space and falls efficacy were measured by the Telephone Assessment of Mobility for homebound older adults and the Tinetti Falls Efficacy Scale at baseline and five months, respectively. Multinomial logistic regression and generalized linear models were used for data analyses. Participants in both samples were, on average, 75 years, predominantly black (86%) and female (85%-86%). Compared to participants in the control group, participants receiving the intervention were more likely to have improved  or unchanged overall life-space  vs. decreased overall life-space. Participants who received the intervention also had significantly higher falls efficacy in performing daily activities . Life-space and falls efficacy can be significantly improved by CAPABLE program. These findings provide more evidence for the reasons for the increased physical independence.


The results indicate that theta-tACS was beneficial for several cognitive functions, including working memory, executive functions, and declarative memory. Gamma-tACS enhanced performance in both auditory and visual perception but it did not change performance in tasks of executive functions. For attention, the results were less consistent but point to an improvement in performance with alpha- or gamma-tACS. We discuss these findings and point to important considerations that would precede a transfer to real-world applications.Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation technique that allows the manipulation of intrinsic brain oscillations. Numerous studies have applied tACS in the laboratory to enhance cognitive performance. With this systematic review, we aim to provide an overview of frequency-specific tACS effects on a range of cognitive functions in healthy adults. This may help to transfer stimulation protocols to real-world applications. We conducted a systematic literature search on PubMed and Cochrane databases and considered tACS studies in healthy adults (age > 18 years) that focused on cognitive performance. The search yielded  Transcranial alternating current stimulation (tACS) is increasingly being used as a method to modulate cognitive performance . tACS noThe modulation of intrinsic oscillations with tACS can be done in several ways , as showFor the modulation of cognitive performance with tACS, online effects can be distinguished from offline effects. By definition, entrainment occurs during stimulation —since the internal oscillation is coupled with an external oscillator. However, successful entrainment likely induces longer lasting aftereffects .For the present systematic review, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines . We pre-https://pubmed.ncbi.nlm.nih.gov/) and Cochrane Library (https://www.cochranelibrary.com/advanced-search). We used the following search terms:We systematically searched for published studies in English with no date restriction in the following databases: PubMed , executive functions, long-term memory, working memory, episodic memory.n = 15 for a within-subject or n = 20 for a between-subject design, and (4) stimulate continuously for at least 5 min.To be eligible for inclusion, studies needed to: (1) apply frequency-specific tACS, (2) focus on (at least) one of the above mentioned cognitive domains, (3) include healthy adults (>18 years or older) with a minimum of Following the PRISMA guidelines, two authors (SP and KK) screened abstracts and titles independently and analyzed studies that met inclusion criteria. We additionally screened the reference lists of included studies to identify additional studies. A third author (JP) monitored the inclusion process at any stage . All authors made a final decision on studies included in the descriptive synthesis.n = 109 studies, of which n = 57 met the inclusion criteria. The search yielded A comprehensive overview of all study designs, stimulation parameters, outcomes as well as risk of bias for all included studies can be found in In the following, we will more thoroughly describe the included studies for each cognitive domain.Auditory perception is the ability to detect, localize, and identify sounds. Therefore, typical auditory perception tasks test the detection of auditory signals within background noise or the differentiation of at least two acoustic signals.In Riecke and colleagues , delta/tZoefel and colleagues ,49 appliRufener et al.  applied Moliadze and colleagues  applied All included studies applied tACS online and placed electrodes over temporal areas. The stimulation duration varied between 18 and 40 min, with an intensity between 0.8 and 1.7 mA peak-to-peak.In sum, the results indicated that slow stimulation frequencies in the delta/theta range (3.125–4 Hz) modulated speech perception when directly aligned with speech rhythms. However, for an auditory signal lacking speech rhythm, delta/theta-tACS seemed to benefit the listener’s perception, when it slightly preceded the auditory input. The alignment of the timing of endogenous processes to exogenous auditory events may be associated with oscillatory activity in the delta/theta range that occurred in the auditory cortex ,87. ThisVisual perception is the ability to perceive the environment through the light that enters the eyes. Typical visual perception tasks include the detection or discrimination of visual stimuli, the identification of spatial relationships, and visual rotation tasks.Brignani et al.  stimulatHerring et al.  stimulatThe most common electrode montages for visual perception were mono- or bihemispheric at parieto-occipital or frontal areas. Stimulation duration varied from 5 to 27 min, with an intensity between 1 and 1.5 mA peak-to-peak. Frontal montages more frequently induced phosphenes.In accordance with previous suggestions of alpha’s role in information gating as well as top-down inhibitory control during visual perception ,20, alphIn very general terms, attention is the ability to focus on information. Attention is multifaceted, sometimes being driven by internal goals  and sometimes by external events . Typical tasks depend on the type of attention that needs to be evaluated: in tasks of sustained attention, participants need to respond to certain stimuli over a long period of time. In tasks of selective attention, they need to respond to one particular stimulus while ignoring others. In tasks of divided attention, they need to respond to two (or more) stimuli simultaneously. Other attention tasks include the assessment of a shift in attention or the investigation of the attentional blink effect.Clayton et al.  comparedHopfinger et al.  stimulatIn a study on selective auditory attention, Deng et al.  comparedIn two experiments, Yaple and Vakhrushev  applied For attention tasks, electrodes were placed mainly over left, right, or center positions of the parietal cortex. Most studies applied tACS online. Stimulation durations varied from 5 to 55 min, with an intensity between 1 and 2 mA peak-to-peak.Stimulation with alpha-tACS stabilized or improved sustained attention. On the contrary, alpha-tACS mainly inhibited selective attention performance, while gamma-tACS improved it. During attentional blink tasks, beta-tACS was particularly helpful to reduce the attentional blink. Since alpha plays an important role in the modulation of the focus of attention  as well Executive functions refer to higher level cognitive processes of planning, problem solving, action sequencing, effortful and persistent goal pursuit, inhibition of competing impulses, flexibility in goal selection, and goal conflict resolution. Typical executive function tasks involve judgement tasks, response inhibition tasks , or tasks that assess cognitive control.Kasten et al.  stimulatFusco et al.  stimulatWiener and colleagues  applied For executive functions, all studies applied tACS online. There was more variation in electrode placement than for attention or perception, as electrodes were placed at frontal, fronto-parietal, or parieto-occipital areas. All studies stimulated for 20 min with an intensity between 0.4 and 2 mA peak-to-peak. For fronto-parietal alpha- and beta-tACS, participants reported more visual and somatosensory side effects compared with delta, theta, and gamma.Theta-tACS as well as alpha-tACS led to increased accuracy and faster responses in a variety of tasks. This is well in line with the suggestion that higher cognitive load is associated with decreased theta and increased alpha and that the level of performance in executive function tasks depends on the interplay between both . Gamma-tWorking memory refers to the capacity to hold information in memory, while performing mental operations on this information. Typical working memory tasks include n-back tasks, digit span  tasks, or corsi block span tasks.In two experiments, Bender et al.  applied Polanía et al.  stimulatViolante  applied Borghini et al.  stimulatWolinski et al.  used twoGutteling et al.  stimulatJausovec et al.  comparedFor working memory, many studies applied tACS online. Comparable to executive functions, electrode montage varied largely and included frontal, fronto-parietal, and parieto-occipital areas. Stimulation duration varied between 6 and 15 min, with an intensity between 1 and 2.25 mA peak-to-peak. Stimulation intensities above 1.5 mA elicited phosphenes when applied close to occipital areas.Parietal theta-tACS enhanced working memory accuracy, while theta-tACS at frontal areas shortened reaction times. This supports the idea of theta’s involvement in working memory  and, morDeclarative memory refers to the ability to retain information about facts or events over a significant period of time as well as to consciously recall the information, usually in response to a specific request to remember. Typical declarative memory tasks are composed of encoding and retrieval  of words, pictures, or paired stimuli .Nomura et al.  stimulatSeveral studies applied stimulation during paired-associative tasks. De Lara and colleagues  applied Javadi et al.,  applied Alekseichuk and colleagues  stimulatAs for other complex cognitive functions, electrode montages differed very much and included frontal, temporal, and parietal areas. Most studies stimulated participants during encoding only, while only two studies stimulated participants during encoding and retrieval. Stimulation duration varied between 10 and 20 min, with an intensity between 0.75 and 3 mA peak-to-peak.In sum, theta-tACS as well as gamma-tACS improved recognition performance for verbal, visual as well as associative stimuli. Beta-tACS had no effect on recognition performance. Theta-tACS interleaved with bursts of gamma-tACS in theta troughs impaired word pair learning. A substantial amount of evidence points towards theta’s role in episodic memory encoding and retrieval . AdditioMotor learning refers to processes associated with practice or experience that lead to the acquisition/reacquisition of relatively permanent movement capability. Typical tasks include implicit or explicit motor learning tasks.Brinkmann et al.  used tACFresnoza and colleagues  applied Nowak et al.  applied For motor learning, electrodes were mostly placed at M1 (left). No effect on motor performance was found when the target electrode was placed on the right hemisphere. Both offline and online stimulation were used for procedural memory. Stimulation duration varied between 5 and 30 min, with an intensity between 0.7 and 2 mA peak-to-peak. Adjusting current intensities may be considered when the return electrode is placed over parietal areas to reduce the occurrence of phosphenes.Performance in the motor domain was mainly modulated by alpha- or beta-tACS. According to the literature, beta seems to be relevant for motor learning as a stronger beta power suppression has been linked to superior learning of a motor sequence .Decision-making is the cognitive process of choosing between two or more alternatives. Typical decision-making tasks include target–distractor differentiation tasks or preference-based decision-making.Yaple et al.  applied We could only include one study in this domain. The electrodes were placed at frontal areas and the stimulation duration was 40 min with an intensity of 0.5 mA peak-to-peak. Only beta-tACS increased voluntary (risky) decision-making. Frontal beta oscillations have been linked to reward anticipation and unexpected reward feedback ,96. In aTwo factors seem to underlie general intelligence: fluid and crystallized intelligence. Fluid intelligence refers to the ability to reason and think flexibly, while crystallized intelligence refers to the accumulation of knowledge, facts, and skills that are acquired throughout the life. Tests of fluid intelligence typically tap reasoning, such as Raven’s Progressive Matrices.Pahor and Jaušovec  applied Comparable to other complex cognitive functions, electrode montages were very different and included frontal, parietal, and temporal areas. Stimulation duration varied between 15 and 48 min, with an intensity between 0.75 and 2 mA peak-to-peak.Online gamma-tACS reduced the amount of time needed to solve the most complex of Raven’s Progressive Matrices, while offline theta-tACS increased accuracy on these complex items. In addition, initially low performers benefitted most from stimulation. Neither gamma- nor theta-tACS had an effect on solving easier items. Interestingly, online gamma-tACS had no effect on a verbal intelligence task, which examined crystalline intelligence. Thus, gamma-tACS may be particularly beneficial for fluid intelligence tasks. In general, fluid intelligence has been associated with theta-gamma coupling ; thus, cThis review summarized how tACS at varying frequencies modulated cognitive performance. The cognitive domains described in this review differ greatly in complexity. Auditory and visual perception, for example, are basic cognitive functions that often serve as a prerequisite for other, more complex functions. For these basic cognitive functions, this review revealed that online stimulation see E with enIn the real world, slow oscillatory tACS may be a useful tool to support processes of brain plasticity after the implantation of a cochlear device . The benAttention, executive functions, and working memory are essential cognitive functions required for higher-order processes. The studies on attention described in this review used visual or auditory stimuli and applied online stimulation, mostly with the goal of entrainment D. PerforFor executive functions, most studies applied online stimulation with the goal of entrainment. Faster responseswere induced by theta-tACS during response inhibition ,57,60 anFor working memory, only one study used offline stimulation: gamma-tACS improved n-back task performance . For onlDeclarative and procedural memory are complex cognitive functions that rely on basic cognitive functions . Studies that applied online stimulation during encoding found that theta-tACS increased familiarity-based recognition performance in young ,83 and oAll studies investigating tACS effects on motor learning applied stimulation online. Individual alpha-peak (IAF) tACS improved older adults’ implicit motor learning performance and alpha-tACS at IAF + 2 Hz improved performance in younger and older adults. On the contrary, online gamma-tACS slowed reaction times, while online theta-tACS had no effect on implicit motor learning ,63,66. GDecision-making and fluid intelligence are also highly complex cognitive functions. For decision-making, all studies applied stimulation online and aimed to entrain specific frequencies: beta-tACS induced riskier decisions, while left-lateralized theta-, alpha-, and gamma-tACS only led to faster responses . For fluIn sum, we found that theta-tACS was beneficial for several cognitive functions, including working memory, executive functions, and declarative memory. Gamma-tACS enhanced both auditory and visual perception but did not change performance in tasks of executive functions. For attention, the results were less consistent but indicated that with alpha- (sustained attention) or gamma-tACS (selective attention), performance was improved. A comparison of online vs. offline effects of tACS was only possible for some of the included cognitive domains. Gamma-tACS was more effective for improving visual discrimination performance  and n-baAlthough the results of our review are promising, we believe that some considerations need to be taken into account before a transfer of tACS from the laboratory to the real-world would be possible. Real-world situations are typically dynamic, complex, and difficult to control. In contrast, experiments in the laboratory are usually well-controlled and simplified, with artificial stimuli. Due to the complexity and dynamics of real-world situations, a breakdown of the individual contribution of each cognitive domain to performance in a cognitive task seems difficult . In addition, real-world situations may be noisier, with many distractors, so focusing on a particular stimulus may be more challenging than in the laboratory. At an intermediate point on the spectrum ranging from approaches with maximal control to those with maximal behavioral relevance, real-world-like laboratory experiments test cognitive functions in settings resembling everyday situations. Specifically, they constrain the range of potential processes present during the experiment by also using process-specific tasks adapted so that the noise characterizing real-world situations is still present, albeit in a more controlled fashion. This intermediate approach allows the study of cognitive functions by scaling up from the simplest to more complex settings that capture some aspects of the complexity of the real-world  while still remaining in the realm of well-controlled stimuli and well-understood tasks.Several attempts have been made for translating laboratory experiments to the real-world. For episodic memory, the What-Where-When task  examines® catalogue [Attention and working memory assessments can be translated into settings that are more realistic too. One study investigated whether working memory-driven attentional capture could also be found in a real-world visual search with stimuli taken from the IKEAatalogue . Anotheratalogue . Others atalogue . Still oatalogue .For other cognitive domains , a transfer to real-world applications might be more challenging. For perception, there are several differences between laboratory and real-life applications that may cause behavioral differences that are rather due to the experimental approach than to behavior. First, participants are typically immobile in the lab, since head movements are prevented with a forehead and chin rest. Second, aside from the respective visual or auditory stimuli, no other sensory input is given that would normally be integrated with the respective modality. Third, no interaction with the environment is possible in the laboratory. Virtual reality may be a step towards a transfer from the laboratory to the real-world.In any case, besides the behavioral assessments of tACS effects outside the lab, it may be particularly interesting to simultaneously apply electrophysiological recordings via EEG. During recent years, mobile EEG equipment has been developed that allows recordings of human brain activity outside the lab using small, wireless hardware and electrode arrays designed to minimize interference and the discomfort of the equipment for participants ,106,107.While tACS has been repeatedly shown to modulate human brain oscillations in the lab, there is evidence that its effects may strongly depend on brain states ,112 and We would like to note that more studies should examine the long-term effects of tACS on cognitive performance. Changes in oscillatory activity beyond the time of stimulation have been reported very frequently  but long-term effects on cognitive performance still need to be determined. We believe that these may help to design and conduct effective real-world paradigms. Besides controlling stimulation parameters, the influence of the menstrual cycle or hormones in general may be considered when planning tACS studies as these variables will likely influence the results.n = 20 (or n = 15 in the case of a within-subject design) might not achieve enough power to detect a true effect. However, the required sample size in a study depends on the reliability of the dependent measure, the design, and the statistical analysis plan, which is why the decision on a minimum sample size for an inclusion in a systematic review is challenging. Although some of the included studies reported a priori sample size calculations adjusted to their particular statistical analysis plan, we would like to encourage future studies to do so more regularly. In addition, we would like to encourage researchers to follow the recommendations of Button et al. [Our review might be limited by the predefined minimum sample size of studies to be included. A sample size of n et al.  to improThis systematic review summarized laboratory studies that applied tACS at varying frequencies to modulate cognitive performance. The successful transfer of tACS from the laboratory to the real-world first requires innovative approaches to validate tACS effects in less controlled environments. If successful, tACS may become a powerful tool to modulate everyday cognitive performance.


To estimate phenotypic and familial association between early-life injuries and attention deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses.Children born in Denmark 1995-2010  were followed from age five until a median age of 14 (IQR: 10–18 years). Using ICD-10 diagnoses, we estimated hazard ratios (HRs) and absolute risks of ADHD by number of hospital/emergency ward treated injuries by age five. In a subsample born 1995 to 2005 with genetic data available , we estimated incidence rate ratios (IRR) for the association between PRS-ADHD and number of injuries before age five and the genetic correlation between ADHD and any injury before age five.Injuries were associated with ADHD , in males  and females , with a dose-response relationship with number of injuries. The absolute ADHD risk by age 15 was 8.4% (3+ injuries) vs. 3.1% (no injuries).st- than 2nd-degree relatives. PRS-ADHD was marginally associated with the number of injuries in the general population , with a genetic correlation of 0.53 (0.21-0.85).ADHD was also associated with injuries in relatives, stronger in 1Early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD. However, even in children with the most injuries, more than 90% were not diagnosed with ADHD by age 15. Despite a low positive predictive value and that the impact of unmeasured factors such as parental behaviour remains unclear, results indicate that the association is partly explained by genetics, suggesting that early-life injuries may represent or herald early behavioral manifestations of ADHD. In typically developing children, impulsive and risk-taking behaviour is more common at a younger age, as are injuries. The ability to plan ahead and foresee unsafe situations improves with age, as executive brain functions mature, and this cognitive maturation is paralleled by a decrease in the risk of injuries. Since the 1960s, studies of pre-school children have found injuries to be correlated with inattention, hyperactivity, and impulsivity. Meta-analyses provide strong evidence that individuals with ADHD have increased risk of emergency ward visits, and unintentional injuries. Traumatic brain injury (TBI) may be causally linked to ADHD, whereas literature on whether other injuries early in life tend to precede a diagnosis of ADHD is sparse.Attention deficit/hyperactivity disorder (ADHD) is more difficult to validly diagnose before age five, as the diagnostic criteria relates mainly to older children, and the clinical presentation of ADHD may differ in pre-school and school. Besides subthreshold symptoms of inattention, hyperactivity, and impulsivity, little is known on early-life manifestations of ADHD. with heritability estimates of around 74%. Independently derived ADHD polygenic risk score (ADHD-PRS) predicts ADHD-status, subthreshold ADHD-symptoms, and other neurodevelopmental traits in the general population. Genome-wide association studies (GWAS) recently identified several genome-wide significant loci, and estimated that common genetic variants explain 22% of the heritability of ADHD.ADHD is a neurodevelopmental disorder, and depression and ADHD are genetically correlated. A twin study suggest a small genetic contribution to injuries before age five, with most variance explained by child-specific environmental effects (including ADHD-symptoms) and familial effects, several of which are known risk factors for ADHD, such as low socioeconomic status (SES), and young and single parenthood. Similarly, a Finnish twin study found little indication of a genetic contribution to injuries in adults. However, Acar et al. found that fathers of children admitted to the emergency ward due to an injury had higher ADHD symptom scores themselves, compared with fathers of children acutely admitted to hospital due to a throat infection. The cross-generational association between ADHD and injuries may be explained by home-environment, parental behaviour, parent-child interactions or genetics.Less is known about the aetiology of early-life injuries. Recently, a Danish register-based study found maternal depression to be associated with injuries during early childhoodWe hypothesize that similar to early subthreshold symptoms of ADHD, injuries before age five are early manifestations of ADHD and may associate with ADHD genetic liability. Using a large Danish population-based cohort, our aims were to (1) estimate the association between the number of injuries before age five and a later diagnosis of ADHD, (2) estimate the association between early-life injuries in siblings and parents and the risk of ADHD, (3) estimate the association between ADHD-PRS and the number of early-life injuries in the general population as well as the genetic correlations between ADHD and early-life injuries. holds data on personal identification number, sex, date of birth, and continuously updated vital status of all persons living in Denmark, enabling accurate linkage of individual-level data across registers. The Danish National Patient Register (DNPR) and the Danish Psychiatric Central Research Register (DPCRR) holds data on all-inpatient admissions, and out-patient and emergency ward visits from 1995 onward and provided data on injuries and psychiatric disorders diagnosed in hospital departments. Diagnoses were registered according to the International Classification of Diseases, 8th revision (ICD-8) in 1969-93, and 10th revision (ICD-10) since 1994. The Danish Neonatal Screening Biobank provided dried bloodspots and The Integrative Psychiatric Research (iPSYCH) consortium processed these for genotyping.Since 1968 the Danish Civil Registration System DNA collection, genotyping and quality control has been described elsewhere. Included individuals fulfilled these criteria: Singletons, born between January 1, 1995 and December 31, 2005, alive and residing in Denmark at age 1, both parents born in Denmark and no diagnosis of TBI before age five. We further restricted to individuals of European ancestry and for genetic correlation analyses to unrelated individuals. See Population-based cohort study of individuals born in Denmark of Danish-born parents between January 1, 1995 and Dec 31, 2010, and living in Denmark at age five. Individuals were excluded if they fulfilled any of these criteria before age five: ADHD-diagnosis or filled prescriptions of ADHD-medication, TBI, or disease of the nervous system. Genetic analyses relied on the population-based iPSYCH2012 case-cohort, including all ADHD cases (N=18 726) and 2% random sample of the general population (sub-cohort) (N=30 000).We defined early-life injury in cohort members and their siblings as a hospital-treated injury before age five. This age cut-off ensured complete coverage of injuries and that injuries preceded the ADHD-diagnosis. We included diagnoses of injuries from all hospital contacts , excluding TBIs  and contParental injuries were based on ICD-8/10 codes  and defiUsing data from DPCRR and DNPR, we defined ADHD as the first hospital contact to a psychiatric, paediatric or neurological department with a diagnosis of ADHD  after the age of five. ADHD subtypes included combined (F90.0) and inattentive subtype ADHD (F98.8). Based on funding available at the time, sampling of ADHD-cases for the iPSYHC2012 case-cohort sample only included cases with ICD-10 code F90.0. and BOLT-LMM software and combined in a linear combination to obtain final PRS  were estimated by Cox regression for the association between early-life injuries and ADHD, using age as the underlying time-axis. Analyses were repeated for the two ADHD subtypes and in strata of parental education (completed high-school yes/no). Individuals were followed from their 5Second, we investigated familial co-aggregation of injuries and ADHD, estimating HRs for associations between injuries in mothers, fathers, full siblings, maternal and paternal half-siblings (exposures), and ADHD in the index child (outcome). All analyses were adjusted for sex, birth cohort , and the interaction between sex and birth cohort. Analyses of parental injuries were additionally adjusted for the parent’s birth cohort . Analyses of average number of injuries in siblings were additionally adjusted for the number of full/maternal half/paternal half siblings . IRRs correspond to a relative increase in the rate of early-life injuries for a one standard deviation increase in the PRS-ADHD. These analyses were adjusted for sex, age and calendar year at first ADHD diagnosis (both continuous), genotyping wave , and the first four principal components (PCs) to adjust for potential remaining population stratification. The PCA method for deriving the PCs used for ancestry outlier removal and adjustment is described in detail elsewhere. Follow-up started at birth and ended at age five, a diagnosis of disease of the nervous system (ICD-10 codes G00-G99), death or emigration from Denmark, whichever came first.Third, incidence rate ratios (IRRs) were estimated by negative binomial regression with the logarithm transformed time-at risk as an offset for associations between PRS-ADHD and the number of injuries before age five. Due to the iPSYCH2012 case-cohort sampling design, including all ADHD cases and a 2% random sub-cohort, inverse sampling probabilities were applied as weights.All analyses were repeated in males and females and applied a cluster-robust variance estimator with clusters defined as individuals having the same mother and father and for half-sibling cohorts defined as individuals having the same mother or father.2SNP) and genetic correlation (rg) between early-life injuries and ADHD were estimated using BOLT-REML software among the iPSYCH2012 ADHD cases and subcohort. SNPs were filtered and LD pruned according to BOLT-REML suggested guidelines .The main analyses were conducted using Stata 15.iPSYCH is approved by the Danish Data Protection Agency, the Danish Health Data Authority, the Danish Scientific Ethics Committee, and the Danish Neonatal Screening Biobank Steering Committee.The study population consisted of 786 543 children born in Denmark between 1995 and 2010, followed for a total of 6 910 193 person-years, until a median age of 13.9 years (IQR: 9.9 – 18.0). In total, 92 691 (11.8%) individuals sustained an injury before age five and 23 107 (2.9%) individuals were diagnosed with ADHD after five years of age and during follow-up. In 34 452 (4.4%) study participants, follow-up ended due to death (n=423), emigration from Denmark (n=11 704), or TBI (including concussion) after age five (n=22 053).Having sustained at least one injury before age five was associated with a subsequent diagnosis of ADHD . Furthermore, an increasing number of injuries was associated with an increased risk of ADHD, suggesting a dose-response relationship . ChildreWe found no significant interaction between injuries (yes/no) and sex (p = 0.455) and associations were similar in sex-specific analyses .We observed a dose-response relation with higher cumulative incidence of ADHD by increasing number of injuries before age five . By 15 yst-degree relatives, including mothers , fathers  and full siblings   and paternal half siblings . The number of injuries in full siblings also increased the HR of ADHD in the index child incrementally. An average number of >2 injuries in full siblings was associated with an increased risk of ADHD , when compared to the risk of ADHD in full siblings without injuries. Similar sex-specific trends were observed (ADHD was associated with injuries in 133-1.46) . The assobserved .g = 0.53 (95% CI 0.21-0.85) , a higher PRS-ADHD was associated with a higher number of injuries before age five , with similar-sized estimates were for males and females . In unre21-0.85) .In this population-based cohort study of almost 800 000 children, early-life injuries were associated with a subsequent clinical diagnosis of ADHD. Having sustained at least one injury before age five resulted in a 64% higher risk of ADHD, relative to those without injuries before age five. The association showed a dose-response pattern, as increasing number of injuries was associated with incremental increased risks of ADHD. Children with three or more injuries had a 2.5-fold increased risk of subsequently being diagnosed with ADHD after age five, when compared with children without early-life injuries. and that ADHD-medication reduces this risk. ADHD is associated with more collisions when riding a bicycle, more risk-taking behaviour, impulsive decision-making, and in adults higher rates of serious traffic accidents. The risk of fatal injuries is also increased in individuals with ADHD and accidents is their most common cause of death.Decades of research provide strong evidence that ADHD is associated with a 39-53% increased risk of injuries, Here, we show for the first time using an objective measure, that early-life injury is strongly associated with later ADHD risk and that increasing number of injures before age five may be a marker of ADHD liability already prior to diagnosis.Other than symptoms of inattention, hyperactivity and impulsivity, little is known about what characterises children with ADHD in their first years of life, prior to being diagnosed. Some retrospective studies have found that children attending emergency wards have higher rates of ADHD-symptoms, than other children.st-degree than 2nd-degree relatives, and in the general population, genetic liability for ADHD, as indexed by ADHD polygenic risk scores, was marginally associated with early-life injuries. However, we also found a genetic correlation of 0.53 between ADHD and early-life injuries; a higher correlation than ADHD shows with other neuropsychiatric disorders. This suggests that their underlying genetic liability is partly shared. However, the SNP-based heritability of injuries was low (6%), in keeping with findings from previous twin studies that have found little evidence for a genetic contribution to injuries. Other shared familial risks could be related the psychosocial environment in the family, which is associated with both injuries and ADHD . Finally, our observations could also be explained by gene-environment correlation whereby genetic liability to ADHD increases the risk for environmental stressors; a phenomenon that to date has only been observed for social stressors.We also found familial co-aggregation of injuries and ADHD, which suggests that the aetiology of the two phenotypes includes shared familial risks. The associations were stronger between 1 Based on that, the concept of ‘accident proneness’ was presented in 1926. During the 1940s and 50s, several publications supported this concept, linking it with different psychiatric symptoms, including distractibility, impulsivity, aggression, impatience, opposition, restlessness, and hyperactivity, and also documenting familial aggregation of accidents. Later, the concept of ‘accident proneness’ was criticised for placing the responsibility of sustaining an injury solely on the injured individuals themselves. While our data suggest shared liabilities for injuries and ADHD, and that individuals more prone to injuries are more likely to have ADHD, this still explains very little of the variance in early-life injuries.We find that the risk of injuries may be linked to individual and familial characteristics, and not merely caused by external factors, which supports a hypothesis suggested in 1919. yet the validity of this ICD-diagnosis in the Danish registers is not fully known. However, we expect this misclassification to be non-differential by groups of the injuries exposure, meaning our estimates of association might be underestimated. Fourth, while BOLT-REML seems to provide robust estimates for the genetic correlation in a setting with shared controls and case-control ascertainments, the estimated SNP-based heritabilities are likely underestimated and should be interpreted with caution. Finally, even in children with the most injuries, more than 90% were not diagnosed with ADHD. Hence, with such a low positive predictive value our data does not support obtaining information about early-life injuries should be recommended as part of the clinical assessment for ADHD, or that such information would improve diagnostic validity.Major strengths of our study include the longitudinally recorded individual-level data on a population-based national sample in a country with free universal health. Furthermore, we were able to link the individual information with information in parents and siblings and to link with genetic information on all with an ADHD diagnosis and randomly selected controls. The randomly selected cohort enables us to present valid estimates of absolute risk in the general population, something most studies cannot. Furthermore, our similar findings among individuals of high and low educated parents suggest that the association between injuries and ADHD is only minimally biased by differences in hospital-seeking behaviour due to SES. However, our study also has some important limitations. First, we did not estimate the potentially mediating or moderating effects of other mental disorders often comorbid to ADHD (e.g. conduct disorder). Second, with TBI excluded we did not hypothesize a direct causal relationship between early injuries and ADHD and hence, we decided not to adjust analyses for e.g. parental SES or mental disorders. However, the impact of home-environment, parental behaviour, or parent-child interactions was not assessed and hence we were not able to fully disentangle the genetic and non-genetic contributions to the observed association. Third, we relied on previously validated data from the national health registries on clinical diagnoses of ADHD from hospital departments, and persons diagnosed by child and adolescent psychiatrists in private practices were not included. According to Danish guidelines, inattention without hyperactivity should be coded as F98.8,To conclude, our study adds important new findings to the literature on what characterizes children with ADHD, years before they are diagnosed and the data suggest that early-life injuries may be an early manifestation of impairment and risks related to symptoms of ADHD. Furthermore, the observed association between early-life injuries and ADHD is partly due to shared familial and genetic risks.Supplement


IBD symptoms, including pain, fatigue, and diarrhea, as well as potential life-long medical treatment and surgery, may be demanding, cause significant challenges, and influence self-esteem.The purpose of this study was to explore self-esteem and associations between self-esteem and sociodemographic, clinical, and psychological factors in patients with inflammatory bowel disease (IBD)In this cross-sectional multicenter study, participants were recruited from nine hospitals in the southeastern and western regions of Norway from March 2013 to April 2014. Data were collected using self-report questionnaires. Self-esteem was assessed by the Rosenberg Self-Esteem Scale, fatigue was assessed by the Fatigue Questionnaire, self-efficacy was assessed by the General Self-Efficacy Scale, and disease activity was assessed by the Simple Clinical Colitis Activity Index for ulcerative colitis (UC) and Harvey Bradshaw Index for Crohn’s disease (CD). Multiple linear regression analysis was applied to examine associations between self-esteem and sociodemographic, clinical, and psychological factors.In total, 411 of 452 (91%) patients had evaluable data and were included in this study. The mean scores on self-esteem, self-efficacy, total fatigue, anxiety, and depression were similar between UC patients and CD patients. Male gender, being employed, and higher self-efficacy were independently associated with higher self-esteem, whereas anxiety and depression were independently associated with lower self-esteem. Neither disease activity nor fatigue were associated with self-esteem in the final multiple regression analyses.Patient-centered interventions that improve self-esteem and reduce anxiety and depression seem to be important to optimize IBD management. Chronic disease and its consequences may be a threat to personal and social identity and, in particular, a person’s self-esteem. Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic inflammation of the gastrointestinal tract and results in recurrent symptoms such as abdominal pain and diarrhea, often with blood and mucus. In addition, patients may have systemic symptoms such as lack of appetite, weight loss, and fatigue, and a high proportion also report psychological comorbidities such as anxiety and depression –3. IBD aFor patients with IBD, symptoms may be experienced as socially embarrassing and as a stressor, which in turn has the potential to shape patients’ emotions, beliefs, and behaviors . Indeed,Self-esteem is a self-concept that refers to the positive and negative feelings and evaluations we have about ourselves and represents our sense of self-worth . While sThus, the aim of this study was to explore self-esteem in an adult IBD population and to investigate associations between self-esteem and sociodemographic, clinical, and psychological factors.In this cross-sectional study, participants were recruited from nine hospitals in the southeastern and western regions of Norway as part of an observational, multicenter study. The inclusion period lasted from March 2013 to April 2014. Inclusion criteria were age > 17 years; a verified diagnosis of IBD based on endoscopic, laboratory, and histological findings according to the Lennard–Jones criteria ; and theSociodemographic variables were self-reported by patients and included age, gender, marital status, educational level, work status, and smoking status. Clinical data were collected by interview, from medical records and from laboratory tests. The disease phenotype was classified according to the Montreal classification . DiseaseThe Rosenberg Self-Esteem Scale (RSES)  assessesThe Fatigue Questionnaire (FQ) was developed by Chalder et al.  and has The General Self-Efficacy Scale (GSE)  measuresThe Hospital Anxiety and Depression Scale (HADS) was developed to assess anxiety and depression among diverse clinical and nonclinical hospital populations . The HADχ2) test for categorical data and the independent sample t test for continuous variables with normal distributions. When the continuous variables had skewed distributions, they were described with medians and ranges, and differences between groups were tested using the nonparametric Mann–Whitney U test. Multiple linear regression analyses were used to determine the associations between self-esteem (dependent variable) and relevant sociodemographic, clinical, and psychological (independent) variables. In addition to gender and age, variables with p values < 0.15 in the univariate analyses were entered into a multiple linear regression model. None of the independent variables included in the final analyses were highly correlated (Pearson’s correlation coefficient > 0.7) with any other possible variable; thus, we assumed no multicollinearity. All tests were two-sided and analyzed using Statistical IBM SPSS Statistics for Windows version 25.0 .Differences between groups were assessed with the chi-square  gave written informed consent. Three patients were excluded due to missing data, bringing the number included in the analyses to 411 (91%). No significant differences in gender or age were found between the patients excluded due to missing data and those included in the analyses (data not shown).Patient characteristics are presented in Table The univariate and multiple associations with self-esteem are shown in Table The multiple linear regression analyses showed, in both UC and CD patients, that higher self-efficacy scores and male gender were independently associated with higher self-esteem. In UC patients, being employed was additionally independently associated with higher self-esteem. Increased anxiety and depression scores were independently associated with lower self-esteem. Clinical factors and fatigue were not significantly associated with self-esteem in the final regression analyses.The key findings in this study were that male gender, being employed, and higher self-efficacy were associated with higher self-esteem, whereas anxiety and depression were associated with lower self-esteem. Clinical factors were not associated with self-esteem.The mean self-esteem score found among the IBD patients in our study  is comparable to previously reported findings in an adult IBD population  . This maThe strong association between self-efficacy and self-esteem found in this study is in line with self-concept theories  and resuThe strong negative relationship between self-esteem and depression and anxiety found in our study is consequently not surprising and aligns with prior studies. In a meta-analysis including 77 longitudinal studies, low self-esteem predicted symptoms of depression and anxiety across gender, age, and populations . The strFatigue was associated with lower self-esteem in the univariate analysis. Increased fatigue scores have been consistently related to depressive symptoms in previous IBD studies 45–46). As self-esteem was strongly associated with depression in the current study, one might expect a relationship between increased fatigue and lower self-esteem as well. However, in the final regression analyses, neither total fatigue scores nor the mental and physical fatigue subscores were independently associated with self-esteem [–46. As sMale gender and being employed were factors independently associated with higher self-esteem in our study. The fact that males reported higher levels of self-esteem than females is consistent with previous research , 47. EmpClinical factors  did not independently influence self-esteem in our study. This is in line with a previous study of IBD patients . The impThe study has some limitations. The complex relationships between the factors examined in this study could not be well explored using a cross-sectional sign. It may be that self-esteem varies over time depending on social, psychological, and clinical status. A longitudinal design may provide a better understanding of how these different factors relate to each other. Moreover, we did not assess body image concerns, which could add important information to the findings in our study.In this adult IBD population, self-esteem was strongly associated with male gender, anxiety, depression, and self-efficacy but not with clinical factors. Patients with IBD vary by disease type, disease severity, surgical history, and sociodemographic and psychological presentation. Therefore, the care and follow-up of patients need to be individualized. Regardless of diagnosis, psychological factors were the strongest contributors to the variance in self-esteem in our study. Patient-centered interventions that improve self-esteem and reduce anxiety and depression seem to be important to optimize IBD management.


This study aimed at comparing bracket placement and excess bonding adhesive depending on different indirect bonding (IDB) techniques and bracket geometries.Four hundred eighty brackets without hook (WOH) and 360 with hook (WH) were placed on 60 plaster models. Three IDB techniques were tested: polyvinyl-siloxane vacuum-form (PVS-VF), polyvinyl-siloxane putty (PVS-putty), and translucence double-polyvinyl-siloxane (double-PVS). PVS-VF and PVS-putty were combined with chemically, and double-PVS was combined with light cured bonding adhesive. Virtual images of models before and after bracket transfer were generated, and computerized images were compared. Linear, angular deviations, and excess bonding adhesive were measured.P < 0.001). Hooks affected bracket placement accuracy in PVS-VF (P < 0.001) and PVS-putty (P = 0.029). Angular differences were observed for brackets WOH between the PVS-VF  and double-PVS group  (P < 0.001) and within double-PVS group . Highest amount of excess adhesive was obtained for PVS-putty group .Linear differences between the three groups were obtained for PVS-VF , PVS-putty , and double-PVS  (The double-PVS group revealed promising results with respect to transfer accuracy, whereas the PVS-VF group provided least excess bonding adhesive. Basically, hooks lead to lower precision and higher excess bonding adhesive. PVS trays for IDB generate high bracket placement accuracy. PVS-putty is the easiest to handle with and also the cheapest, but leads to large excess bonding adhesive, especially in combination with hooked brackets or tubes. Orthodontically treated fixed straight-wire appliances allow three-dimensional tooth movements. To reduce the need for arch wire bends or bracket repositioning, brackets should be ideally placed. Four parameters must be considered for achieving the ideal bracket position : 1) bracSilverman et al. was the first to introduce the indirect bonding (IDB) technique . For thiAnother important aspect of bracket attachment is excess bonding adhesive . A suffiThe present study aimed at investigating the influence of three different three-dimensional IDB techniques, as well as the influence of bracket geometry on bracket placement accuracy and excess bonding material. The first hypothesis was that neither the different transfer techniques nor the presence of hooks on the brackets would lead to differences between the working and transfer models of bracket position. Furthermore, the second hypothesis was that there are also no differences in the excess bonding adhesive depending on IDB technique or bracket geometry.Sixty plaster models  of a maxillary as well as mandibular typodont  were prepared. Thirty maxillary and mandibular models (10 per group) served as working models, and 30 served as transfer models. The working models were coated with a separating agent . After drying, adhesive pre-coated  brackets and tubes  were placed and adhesive excesses around the bracket were removed. Then the brackets were light-cured in ideal positions  on incisors, canines, premolars, as well as first and second molars  and 2 (PVS-putty), a two-part chemically cured bonding adhesive was used for IDB . Sealant part A was applied to the individual composite bracket base and part B to the transfer models. Each tray was equally seated with determined pressure by one investigator with both hands. After 3 min, the bonding adhesive was cured and the trays were removed from the lingual to the buccal side of the teeth. In group 3 (double-PVS), a light-cured bonding adhesive was used for IDB . After adhesive bonding, a low viscosity composite was applied on the individual composite bracket base  and trays were seated with determined pressure on the transfer models. Each tooth was subsequently exposed to LED light for 20 s, and the trays were finally removed from the lingual to the buccal side of the teeth. After tray removal, the brackets were again sprayed with scanspray and transferred to virtual reality using the 3D model scanner.Stereolithographic files were imported into the Geomagic Qualify software . Using automatic surface registration of the virtual models on the basis of an iterative closest point algorithm, working and transfer models were compared Fig. . TherefoP ≤ 0.05 was considered statistically significant. All results are expressed as mean ± SD.For each parameter, a mixed-model measure ANOVA was performed to examine the influence and possible interaction between the IDB techniques  and bracket geometry (with and without hook). Furthermore, the differences in maximum linear and angular deviations as well as excess adhesive were compared using the Tukey’s multiple comparisons post hoc tests using the statistical program Prism . Of 840 brackets, 11 remained in the trays after removal from the transfer model: 5 in the PVS-VF group , 4 in the PVS-putty group , and 2 in the double-PVS group .P-values are listed in Table P-values of bracket deviations and excess adhesive.The maximum linear and angular deviations of the brackets as well as the excess adhesive depending on the IDB techniques  and bracket geometry (WH and WOH) are shown in Table P < 0.001). Between the WH and WOH subgroups, significant differences were observed within the PVS-VF (P < 0.001) and PVS-putty group (P = 0.029).Statistically significant differences in maximum deviations were obtained between the PVS-VF  and PVS-putty  as well as the double-PVS group  for comparisons WH and WOH (P < 0.001) and for the comparison of brackets WH and WOH in the double-PVS group .Concerning the maximum angular deviation, significant differences between the groups were only observed between PVS-VF and double-PVS WOH , PVS-VF vs. double-PVS , and PVS-putty vs. double-PVS . No statistically significant differences were observed between the IDB techniques for brackets WOH. Within the subgroup, statistically significant differences were obtained in the PVS-putty group . For all measurements, the mean variation was basically higher using brackets WH, except for the maximum angular deviation in the double-PVS group.Highest excess adhesive values were determined after using the PVS-putty technique around brackets WH. Statistically significant differences were determined by comparing the excess adhesive between all IDB techniques using brackets WH: PVS-VF vs. PVS-putty . While the use of brackets WH and WOH combined with PVS-VF technique led to similar deviations in angulation, the combination with double-PVS technique conducted greater deviations for brackets WH. Ordinal effects for the bracket geometry existed between PVS putty and double-PVS, and a disordinal effect between PVS-VF and PVS putty. This means less deviation when using brackets WOH combined with PVS-VF technique  techniques . In contComparing the maximum angular deviations, significant differences were found only between the PVS-VF and double-PVS group. Likewise, differences in hook presence were observed only within the double-PVS group. Therefore, according to this parameter, the transfer material appears less important. Nevertheless, the interaction between the type of IDB technique and the bracket geometry seems to have an effect on the angular deviation.Compareing the results of the present study to Shpack et al. less angular deviation but more linear deviation was found. Shpack et al. reported a torque error about 3.02° and rotation deviation about 0.75 mm . The difGrünheid et al. also investigated the transfer accuracy of vinyl polysiloxane trays for IDB . PatientA common method for investigating excess adhesive around brackets is using a microscope combined with a corresponding computer measurement tool. For this purpose, the distance between the bracket edge and the most/least leaked adhesive margin was metrically registered. Multiple values for every bracket side must be measured for this technique; however, this only creates an estimate and does not perform an exact measurement. In the present study, for the first time, excess bonding adhesive was measured in three-dimensions depending on the IDB technique and bracket geometry. With regard to the excess adhesive, there were particular differences in the extent of the brackets WH depending on the IDB technique. The largest excess bonding material area was observed in brackets WH in the PVS-putty group followed by the double-PVS and PVF techniques. Between brackets WH or WOH, significant differences were observed only in the PVS-putty group. This is probably due to the fact that the hooks are not completely enclosed by the putty material and subsequently space for the adhesive resulted. Furthermore, it has to be taken into account that differences in the adhesive systems between PVS-VF or PVF putty and double-PVS existed and in the double-PVS group a low viscosity composite was slightly used. This could have had an impact on the flow properties in context of the entire bonding adhesive. However, the present results suggest no influence due the excess adhesive was the largest in the PVS group even no low viscosity composite was used here. Therefore, it can be assumed that both IDB technique and bracket geometry influence the placement accuracy; however, the combination of brackets WH and PVS-putty as the tray material leads to particularly large excess bonding adhesive area, which probably increases the risk of caries or white-spot lesions.Although the precision of the indirect bonding techniques of vinyl polysiloxane trays is already very high, there are significant differences between various materials, which can be additionally enhanced by the presence of hooks on the brackets. In this in-vitro study, the double-PVS group exposed promising results with respect to transfer accuracy, whereas the trays in the PVS-VF group offered least excess bonding adhesive and the highest bracket placement accuracy was generated in the PVS group. In this context it should be noted that PVS-putty is the easiest to handle with and also the cheapest, but leads to large excess bonding adhesive, especially in combination with hooked brackets or tubes. Regarding the present of hooks, those braces seem to be disadvantageous for IDB as they lead to lower precision and higher excess bonding adhesive. Further studies must show whether tooth positioning effects, tooth shapes or crowding, which must be expected in clinical practice will increase the measured transfer inaccuracies or might level off.