COVID-19 remains a significant public health problem in New South Wales, Australia. Although the NSW government is employing various control policies, more specific and compelling interventions are needed to control the spread of COVID-19. This paper presents a modified SEIR-X model based on a nonlinear ordinary differential equations system that considers the transmission routes from asymptomatic (Exposed) and symptomatic  individuals. The model is fitted to the corresponding cumulative number of cases in metropolitan and rural health districts of NSW reported by the Health Department and parameterised using the least-squares method. The basic reproduction number  Not only are they an ‘enclosed society’ characterized by a high degree of contact among people, but persons deprived of their liberty have little means to implement the necessary measures of COVID-19 prevention such as social distancing, hand hygiene and isolation.COVID-19, the disease caused by the novel SARS-COV-2 virus, is still posing a heavy burden on the health systems in many countries all over the world. In Australia, New South Wales (NSW) and other states have been highlighted as settings at particular risk of COVID-19 spread2. Seven local health districts such as Far West, Hunter New England, Mid North Coast, Murrumbidgee, Northern NSW, Southern NSW and Western NSW cover the rural NSW region2. Fig. There are six states in Australia, NSW is one of them and it is situated on the east coast of Australia. NSW connects Queensland to the north, Victoria to the south, South Australia to the west and encloses the entire of the Australian Capital Territory see Fig. . NSW is 3. Many countries have responded to the threat by diverting persons away from COVID-19 test centres. However, peer-reviewed literature regarding COVID-19 and places of positive test results is restricted to opinion pieces or commentaries. These universally emphasize the vulnerabilities of COVID-19 test centres during this pandemic. However, they make no attempt to enumerate the potential cause and consequences of an outbreak, nor set targets for inmate reductions. COVID-19 outbreaks in COVID-19 test centres  have largely gone unremarked in the peer-reviewed literature. In contrast, the ‘super spreader’ event onboard the Diamond Princess cruise ship has been the subject of numerous epidemiological publications4 leading to many lessons learnt.Concerns about COVID-19 occurring in places of positive test results have been made real from numerous outbreaks that have already taken place throughout the pandemic5. In this way, conditions of positive test results have been described as ‘amplifiers of infectious disease’6. Numerous outbreaks, particularly reports of influenza7 and tuberculosis8 demonstrate the propensity for outbreaks to spread rapidly.Experience with respiratory outbreaks and other diseases have repeatedly demonstrated that no matter how isolated a community is, it is not necessarily insulated from infection. Even where there are no complicating factors, such as the age distribution or the presence of individuals with greater susceptibility in the enclosed population, their organization tends to increase transmission and secondary infection risk9. Researchers have been using various models to provide insights and guide interventions to control the spread of COVID-19. These have been undertaken in various settings such as the epicentre of Wuhan, China10, in high-income countries to predict health service needs12, in middle-income countries to check the effects of total population and population densities14 to refugee camps and other low-income settings16.Modelling has been utilised as a tool to address gaps in knowledge and inform detention health policies in the prevention and control of infectious disease in detention settingsth of February 2022, 988,357 out of the 2,433,278 COVID-19 cumulative cases (around 40%) in Australia occurred in NSW17. Strong contingency planning is needed so that health authorities can act accordingly18. To this end, mathematical modelling offers an alternative source of information to enlighten preparedness and preventative interventions. Given the differences between metropolitan and rural areas in NSW, a model that allows different parameters under different control settings and locations is needed. Motivated by the continuing and distinctive spread of COVID-19 infections in metropolitan and rural areas of NSW  of the Critical individuals move to the Non-hospitalised and Hospital compartments at an average period To ensure the population size remains constant, we replace all deaths by newborns in the susceptible class. This includes deaths through natural causes, which occur in all states at a constant rate In this case, the model can be expressed by the following deterministic system of nonlinear ordinary differential equations:Given the non-negative initial conditions for the system above, it is straightforward to show that each of the state variables remains non-negative for all entclass1pt{minimaThis shows that the total population size entclass1pt{minima21.The basic reproduction number  are  are \doc in Eqs. –(7)\docuHere, these Ordinary Differential Equations (ODEs) in –14) are are14) aBy setting The matrix 22 The next-generation matrix, The dominant eigenvalue of The first term represents the probability of becoming infectious once infected with mean infectious period We provide detailed analysis, including the existence and stability of the equilibrium points, for the proposed COVID-19 model –(9) in t23. In order to parameterize the model, we obtained some of the initial parameter values from literature (see Table We estimated the COVID-19 model parameters from fitting different combinations of parameters in Eqs. –(9) to t29. For this purpose, we calculate the partial rank correlation coefficient (PRCCs)31 between each of the model parameters and several output variables  using a Latin Hypercube Sampling. Specially, a uniform distribution is allocated from half to fourfold baseline value  is tAs discussed in earlier sections, the scale and severity of COVID-19 transmission are directly related to the basic reproduction number 32:Thus, from the explicit formula for The sensitivity indices for the model –9) are  are 9) aAdditionally, contour plots of https://data.nsw.gov.au/search/dataset/ds-nsw-ckan-aefcde60-3b0c-4bc0-9af1-6fe652944ec2/details?q = .This study is based on aggregated COVID-19 surveillance data from the New South Wales (NSW) in Australia provided by the NSW government. No confidential information was included because mathematical analyses were performed at the aggregate level. We compiled data from the publicly available website 36 were considered to see their effectiveness in controlling the spread of COVID-19 in the population of the metropolitan and rural area. This is executed by introducing two time-dependent control variables i.ii.With consideration of the sensitivity result, control measures that were implemented to other diseases models37 is used to solve the subsequent optimal control problems38. The incremental cost-effectiveness ratio (ICER) is used to determine the intervention strategy for the cost-effective analysis that is the best value for money. We provide detailed analysis of the optimal control of our proposed model in the supplementary materials .The forward–backward sweep method39. Details of the numerical procedure for simulating the obtained optimality system are contained37.We implemented the Runge–Kutta fourth order forward and backward method using MATLAB programming language to solve the subsequent optimality system which consists of , which is defined as the extra cost per additional intervention outcome. Incrementally, when analysing two or more competing intervention policies, one intervention is associated with the next less effective option. The ICER numerator is given by the total difference in intervention costs, active COVID-19 cases averted costs and averted productivity losses if applicable, between each scenario and baseline. The ICER denominator is the total number of active COVID-19 cases averted. Hence, the following formula obtains the ICER:The total cost for each of the single implementation and mutual effort of the optimal control strategy is obtainable from the objective function (S13). The cases averted is invaded by computing the difference between infectious individuals with and without control strategy. Let, entclass1pt{minimaThe ICER results for entclass1pt{minimaComparing COVID-19 is one of the most pressing public health problems in NSW. Overall, the transmission dynamics and epidemiology of COVID-19 in NSW is not entirely understood. The NSW government initiated various intervention programs to eliminate COVID-19 last year. Although COVID-19 control in NSW has remarkably progressed—accurate contact tracing, availability of free diagnostic and treatment services, the participation of many partners such as community health care agencies and general practitioners, newer diagnostic services, sufficient human resources, sufficient capacity e.g. hospital admission capacity, and guidelines—more effort is required. To reduce COVID-19 incidence and prevent deaths from COVID-19 in metropolitan and rural health districts of NSW, we need to identify the critical factors for developing COVID-19 disease, improve preventive and management strategies, treatment effectiveness, and reduce failure of treatment in infectious individuals.In this study, we presented a mathematical analysis of transmission dynamics of the COVID-19 outbreak to deliver further understandings into the disease transmission and explore potential prevention and control strategies capable of reducing the disease spread at the metropolitan and rural districts for better health management in NSW. A compartmental mathematical model was formulated by subdividing the host population into Susceptible, Exposed, Mild, Critical, Non-hospitalised, Hospital, Recovered, and Death. The nonlinear mathematical model has been established by considering transmission routes from Exposed, Mild and Critical population individuals.The formulated model was fitted to the reported data at the metropolitan and rural health districts in NSW, Australia. The least-square method was applied to estimates parameters such as transmission rate 41 and formulated the optimal strategies for controlling the COVID-19 epidemic at metropolitan and rural areas in NSW. Two different control strategies were considered including preventive strategy 26. Therefore, our results suggest that the NSW government should improve preventive control interventions when only one control strategy is used. Naturally, this strategy actively decreases and/or stops the contact between susceptible and infectious individuals of COVID-19. However, combined implementation of preventive and management strategies is the most cost-effective measure for reducing the burden of COVID-19 in both metropolitan and rural districts in NSW.We implemented an optimal control approach via Pontryagin’s Maximal principle46, which is similar to our results. However, our finding also suggests that combining control strategy with health management strategy, including enhanced services facilities and health management is the most effective way to decrease the COVID-19 burden in metropolitan and rural districts in NSW, consistent with previous works45.Optimal control strategies have been applied in other endemic settings to minimise COVID-19 cases and intervention implementation costs. Previous studies show that preventive strategy is the best strategy for the single control strategy implementation to decrease COVID-19 cases and intervention costsFinally, in NSW, infectious disease surveillance is fully recognised, but the risk of bias cannot be precluded. More accurate data should be put in place to address concerns related to COVID-19. Accurate data leads to better estimation of crucial parameters, and this means our proposed intervention to decision support is data-dependent. Hence, local, state and federal level policy-makers need to adjust the possibility of under-reporting bias when investigating our outcomes. Therefore, more accurate data could be included in the model to explore the impact of preventive and management interventions on COVID-19 dynamics in NSW. Of the single intervention strategies, enhanced preventive strategy is cost-effective compared to management control strategy and prompt reducing COVID-19 cases in NSW. Yet, combining both preventive and management interventions is found to be even more cost-effective.In summary, the paper provides mathematical modelling and optimal control strategy of COVID-19 in metropolitan and rural health districts of NSW for better pandemic management in Australia. We derived the basic reproduction number and found that it’s play an important role in the outbreak of COVID-19 in both districts. Sensitivity analysis also performed to identify the most important risk factors and found that transmission rate had largest influence on COVID-19 prevalence. We adopted optimal control analysis via Pontryagin’s Maximal Principle and formulated the optimal control strategies for controlling the COVID-19 outbreak in NSW, Australia. However, in our model we considered the total population size is constant and mixes homogeneously. That means that each individual in a compartment has identical disease susceptibility, infectiousness and transmission frequency with others, which neglects social behaviours of children, younger and older people that are known to be important risk factors in the spread of COVID-19. In addition, in our model individual-level COVID-19 natural history is not incorporated and not justified based on any empirical evidence. Therefore, future research could focus on individual-level data and quantifying any data-oriented reporting bias and modelling appropriate priority-based vaccination coverage.Two different control strategies including preventive strategy and management control strategy were implemented to measure their cost-effectiveness for improved and consistent health service facilities to the communities. Among the two single-controls, the preventive control strategy is the most cost-effective. Therefore, when single control strategy is used, our results suggest that NSW government should improve preventive control strategy, reducing contact between infectious and susceptible individual. Our principal finding is that the combination of preventive and management control strategies such as the rapid provision of additional services means is the most impactful and cost-effectiveness strategy for reducing the spread of COVID-19 in NSW, Australia. The same modelling framework can be utilised for data obtained in other places around the globe.Supplementary Information.


The arterial switch operation is the gold-standard treatment for dextro-transposition of the great arteries. Long-term follow-up data are beginning to reveal its natural history and associated late complications, including various reoperations for those complications. Given the unique anatomy and the increasing longevity of these patients, there is a need for effective surgical repair options to address aneurysmal and degenerative changes in both neoaortic and pulmonic roots. Thereby, we describe our technique and the novel considerations for prosthetic choice with reconstruction of both the neoaortic root and pulmonary artery, with satisfactory postoperative results. An asymptomatic 28-year-old man with a history of dextro-transposition of the great arteries and arterial switch operation (ASO) after birth was found on routine follow-up with a congenital cardiologist to have progressive severe pulmonary regurgitation with dilated right ventricle (RV) and an aortic root aneurysm, measuring a maximum diameter of 55 mm on magnetic resonance imaging, with moderate aortic regurgitation . There wThe patient was taken to the operating room for an elective redo-sternotomy. The chest was opened, and scar tissue was dissected. Sufficient mobilization was achieved to free the RV, right atrium, and ascending aorta. The RPA crossed the aorta anteriorly, an anatomic result of a LeCompte manoeuvre from the ASO. Cardiopulmonary bypass was initiated with cannulations to the right femoral artery and right atrium. Cardioplegia was delivered into the aortic root and subsequently via direct coronary ostial cannulations.The aorta was transected above the sinotubular junction. A 3-mm VSD was identified at the membranous septum. The VSD was associated with a redundant fibrous rim, and thus, it was primarily closed with 2 interrupted 4-0 Prolene sutures. The root was aneurysmal, and the aortic annulus was measured 27 mm. The aortic valve was tricuspid with normal geometric heights. We therefore proceeded with a valve-sparing operation with the reimplantation technique. Both coronary buttons were dissected, and the aortic root was circumferentially skeletonized down to the ventricular-aortic junction. Using a row of nine 2-0 braided subannular sutures, the aortic valve was reimplanted within a 30-mm Valsalva graft , tying the annuloplasty sutures around a 24-mm Hegar dilator and a second layer of running 4-0 Prolene starting at each nadir and running up to the top of all 3 commissures. The coronary buttons were sewn to the neoaortic root with 5-0 Prolene running sutures.The PA was transected at the bifurcation. The pulmonary cusps were tricuspid, but thickened, shortened, and not amenable to repair. The native main PA and valve were resected. A 30-mm pulmonary homograft  was tailored and anastomosed to the native pulmonary bifurcation. The proximal homograft was anastomosed to the outflow tract of RV with running 4-0 Prolene sutures.The native ascending aorta was transected distally below the cross-clamp and anastomosed to the root graft with running 4-0 Prolene sutures.The RPA was distally stenotic, secondary to tenting from the ascending aorta. The RPA was transected, and a 4-cm-length 16-mm Dacron interposition graft was inserted with running 5-0 Prolene sutures, which completed the repair . Cross-cThe patient recovered well without complications and was discharged home on the fourth postoperative day. His transthoracic echocardiograms at discharge and at 3-month follow-up showed normal biventricular function, with no residual VSD. There was no aortic regurgitation with a peak gradient of 7 mm Hg. The pulmonary homograft was well seated with no regurgitation or stenosis.Long-term follow-up reports for ASO have shown excellent survivals of 87% survival at greater than 20 years.2We elected to preserve his aortic valve with the reimplantation technique as one would do given the anatomy. We decided further to reduce the aortic annulus diameter from 27 mm to 24 mm by tying subannular sutures against the 24-mm Hegar dilator to increase leaflet coaptation heights to achieve an optimal result with a longevity for this young patient.We routinely use pulmonary homografts to replace nonrepairable pulmonary valves, rather than other bioprosthetic valves for young patients. Recent data in redo-tetralogy patients for pulmonary regurgitation have shown that homografts had significantly lower transvalvular gradients on follow-up and lower rates of reintervention for structural valve degeneration, compared with bioprosthetics.After taking off the cross-clamp, we accidentally found that the rather stiff Dacron aortic graft exacerbated compressive tenting of RPA leading to more RPA stenosis, a consequence of the posterior positioning of the aorta in relation to the RPA.•For arterial switch operation patients requiring reoperation for lesions of the great arteries, there are important and novel considerations with regards to longevity, anatomy, and prosthetic choice to ensure continued satisfactory long-term results.In ASO patients who require complex repairs of both great arteries as in this case, careful preoperative evaluations, understanding the unique anatomy, and explicit planning are the keys to the optimal results of this type of redo surgery. This case provides a rationale to approach multilesion ASO late complications though further reoperative data are needed for favourable long-term outcomes.


Attention deficit hyperactivity disorder (ADHD) has been characterized by impairments among distributed functional brain networks, e.g., the frontoparietal network (FPN), default mode network (DMN), and reward and motivation-related circuits (RMN). In the current study, we evaluated the complexity and functional connectivity (FC) of resting state fMRI (rsfMRI) in pre-adolescents with ADHD for pathology-relevant networks.We leveraged data from the Adolescent Brain and Cognitive Development (ABCD) Study. The final study sample included 63 children with ADHD and 92 healthy control children matched on age, sex, and pubertal development status. For selected regions in relevant networks, ANCOVA compared multiscale entropy (MSE) and FC between the groups. Finally, differences in the association between MSE and FC were evaluated.We found significantly reduced MSE along with increased FC within the FPN of pre-adolescents with ADHD compared to matched healthy controls. Significant partial correlations between MSE and FC emerged in fewer regions in the participants with ADHD than in the controls.The observation of reduced entropy is consistent with existing literature using rsfMRI and other neuroimaging modalities. The current findings of complexity and FC in ADHD support hypotheses of altered function of inhibitory control networks in ADHD. ADHD occurs worldwide and is estimated to affect 5% of children and approximately 2.5% of adults . AlthougIn ADHD, altered functional connectivity has been reported in the default mode network (DMN), frontoparietal network (FPN), and reward and motivation-related circuits RMN; . ImportaAlongside functional connectivity analyses that assess the signal coherence between nodes, nonlinear analyses of neural signals from fMRI that characterize the signal complexity within a node have been proposed as measures for information processing capacity of brain areas and networks , or indiIn the current study, we aimed to address this critical gap in the extant literature and evaluated the functional connectivity and complexity of rsfMRI in pre-adolescents with ADHD for the three main networks commonly associated with ADHD: FPN, DMN, and RMN. We combined MSE complexity analysis with functional connectivity analysis to elucidate the functional alterations present in ADHD on network nodes, at node-to-node edges, and on nodal complexity and node-to-node connectivity interaction levels. According to the literature, we hypothesized that compared to the healthy controls, pre-adolescents with ADHD had lower MSE in the FPN and altered functional connectivity in the FPN, DMN, and RMN. Due to the lack of previous studies, we did not postulate a hypothesis in terms of the difference between ADHD and control groups on the association between MSE and functional connectivity.2.2.1We leveraged the baseline demographic, clinical, T1 structural, and rsfMRI data from the Adolescent Brain and Cognitive Development (ABCD) Study . The ABC2.23, 256 × 256 matrix, flip angle = 8°, and 2x parallel imaging. Other scan parameters slightly varied by scanner platform, i.e., Siemens Prisma, Philips, or GE 3T scanner16. Each participant had 3–4 eyes-open (passive crosshair viewing) rsfMRI scans, each of which was approximately 5-minutes in duration. All rsfMRI scans were collected using a gradient-echo EPI sequence of 383 volumes in total . Head motion was monitored during scan acquisition using real-time procedures to adjust scanning procedures as necessary.All T1-weighted scans were acquired with voxel resolution = 1mmFor the current study, we used rsfMRI run1 and run2. Spatial and temporal image preprocessing was performed in the CONN toolbox . Default parameter setup was used including motion-realignment, coregistration and normalization to MNI152 template space and smoothing with a 6mm FWHM Gaussian kernel. In the denoising process, white matter, CSF, and motion realignment parameters were included for temporal preprocessing and denoising of rsfMRI data. While motion-scrubbing was included in the preprocessing for functional connectivity analysis, this step was excluded for complexity analysis.2.32.3.1github.com/kayjann/complexity) for each preprocessed and denoised rsfMRI sequence for each participant. SampEn is defined as the natural logarithm of the conditional probability that a pattern length of Voxel-wise multiscale entropy (MSE) was computed using the in-house developed LOFT Complexity Toolbox  by 2  analysis of covariance (ANCOVA) on the mean MSE in each ROI was conducted with PDS (self-reported) and scan-site as covariates. We were only interested in the main effects of Group here and in this study’s other ANCOVA analyses. To reduce skewness and kurtosis , PDS scores were Rankit-transformed and then z-scored. These values were used as the continuous covariates in all the ANCOVAs in the current study. A Benjamini-Hochberg correction  was perfIn order to evaluate the association between complexity and ADHD behavior symptoms, the partial correlation between MSE and CBCL DSM5 ADHD scores controlling for sex, PDS z-score, and scan-site was computed for the whole sample. We also computed the partial correlation between SampEn at each temporal scale and the CBCL DSM5 ADHD scores controlling for the same covariates for the whole sample. Note that the CBCL DSM5 ADHD scores were Rankit-transformed and then z-scored in this partial correlation analysis.2.3.2After data preprocessing and denoising, the first-level analyses on functional connectivity were conducted for each participant across both runs using the CONN toolbox default setup. Time series were averaged over voxels in each ROI, correlated between each pair of ROIs using Pearson’s correlation analysis, and then Fisher’s Z-transformed. The same ANCOVA including PDS z-score and scan-site as covariates was then performed for functional connectivity (Fisher’s Z-transformed) using a seed-to-seed analysis. A Benjamini-Hochberg correction  was perfIn order to evaluate the association between functional connectivity and ADHD behavior symptoms, the partial correlation between functional connectivity and CBCL DSM5 ADHD scores controlling for sex, PDS z-score, and scan-site was computed for the whole sample. Note again that the CBCL DSM5 ADHD scores were Rankit-transformed and then z-scored in this partial correlation analysis.2.3.3z score) between functional connectivity (between each seed ROI and each other ROI) and MSE in each seed ROI for each group by controlling for sex, PDS z-score, and scan-site. A group comparison (ADHD vs. controls) was conducted on the partial correlations for each  linkage. The same analysis was repeated for the partial correlation between SampEn at each temporal scale and functional connectivity.To investigate the association between complexity and functional connectivity, we computed the partial correlation  by 2  ANCOVA on the mean MSE in each ROI was conducted with PDS z-score and scan-site as covariates. The same ANCOVA was repeated for SampEn at each temporal scale and for functional connectivity at each seed-to-seed edge.3.3.1There were no group differences in age 3.2t-tests indicated that the participants with ADHD had lower MSE values than the controls in all the ROIs in FPN  by 2  ANCOVA on the mean MSE in each ROI was conducted with PDS z-score and scan-site as covariates. Please refer to The same ANCOVA was replicated for functional connectivity at each seed-to-seed edge. It revealed significant main effects of Medication at two edges, i.e., left middle frontal gyrus-to-right frontal orbital cortex  reduced rsfMRI complexity in areas of the FPN in pre-adolescents with ADHD as compared to the matched controls, and (2) increased functional connectivity between anterior portions of the FPN in the ADHD group relative to the control group. We did not observe a significant group difference in terms of the association between complexity and functional connectivity in any interested linkage.The FPN has been hypothesized to play a role in instantiating and flexibly modulating cognitive control . CognitiThe observation of significant reductions in MSE in rsfMRI time series in pre-adolescents with ADHD was consistent with the findings in adults with ADHD using the same modality . Guan etenhanced connectivity within FPN, i.e., the right superior frontal gyrus and left middle frontal gyrus using the anterior cingulate gyrus as the seed in pre-adolescents with ADHD  by 2  ANCOVA on the mean MSE, SampEn at each temporal scale, and functional connectivity in each ROI was conducted with PDS z-score and scan-site as covariates. The result after correction indicated no significant main effects of Medication for MSE, SampEn at each temporal scale, and functional connectivity in any ROI. Second, it is worth mentioning that the patients included in the current work had no previous or current psychiatric diagnoses other than ADHD. Many previous complexity studies in ADHD indeed examined ADHD with potential various comorbidities such as oppositional defiant disorder/conduct disorder that might confound the results. The current results removed this concern and further confirmed the finding of reduced complexity. Moreover, the lack of a unified understanding of functional connectivity in ADHD across literature may be due in part to different rates of comorbid conditions in those studies. The current finding of enhanced functional connectivity in ADHD relative to the controls in the FPN might potentially contribute to clarifying the mystery and provide a greater understanding of this field. Third, due to the limitation of networkwise Benjamini-Hochberg correction, the group difference in terms of cross-network functional connectivity and cross-network partial correlation between MSE and functional connectivity was absent. However, we showed significant cross-network group differences in In conclusion, our analyses support the feasibility and utility of temporal signal entropy in investigating the changes in complexity of rsfMRI signals in pre-adolescents with ADHD when compared to healthy controls. We found reduced complexity in the anterior cingulate gyrus, bilateral middle frontal gyrus, and bilateral superior frontal gyrus in the FPN and greater functional connectivity in the right superior frontal gyrus and left middle frontal gyrus using the anterior cingulate gyrus as the seed in pre-adolescents with ADHD. We suggest that combining analyses of complexity and functional connectivity is a useful and easily obtainable measure to reveal changes in ADHD brain dynamics.Supplement 1


We assessed the feasibility and validity of remote researcher-led administration and self-administration of modified versions of two cognitive tasks sensitive to ADHD, a four-choice reaction time task (Fast task) and a combined Continuous Performance Test/Go No-Go task (CPT/GNG), through a new remote measurement technology system.n = 40).We compared the cognitive performance measures , omission errors (OE) and commission errors (CE)) at a remote baseline researcher-led administration and three remote self-administration sessions between participants with and without ADHD (The most consistent group differences were found for RTV, MRT and CE at the baseline researcher-led administration and the first self-administration, with 8 of the 10 comparisons statistically significant and all comparisons indicating medium to large effect sizes.Remote administration of cognitive tasks successfully captured the difficulties with response inhibition and regulation of attention, supporting the feasibility and validity of remote assessments. Extensive past research links attention deficit hyperactivity disorder (ADHD), in both children and adults, to a cognitive profile that indicates difficulties with the regulation of attention and aspects of executive functioning, such as response inhibition . CognitiWhile cognitive task administration typically involves the participant attending an assessment session at a clinic or a research center, the possibility of remote administration of cognitive tasks has immense appeal. Remote self-administration of cognitive tasks would enable long-term monitoring for either research or clinical purposes. The Covid-19 pandemic has further illustrated the importance of remote data collection methods for times when in-person visits to clinics may not be feasible. Diversity and inclusion of participants can also improve, as remote assessments are more accessible to less mobile individuals or those living in isolated areas. Yet remote self-administration of cognitive tasks is not without challenges; its validity must be demonstrated.We have recently developed a new remote measurement technology (RMT) system for adults and adolescents (ages 16+) with ADHD that also incorporates two cognitive tasks for remote self-administration. The initial goal for the development of the ADHD Remote Technology (ART) system is to enable long-term, real-world monitoring of symptoms, impairments, and health-related behaviors. ART is linked to the open source mobile-health platform RADAR-base  and consThe cognitive tasks in the ART system consist of modified versions of the Fast task and a combined CPT/GNG task. The Fast task is a four-choice reaction time task that probes attention regulation (see Methods for a full description of the task). Individuals with ADHD show increased reaction time variability (RTV) on the task, which is associated with neurophysiological measures of attention allocation and arousal dysregulation . Mean reAs part of a 10 week remote monitoring pilot study on the ADHD Remote Technology (ART) system that involved an initial baseline remote administration by researcher and three subsequent remote self-administrations of the cognitive tasks, we addressed the following research questions and tested the following hypotheses:Remote administration by researcher: Does remote administration of the Fast task and the CPT/GNG task by a researcher produce the ADHD-control differences expected based on past research? Our hypothesis is that participants with ADHD perform less well than control participants on each of the outcome variables  at baseline administration by the researcher. The pilot study was carried out during the Covid-19 pandemic, which required remote (rather than in-person) baseline assessments by the researcher. The demonstration of the validity of such remote assessments is therefore the first step.Remote self-administration: Does remote self-administration of the Fast task and the CPT/GNG task produce similar ADHD-control differences as observed during the baseline researcher-administration of the tasks? Our hypothesis is that participants with ADHD perform less well than control participants on each of the outcome variables  at study week 2 (first self-administration).Group differences at study weeks 6 and 10: Are similar ADHD-control group differences still observed at study weeks 6 and 10? We have no directional hypothesis here, as it is uncertain how participants may cope with the repeated administration of these typical ADHD tasks that are designed to be challenging for people with ADHD and are therefore purposefully rather monotonous.https://www.callforparticipants.com/). Exclusion criteria for the individuals with ADHD were: (1) having psychosis, major depression, mania, drug dependency, or a major neurological disorder, (2) any other major medical condition which might impact upon the individual’s ability to participate in normal daily activity, (3) pregnancy, (4) IQ of <70 and (5) not currently taking medication for their ADHD. Exclusion criteria for the control group were: (1) meeting diagnostic criteria for ADHD based on the self-report on Barkley Adult ADHD Rating scale on current symptoms (BAARS-IV) and Barkley ADHD functional impairment questionnaire, (2) having psychosis, major depression, mania, drug dependency, or a major neurological disorder, (3) any other major medical condition which might impact upon the individual’s ability to participate in normal daily activity, (4) pregnancy, and (5) IQ of <70.We recruited 20 individuals with ADHD and 20 control participants between the ages of 16 and 39 into the study . ParticiThe study was approved by the North East—Tyne and Wear South Research Ethics Committee (REC reference: 20/NE/0034). Informed consent was obtained from participants before the assessments started. Participants were compensated £30 after completion of the baseline sessions, £20 after the first remote active monitoring follow-up (end of week 5) and a further £50 at study endpoint (end of week 10).ART-pilot is an observational non-randomized, non-interventional study, using commercially available wearable technology and smartphone sensors, representing no change to the usual care or treatments of participants due to participation.https://projectredcap.org) baseline questionnaires. The second session was administered once participants had received their wearable device and smartphone by post, approximately a week after the first session. The second session included: (1) administration of two cognitive tasks (the Fast task and the combined cued continuous performance test (CPT-OX) and Go/NoGo (GNG) task), and (2) a training session on the use of the wearable device, and a smartphone Passive and Active App. The participant also received a leaflet summarizing key information (Participant Technology User Guide) and researcher contact details for future reference. Each session lasted for approx. 1.5 hr. Control participants were assessed in the same way, except that instead of the full ADHD diagnostic interview, they completed the ADHD symptom and impairment questionnaire  the Diagnostic Interview for ADHD (DIVA) in adults  to confiionnaire .Immediately following the second baseline session, participants then took part in a 10-week remote monitoring period, which included passive and active monitoring measures. Passive monitoring involved using the RADAR-base smartphone Passive App and a wrist-worn activity monitor (Fitbit Charge 3) , 2022.Active monitoring involved the participant completing clinical symptom questionnaires on the RADAR-base smartphone Active App, which is beyond the scope of this current analysis, and the two cognitive tasks on their home PC or laptop, and took place three times: at 2 weeks (the first remote self-administrated assessment), 6 weeks (the second remote self-administrated assessment) and 10 weeks (the third remote self-administrated assessment) after the baseline remote researcher-led session. We asked participants to complete the cognitive tasks in a quiet environment, free from distraction. Participants received an event notification on the Active App, which reminded the participant that it was time to complete their questionnaires and the cognitive tasks. Participants were asked to complete the cognitive tasks within 3 days of receiving the event notification. However, where the participant had to delay completing the tasks , the data were included in the analysis. Each participant was in the study for 10 weeks.The Fast task is a computerized four-choice RT task, which measures performance under a slow-unrewarded and a fast-incentive condition . In bothThe combined CPT/GNG task probes attention and response inhibition. The version we have developed for ART is partly based on a CPT-OX task we have used previously  but furtThe BAARS-IV is an empirically developed self-report measure, based on DSM diagnostic criteria, for assessing current ADHD symptoms . The scaThe BFIS is a 10-item scale used to assess the level of functional impairments commonly associated with ADHD symptoms in five areas of everyday life: family/relationship, work/education, social interaction, leisure activities, and management of daily responsibilities. The BFIS has a reported alpha of .92 . The resThe Diagnostic Interview for ADHD in Adults (DIVA) is a validated structured interview for ADHD . The DIVThe vocabulary subtest of the Wechsler Abbreviated Scale of Intelligence (WASI-II)  was admiThe digit span subtest of the Wechsler Adult Intelligence Scale WAIS-IV;  was admit-tests to examine group differences in age and WASI-II vocabulary subscale, and the chi-square test to test for a group difference in gender. We compared the performance measures in the cognitive tasks at four time points  between participants with ADHD and controls. Specifically, we calculated MRT, RTV, OE, and CE for the combined conditions of the CPT/GNG task. Similarly, we calculated MRT and RTV for the combined conditions of the Fast task. The exclusion criteria were uncompleted tasks, implausible reaction time (<150 ms), and proportion of correct responses lower than 50% (for the CPT/GNG task). The number of excluded data points is given in p-value ≥ .05 was considered normal distribution  and to avoid over correction for multiple comparisons involving multiple correlated variables. Effect sizes were estimated as the standardized Z value divided by the total number of samples for the Wilcoxon rank-sum test. For small, medium and large effect size, the required thresholds are 0.1, 0.3, and 0.5, respectively  system, we show that both remote researcher-led administration and self-administration of cognitive tasks capture the difficulties people with ADHD have with the regulation of attention and response inhibition, supporting the feasibility and validity of remote assessments. Reaction time variability (RTV), mean reaction time (MRT) and commission errors (CE) were the variables most consistently sensitive to ADHD-control group differences at the remote baseline researcher-led administration and the first remote self-administration, with medium to large effect sizes . Subsequent remote self-administrations of the tasks showed that group differences became small and non-significant at week 6, but emerged again as significant for the Fast task RT variables at week 10.The remote researcher-led cognitive assessments indicated the expected ADHD-control group differences  on nearlp = .07); all effect sizes were medium. On the Fast task, a significant group difference, with a medium effect size, emerged for RTV. Overall, these results indicate that remote researcher-led task administration of the Fast task and CPT/GNG task is a valid alternative to the traditional in-person task administration with adults and young people with and without ADHD.less well than control participants on RTV, MRT, and OE, with the CE result further at trend-level (The first remote self-administration (week 2) produced overall similar ADHD-control differences as observed for the researcher-led baseline administration. At week 2, the group comparisons on the CPT/GNG task RTV and MRT, and Fast task RTV remained significant; the OE result was no longer significant, however. In addition, the group comparisons on the Fast task MRT and CPT/GNG task CE were now significant too. Effect sizes were medium to large. This illustration of how remote self-administration of cognitive tasks can successfully capture the difficulties with attention regulation and response inhibition in adults and young people with ADHD is highly promising for future remote measurement studies. Aspects of the set up and research process that may have contributed toward this successful outcome include: the training on task administration provided as part of the baseline researcher-led session, and clear written task instructions.p-values of .11 and .06). Due to the lower numbers of completed tasks at week 10, with data available from only 12 participants with ADHD, the statistical power for the week 10 CPT/GNG task analyses would be substantially reduced for MRT and RTV. The overall variability in these results of showing group differences only at week 10 and not at week 6 might relate to factors that influence how well participants cope with repeated administration of tasks that are purposefully rather monotonous. Future research with larger sample sizes may investigate this variability further.Further repeated remote self-administrations of the tasks resulted in significant group differences at week 10, but not at week 6. For the Fast task, group comparisons for both RTV and MRT were significant at week 10, with medium effect sizes. For the CPT/GNG task, no group comparison was statistically significant at week 10, but medium effect sizes emerged also for MRT and RTV  that did not pick up significant group differences in this pilot study. Another limitation of the study is that we were unable to randomize the order with which the cognitive tasks were presented due to our programing settings. We have improved this in our new, ongoing European Commission-funded clinical study “ART-CARMA”  versus those that are enduring differences . Using the Fast task and a CPT-OX task, our previous ADHD follow-up study indicated that attention-vigilance measures, including RTV, were markers of remission, whereas executive control measures were not sensitive to ADHD outcomes (persistence/remission; . IQ furtRemote monitoring technology and the mobile-health platform infrastructures supporting them are bringing major advances and opportunities for longitudinal research. One advantage is the possibility to collect data simultaneously, in the real world, on a wide range of both novel and conventional measures. Our data here show that remote self-administration of cognitive tasks, designed for ADHD research, is a feasible part of such remote data collection for studies on adults and young people with ADHD, supporting their inclusion in the ART system.