Dementia is under-diagnosed in primary care. Timely diagnosis and care management improve outcomes for patients and caregivers. This research evaluated the effectiveness of a nationwide Continuing Medical Education (CME) program to enhance dementia-related awareness, practice, knowledge and confidence of general practitioners (GPs) in Australia.Data were collected from self-report surveys by GPs who participated in an accredited CME program face-to-face or online; program evaluations from GPs; and process evaluations from workshop facilitators. CME participants completed surveys at one or more time-points  between 2015 and 2017. Paired samples t-test was used to determine difference in mean outcome scores  between time-points. Multivariable regression analyses were used to investigate associations between respondent characteristics and key variables. Qualitative feedback was analysed thematically.Mpost-pre = 0.9, p <  0.0005), practice-related items , knowledge , confidence . Significant increases were seen in all four outcomes for GPs who completed these surveys at both pre- and follow-up time-points. Male participants and those who had practised for five or more years showed greater change in knowledge and confidence. Age, years in practice, and education delivery method significantly predicted post-program knowledge and confidence. Most respondents who completed additional program evaluations (> 90%) rated the training as relevant to their practice. These participants, and facilitators who completed process evaluations, suggested adding more content addressing patient capacity and legal issues, locality-specific specialist and support services, case studies and videos to illustrate concepts.Of 1352 GPs who completed a survey at one or more time-points , mean scores increased between pre-CME and post-program for awareness (The sustainability of change in key elements relating to health professionals’ dementia awareness, knowledge and confidence indicated that dementia CME programs may contribute to improving capacity to provide timely dementia diagnosis and management in general practice. Low follow-up response rates warrant cautious interpretation of results. Dementia CME should be adopted in other contexts and updated as more research becomes available. Dementia (Major Neurocognitive Disorder) is a syndrome characterised by deterioration in memory, problem-solving and behaviour resulting in reduced functional ability in daily activities . DementiGeneral practitioners (GPs) are the customary first point of contact for people with dementia and their caregivers. They play a pivotal role in symptom recognition, assessment and referral  and are The timely diagnosis of dementia in primary care requires GPs to be able to differentiate normal ageing from dementia , 28. DifContinuing Medical Education (CME) are ongoing education and retraining programs for licensed medical professionals incorporating clinical guidelines and best research evidence to foster demonstrated changes in the performance, knowledge, skills, actions and attitudes of practicing professionals , 43. CMEThe Supporting GPs and Practice Nurses in the Timely Diagnosis of Dementia project was commissioned by Dementia Australia  . The proDementia: 14 Essentials of assessment and care planning” [Dementia: 14 Essentials of management” [In accordance with RACGP guidelines, the CME program comprised a minimum of 6 hours of thematically-linked structured educational content, including at least two-thirds interactive or experiential content (such as case studies and discussion) and three to five learning outcomes , 45. Thelanning”  and  categories  .Participants who attended face-to-face sessions completed paper-based pre- and post-program surveys. Participants who engaged with the education online began the CME with the pre-program survey and exited the CME with the post-program survey. All participants who provided an email address for follow-up received: 1) an emailed invitation to take part in the follow-up survey containing a link to the survey on SurveyMonkey; 2) an emailed reminder after 7 days; 3) an emailed reminder after 14 days.Program evaluation feedback forms required for CME point allocation were collected online and by the event organizer at GPCE events; research team members collected required forms from GPs attending small group workshops. GPs evaluated the CME program by rating the extent to which their learning needs were met  and the extent to which the program was relevant to their practice . GPs were also given the option to provide summative feedback about the program and recommendations for improving the program.All process evaluation data was collected between June and July 2017. Workshop facilitators received an emailed invitation to take part in the process evaluation. A copy of the questionnaire was attached to the emailed invitations. Facilitators were offered the choice of responding by completing and returning the questionnaire by email or by answering the questions over the phone with a research assistant. Workshop facilitators evaluated the program implementation process by answering open-ended questions regarding barriers and enablers to workshop delivery, aspects of the program format and workshop organization, and how to improve future workshop delivery. Questionnaire items are noted in Additional File Survey response rates were calculated as the number of returned questionnaires divided by the total number of individuals who enrolled in the CME program. Descriptive statistics were used to analyse participant demographic characteristics. Due to small numbers in Outer Regional and Remote and Very Remote categories, Inner and Outer Regional were combined and recoded as “Regional” and Very Remote was coded with “Remote” for analyses. Chi-squared tests were used to compare characteristics of participating GPs with characteristics of GPs in Australia generally , and to A composite index was calculated to represent participant level of awareness and current practice in managing care at each time point. Each composite index was based on a participant’s average response to survey items within each of the two categories (awareness and practice) and adjusted for missing values by dividing the total score by the total number of responses. Additionally, an overall average score was calculated for each item for awareness and for current practice. Mean scores were also calculated for knowledge and confidence, respectively, at each time point.Immediate training effects were calculated for individual items for all respondents using the average difference between pre- and post- CME program scores. Subgroup analysis was used to explore potential variability in the effects of face-to-face and online delivery methods. Paired t-tests were used to compare the mean scores of six to nine month follow-up and pre-CME program from the subset of participants who completed surveys at all three time points in order to examine longitudinal effects of the program on the GPs’ overall awareness, practice, confidence and knowledge, respectively.Pre- CME program scores were dichotomised for awareness  and practice . Logistic regression was performed controlling for participant characteristics  and program delivery method (online and face-to-face) to assess the factors significantly associated with: 1) the likelihood that GPs would endorse that they were aware, as opposed to unaware, of dementia diagnosis and management topics, and; 2) the likelihood that GPs would endorse that they applied recommended diagnosis and management actions in practice more than half the time, as opposed to less than half the time, prior to engaging in the CME program. Linear regression was performed, and the same variables were controlled in order to assess the impact of GP characteristics on knowledge and confidence at pre- and post-program.The analysis of qualitative data synthesised and summarised both GP and facilitator comments and recommendations for improving the CME program. Examples of both GP and facilitator feedback were coded thematically, and results summarised in a narrative manner.n = 2342) engaged online rather than face-to-face. Of the 44% of GPs (n = 1732) who enrolled for the full 40 CME point program, 83% completed all required activities .Of 3923 unique GPs who participated in the educational program between July 2015 and July 2017 , just over 33% (n = 1303) responded at baseline, 51.4% (n = 2017) responded at post-program, and 3.5% (n = 138) responded at follow-up  of GPs who responded at baseline were 45 years of age or younger, 51.2% (n = 670) were women, 68.6% (n = 882) practised full-time and 19.2% (n = 259) were GP registrars. Over 36% (n = 451) practised in regional and remote areas. The majority of GP respondents  attended the program face-to-face  and less than 35 years of age  compared to that reported nationally , and lower proportions of GPs working in major cities  and remote areas , compared to the national workforce.A higher proportion of GP participants were female  = 13.48, p < 0.0005, with a higher proportion of males engaging online  compared with females . Practice location was associated with choice of program delivery method x2  = 44.12, p < 0.0005. Compared to GPs practising in regional and remote areas, those practising in major cities were more likely to engage with the program online than face-to-face , knowledge , and confidence . Sensitivity analyses indicated that registrars had slightly lower scores compared to GPs pre- CME program; scores increased significantly for both registrars and GPs between pre- and post-program  of the GP respondents were 55 years of age or older, over half  had been in practice more than 20 years, and nearly 90% had engaged face-to-face. These GPs reported higher mean scores at six to nine months follow-up than reported pre- CME program in all four outcomes  = 48.58, p < 0.0005 and distinguished between respondents who were aware and those who were unaware of key dementia diagnosis and management topics prior to engaging in CME. Although the model correctly classified 78.3% of cases, it explained only 4% (Cox and Snell R-square) to 6.1% (Nagelkerke R-squared) of the variance in awareness and thus indicated that participant characteristics had little association with prior awareness of topic areas. The model for practice was significant x2  = 58.69, p < 0.0005, correctly classified 53.3% of cases and explained 5 to 6.4% of the variance in practice.Results of logistic regression of GP characteristics on pre- CME program awareness and practice are provided in Additional file OR = 1.84), than were GPs with fewer than 5 years’ experience.At the pre- CME program stage, face-to-face participants were 2.15 times more likely than online participants to report awareness of key elements in the diagnosis and management of patients with dementia, and 1.5 times more likely to report that they incorporated recommended diagnosis and management actions in practice more often than not. GPs who had practised 11 to 15 years were twice as likely to endorse both awareness of topics and use of diagnosis and management methods in usual practice than were GPs with fewer than 5 years’ experience, controlling for other factors in the model. GPs with more than 20 years’ experience were similarly more likely to endorse actions in practice  = 7.75, p < 0.0005. The total variance in confidence scores explained by the model as a whole was 8.6% (Adjusted R Square), F  = 10.45, p < 0.0005. Participants’ sex and years of practice experience contributed significantly to the model. Male participants had slightly higher self-rated pre- CME program knowledge and confidence scores compared with female participants. Having up to 5 years of practice experience was associated with lower self-rated knowledge and confidence scores than having more than 5 years’ practice experience, controlling for other variables.Results of linear regression of GP characteristics on pre- CME program knowledge and confidence scores are provided in Additional file F  = 11.02, p < 0.0005 and for confidence was 14.9%, F  = 14.50, p < 0.0005. Program delivery method, age and years of practice experience contributed significantly to the models for post-program knowledge and confidence scores. Face-to-face delivery was associated with slightly lower self-rated knowledge and confidence scores than online delivery. Compared to being less than 35 years of age and having fewer than five years practice experience (respectively), being at least 45 years of age and having between 5- and 20-years practice experience were associated with higher self-rated knowledge and confidence scores at post-program.Results of linear regression of GP characteristics on post-program knowledge and confidence scores are provided in Additional file n = 1005) returned a program evaluation survey. Most GPs (86.9%) felt that their learning needs were entirely met and that the program was entirely (91.9%) relevant to their practice. Examples of GP feedback are detailed in Additional file Over a quarter of GPs (Most GPs 6.9% feltEight workshop facilitators (53.3%) completed a process evaluation survey. Examples of facilitator responses are detailed in Additional file GPs who participated in the survey evaluation of this accredited dementia-focused CME program indicated that their awareness, use of tools and management strategies in practice, and knowledge and confidence in diagnosing and managing dementia in practice, increased following participation in the CME. The program reached approximately 11% of the nation’s GPs during the study period. Participants were generally aware of most topics covered in the CME prior to participation in the program, but some GPs were unaware of key areas such as the difference between MCI and dementia, the cumulative anticholinergic effect of medications, and legal issues involved in care and management of dementia. Results for participants who were followed across all three time-points indicated that significant improvements were maintained with little decline at six to nine months post- CME program. The declining trend in follow-up survey highlights the importance of offering continuous training and keeping participants abreast of the most up-to-date knowledge and evidence. Outcomes of this evaluation informed tailoring of the educational material and delivery methods of the CME program  as it continued to provide dementia-focused education through the triennium ending in 2019, and were a first step toward measuring impact.Online modules attracted the most professionals. Online education allowed GPs to proceed at their own pace and GPs completing modules online may have taken more time with the materials. Concurrently, results add to existing evidence that many GPs clearly remain interested in attending face-to-face training with colleagues , 48. GenSurvey respondents who engaged in the face-to-face program included GPs who attended large GPCE and / or small group workshops. Professional conferences such as GPCE attract large numbers and are more suited to delivering short educational sessions and less-intensive CME programs. However, large numbers limit individualised interaction with participants and shorter sessions may allow less time for participants to absorb and reflect on materials. Small group workshops and/or online modules provide greater scope for delivering interactive, time-intensive programs. These differences may account in part for better outcomes for GPs who completed the program online.GP characteristics had little practical association with awareness and current practice prior to the CME program and no association with their post-program outcomes. However, age and number of years in practice influenced self-reporting of knowledge and confidence. GPs with five or more years in practice reported more knowledge and confidence prior to the program than did their less experienced colleagues. GPs 45 years and older and those with between 5- and 20-years’ experience reported more knowledge and confidence after completing the CME than did their younger colleagues and those with fewer years in practice. Results are consistent with previous studies reporting that older, more experienced GPs feel more confident and knowledgeable than their younger counterparts regarding dementia-related care .Six-hundred and fifty-seven GP registrars engaged in the program. Although all GPs reported better outcomes after participating in the CME program, registrars rated their own knowledge and confidence as below average going into workshops and just above average afterwards. Registrars having had less time in practice were less likely to have accumulated dementia-related case-knowledge compared with their more experienced colleagues. Registrars also participated in the shorter, overview workshop rather than the longer, 40-point CME workshop and this may have contributed in part to observed differences in age and experience effects. However, in a similar recent evaluation of dementia education, GP registrars self-reported pre-workshop levels of dementia knowledge were comparable to those of their more experienced supervisors .Few GPs chose to continue research participation at six to nine months' follow-up. Participants were not asked about their motivation for participating. Age and practice experience appeared to influence longitudinal participation rates, as did CME program engagement method. Greater practice experience and possibly greater experience in dementia-related care may have made some GPs more receptive to the longer research commitment. GPs who interacted with colleagues face-to-face in group workshops may have been more willing to contribute to the CME research than were GPs who completed CME independently online.Participant and facilitator feedback suggested that more tailored information on local services was desired. GPs emphasised the importance of involving local health care professionals who could provide local knowledge, as well as including caregivers of people living with dementia. As described previously , 53, CMEWorkshop facilitators noted geographical distance and small numbers of practising health professionals as barriers to conducting workshops in some regional and remote areas. Facilitators noted that some attendees in regional and remote venues had their first face-to-face professional contact with a geriatrician or specialist at the workshop. Australia’s population is concentrated primarily in major metropolitan areas along the country’s east and south-east coast and the south-west coast . Lack ofParticipants and facilitators flagged the need for more education addressing assessment of client capacity, legal issues and guidelines related to dementia and end of life issues, pharmacological management, and social impact for the client and family. These ongoing needs for training, education and specific guidelines to clinicians are widely acknowledged in the medical and legal community , 61. PhaThis study has several strengths. It is the first study to investigate the effectiveness of a nation-wide accredited dementia-focused CME program in Australia designed to enhance GP awareness, practice, knowledge and confidence in delivering timely diagnosis and management of dementia in general practice. Delivery and evaluation of the education program involved collaboration with multiple stakeholders including a national dementia advocacy organisation, a government-funded consortium of dementia education providers, private industry providers of medical education, and national medical professional accreditation organisations. The evaluation attracted a substantial, heterogeneous sample of GPs including a significant proportion of GPs practicing in regional areas.The research ascertained GP self-appraisals of awareness, practice, knowledge and confidence regarding dementia-related topics. It synthesised data from self-evaluations, program evaluations, and process evaluations to identify current gaps in GP awareness, to track program effectiveness in improving self-reported capacity, and to identify areas for improving future training.Limitations of this study include absence of a control group, use of a purpose-designed survey, participant self-selection, low survey response rates relative to the number of program participants, and use of self-report data. While participant self-selection could have introduced bias, the sample represented over 10% of Australian GPs. The study employed a one-group pretest-posttest design. It is possible that completing surveys prior to engaging in the education could have raised participants’ awareness of specific topics and therefore altered how they approached the education as well as their responses on the posttest.Scales exist to measure GP dementia knowledge and awareness , 63, 64.The CME evaluation included self-report of current practice and intended practice, but it did not measure planned practice change –67 usingLow response rates are not uncommon in survey research with GPs and study response rates were similar to those reported elsewhere , 70, 71.Survey participants self-selected and may have been more motivated than other GPs. Survey participants were generally younger than the national GP profile; GPs over 45 were under-represented. Follow-up response rates were low and comparison of GPs who submitted surveys at all three time-points with GPs who submitted surveys only at pre-, or at pre- and post- CME program indicated that longitudinal results primarily represented outcomes for face-to-face workshop attendees with greater practice experience. Longitudinal outcomes for online participants and GPs with less time in practice and registrars are not well represented. However, whilst acknowledging that there were differences between GPs who completed surveys at all three time-points and the majority who did not, results for completers and others were similar.Although GP self-report provides insights into how GPs perceive their own abilities and educational needs, physician self-assessment is less accurate compared to external observations of competence . FurtherDementia-focused education is useful and relevant for GPs of varied experience levels. Most GPs had general awareness of dementia topics which improved further following education. Registrars had less knowledge and confidence in dementia-related assessment and management and may benefit from greater exposure to dementia education.The CME program met GPs’ educational needs in both face-to-face and online formats. Time-poor GPs may prefer less background theory and more applied, practical information delivered in condensed formats such as reference sheets, webpages and video clips. The development of online learning modules provided a readily accessible free resource for GP self-directed CME training. The modules are now offered as an ongoing dementia training resource . Online Meeting perceived educational needs and increases in self-rated indices of key outcomes may or may not translate to measurable improvements in practice. In order to address parameters influencing GP intention and implementation of practice change consistent with course objectives, future CME development and evaluation should involve a theory-based practice change approach with data triangulation to validate and enhance interpretation. In order to determine the sustained effectiveness of the CME program and identify emerging GP educational needs, future research should examine diagnosis rates and accuracy and adherence to clinical guidelines , gauge cGPs have a pivotal role in dementia recognition, assessment and referral, and are well-situated to provide continuing care co-ordination and support for patients. The scale of GP engagement showed that dementia CME programs, delivered both face-to-face and online, are relevant to GPs. The sustainability of self-reported change in key elements relating to dementia awareness, knowledge and confidence by health professionals taking part in this program showed that dementia CME programs may contribute to improving capacity to provide timely dementia diagnosis and management in general practice. Dementia-focused CME programs should be continued and updated as more research becomes available. Future research should measure outcomes in practice.Additional file 1. Figure S1. Flowchart of survey response rates in a convenience sample of GPs engaged in dementia-focused CME.Additional file 2. Table S1. Comparison of GP characteristics with national average.Additional file 3. Table S2. Use of CME program delivery method by age and practice location .Additional file 4. Table S3. Mean score change for subset of GPs who submitted surveys at each of two time-points.Additional file 5. Table S4. Logistic regression of General Practitioner characteristics on pre-CME program awareness and practice.Additional file 6. Table S5. Linear regression of General Practitioner characteristics on pre-CME program knowledge and confidence.Additional file 7. Table S6. Linear regression of General Practitioner characteristics on post-CME program knowledge and confidence.Additional file 8. Table S7. Exemplars of General Practitioner suggestions for improving future dementia-focused Continuing Medical Education programs.Additional file 9. Table S8. Continuing Medical Education workshop facilitators’ responses to process evaluation survey questions.Additional file 10. Completed SURGE (SUrvey Reporting GuidelinE) checklist.


In Australian prisons approximately 20% of inmates are chronically infected with hepatitis C virus (HCV), providing an important population for targeted treatment and prevention. A dynamic mathematical model of HCV transmission was used to assess the impact of increasing direct-acting antiviral (DAA) treatment uptake on HCV incidence and prevalence in the prisons in New South Wales, Australia, and to assess the cost-effectiveness of alternate treatment strategies. We developed four separate models reflecting different average prison lengths of stay (LOS) of 2, 6, 24, and 36 months. Each model considered four DAA treatment coverage scenarios of 10% (status-quo), 25%, 50%, and 90% over 2016–2045. For each model and scenario, we estimated the lifetime burden of disease, costs and changes in quality-adjusted life years (QALYs) in prison and in the community during 2016–2075. Costs and QALYs were discounted 3.5% annually and adjusted to 2015 Australian dollars. Compared to treating 10% of infected prisoners, increasing DAA coverage to 25%, 50%, and 90% reduced HCV incidence in prisons by 9–33% (2-months LOS), 26–65% (6-months LOS), 37–70% (24-months LOS), and 35–65% (36-months LOS). DAA treatment was highly cost-effective among all LOS models at conservative willingness-to-pay thresholds. DAA therapy became increasingly cost-effective with increasing coverage. Compared to 10% treatment coverage, the incremental cost per QALY ranged from $497-$569 (2-months LOS), -$280–$323 (6-months LOS), -$432–$426 (24-months LOS), and -$245–$477 (36-months LOS). Treating more than 25% of HCV-infected prisoners with DAA therapy is highly cost-effective. This study shows that treating HCV-infected prisoners is highly cost-effective and should be a government priority for the global HCV elimination effort. Nearly 200,000 Australians have hepatitis C infection, a leading cause of liver-related deaths, with around 400 deaths per 100,000 population are attributed to hepatitis C virus (HCV) infection in 2015 . The risRecent advances in HCV treatment have revolutionised the clinical management of viral hepatitis. The development of direct-acting antiviral (DAA) therapy for HCV provides a safe and highly effective cure rate of over 95% –8. In MaPrisoner populations are characterised by high rates of exposure to blood-borne viral infections such as HCV –15. The Transmission of HCV in prison is strongly associated with injecting drug use and sharing contaminated injecting equipment . Around We developed a mathematical model that describes HCV transmission dynamics in the NSW prison setting, accounting for key risk behaviours (e.g. injecting drug use), prison dynamics (e.g. duration of incarceration), natural history of HCV-related liver disease, and healthcare costs associated with DAA treatment interventions and burden of living with HCV. Mathematical models are useful tools for understanding complex dynamical systems, such as infectious disease epidemics and are typically used to study the mechanisms of disease spread and to predict future disease outbreaks. Future transmission of infectious disease epidemics such as HCV are difficult to predict, but by using mathematical models to identify dominant factors of disease transmission, future patterns of disease spread and impact can be predicted. Mathematical models provide transparency, and the calibration phase of modeling enables epidemiological assumptions to be tested by comparing model results with observed patterns , 25. By The mathematical model is compartmentalized and implemented as a system of ordinary differential equations detailing sub-populations of prison inmates according to injecting drug use, sharing of injecting apparatus, and liver disease status. The DAA treatment interventions were modelled for 30 years in prison (2016–2045), with healthcare costs and quality-adjusted life years (QALYs) tracked for a further 30 years post prison (2046–2075) to capture long-term costs and health gains from high cure rates. We assumed status quo for 2016 with HCV treatment coverage providing DAA treatment to 10% the prison population regardless of liver disease stage (F0 to F4) and genotype, using a nurse-led model of care . The modThe model tracks the acute stage (A) of HCV infection which results in spontaneous clearance in 25%  of casesThe model calibration was conducted using available data on HCV incidence and prevalence , 25%, 50%, and 90% treatment coverage .The costs of treatment including the cost of the DAA medication and delivery under a nurse-led model of care were assigned according to the perspective of the NSW Justice Health and Forensic Mental Health Network and Corrective Services NSW, the former providing medical services to prisoners in NSW and the latter security. Salaries for nursing and medical staff to administer the treatment program and pharmacists’ were sourced from Australian Government’spublished pay scales . The cosAccordingly post-treatment, the annual public healthcare resources consumed for lifetime care (burden of disease) associated with HCV infection and sequalae were calculated from a healthcare perspective. Micro-costing methods were used to determine the unit costs and volumes of the annual care of patients with HCV stages F0-F3 (first year and subsequent years), F4 (compensated cirrhosis), decompensated cirrhosis, liver failure, and hepatocellular carcinoma. Costs included specialist visits, clinical care nurse visits, pathology, medical procedures, and hospital admissions. Unit costs were obtained from the Australian Medical Benefits Scheme(assuming 100% government benefits) for medical services, procedures, and pathology tests. Medication costs were sourced from the Australian Pharmaceutical Benefits Scheme , 31. InpThe cost-effectiveness analysis applied the costs and QALYs to the forecasted epidemiological outcomes using the trajectory of HCV infection among Australian prison detainees over a treatment period of 2016–2045, and follow-up period to 2075. Health state utilities used in the derivation of the QALYS were obtained from the literature and attached to each liver disease stage . QALYs wIncremental cost-effectiveness ratios (ICERs) were reported separately for the four LOS models . Within each model a pair-wise comparison was conducted between 10% DAA coverage with 25%, 50% and 90% coverage of HCV-infected inmates, resulting in 12 scenarios. The ICER was expressed as the incremental change in total costs and QALYs relative to 10% DAA coverage for each LOS scenario. Strategies were considered to be cost-effective if they generated an ICER less than the willingness-to-pay threshold (lambda) considered to represent good value for money for healthcare interventions in Australia  .The uncertainty around the costs and QALYs was explored through probabilistic sensitivity analysis (PSA) . This waA Net Monetary Benefit (NMB) approach was also used allowing multiple alternatives to be assessed for cost-effectiveness without requiring repeated pair-wise comparisons and allows the most cost-effective alternative to be easily identified for different willingness-to-pay thresholds. The NMB is defined as: –). NMB is calculated by assuming a threshold for willingness-to-pay, then converting QALYs into the corresponding dollar values. The cost associated with each treatment strategy is then subtracted by the baseline scenarios, resulting in the net benefit of each strategy expressed in the monetary units.The model predicted a sharp decline in new HCV infections in all LOS scenarios . SimulatAnalysis of prevalence showed a linear increase over time, regardless of the average LOS, and lower prevalence with higher treatment coverage . The incThe number of NSW male prisoners treated between 2016–2045 ranged from 21,473 in the 36-month average LOS in prison with 10% coverage to 176,985 prisoners in the 2-month average LOS in prison with 90% coverage. The total cost attributed to the treatment of HCV-infected prisoners over a 30-year treatment period (2016–2045) plus the lifetime cost of care for a further 30 years ranged from $3,469 to $3,997 million with 10% DAA coverage . IncreasTreating 25% of infected prisoners was less costly and more effective for all LOS except 2 months LOS. The cost per QALY gained increased with increasing DAA coverage. For example, for the 6-month average LOS prison model; compared to 10% treatment coverage of HCV infected prisoners, treating 25%, 50%, and 90% of infected prisoners resulted in ICERs of -$280, $88, and $323, respectively. Similarly, for the 36-month average LOS prison model, treating 25%, 50%, and 90% of infected prisoners resulted in ICERs of -$245, $268, and $477, respectively . AdoptinUsing a dynamic model of HCV transmission, compared to treating 10% of HCV-infected prisoners, the incidence of HCV infection in NSW prison was reduced by 26% to 70% depending on the average LOS in prison and the uptake of DAA therapy. Taking into account the cost of treatment and lifetime care costs of living with HCV, our model indicates that DAA therapy is increasingly cost-effective with increasing coverage in prisons among all LOS and at least 25% coverage of HCV-infected inmates. All ICERs for an HCV-infected prisoner were below $500 when life-long health-related quality of life were considered which is lower than the Australia’s willingness-to-pay threshold $28,000 per QALY gained, and thus considered good value for money in terms of healthcare expenditure.Most of the benefit from treatment in prisons is realized in the community following release. Our model therefore not only looked at the reduction in HCV prevalence in prison, but also the long-term cost, health-related quality of life and cost-effectiveness of DAA therapy when prisoners are released back to the community. The fact that much of the costs associated with treatment is carried by the state prison budgets  rather than national healthcare budget suggests that prison budgets should be compensated for the health and custodial infrastructure costs of delivery of the DAA treatment, where drug costs are covered by the Commonwealth Government of Australia.Ensuring access to treatment for large numbers of individuals with chronic HCV infection has put prisons firmly in the spotlight as a setting in which to identify and treat large numbers of hard-to-reach individuals impacted by HCV . InternaTo our knowledge, only one other study has specifically investigated the cost-effectiveness of DAA treatment in the prison setting . This stThe strength of this study is that it investigates several treatment scenarios in prison and included the long-term cost and outcomes both in prison and the community associated with HCV treatment and care. A limitation of this study is that is does not track reinfection of those treated, that is, it assumes that once cured individuals it goes back to the susceptible population. The rates of reinfection in inmates are relatively high, estimated to be 5.27 cases per 100 person years under older interferon-based treatments . HoweverIn conclusion, treating HCV-infective prisoner is highly cost-effective and should be a priority for the global HCV elimination efforts.S1 File(DOCX)Click here for additional data file.


Blood samples were collected for the assessment of the inflammatory biomarkers C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), IL-10, IL-18, and monocyte chemoattractant protein-1 (MCP-1). Data were analyzed using multiple linear regression models. Total and bouts of ≥10 min of sedentary time were inversely associated with the anti-inflammatory marker IL-10 in older men . Associations were independent of moderate-to-vigorous physical activity (MVPA) and total PA volume. In women, total and bouts of ≥10 min of sedentary time were detrimentally associated with the pro-inflammatory marker fibrinogen . Associations remained between accumulated sedentary time and fibrinogen when adjusting for MVPA and total PA volume. This study highlights sex-specific routes by which sedentary patterns impact on pro- and anti-inflammatory biomarkers in older adults. The findings support efforts to promote accumulation of time spent in PA at the expense of time in sedentary pursuits on low-grade inflammation in older men and women.The study aimed to examine sex-specific associations between objectively measured sedentary patterns and pro- and anti-inflammatory biomarkers in older adults when considering the moderating impact of physical activity (PA). Accelerometer-based monitoring of sedentary patterns and PA was conducted in a population of older men ( Leading a sedentary lifestyle is implicated with increased risk of several chronic conditions, including cardiovascular and metabolic diseases . In thisAssociations have been evidenced between daily sitting time, including TV viewing time, and the two common acute-phase reactants CRP and fibrinogen, indicating a potential detrimental influence of a sedentary lifestyle on systemic inflammation . HoweverAnother important question to address is whether potential links between sedentary patterns and pro- and anti-inflammatory biomarkers are independent of physical activity level. Some studies have previously reported independent associations between sedentary time and a few clinical markers of inflammation, indicating that moderate-to-vigorous physical activity (MVPA) time may not mitigate the detrimental impact of sedentary time . HoweverTaken together, to what extent sedentary patterns are associated to systemic inflammation independent of PA level in older adults, and whether these links are sex-specific, remains to be clarified. Such knowledge is warranted in order to tailor sex-specific guidelines on health-related PA behaviors in order to dampen age-related systemic inflammation. Therefore, the aim of the present study was to explore relationships between objectively assessed sedentary patterns and pro- and anti-inflammatory biomarkers in older men and women when considering potential moderation by PA level.The present study included 252 community-dwelling older men and women, 65–70 years old, recruited within the frame of the EURODIET project. Inclusion criteria: age between 65 and 70 years. Exclusion criteria: overt disease such as diabetes mellitus or diagnosed coronary heart disease, disability with respect to mobility, smoking, and anti-inflammatory treatment. All clinical investigations were conducted in accordance with the Declaration of Helsinki and all participants provided written informed consent. The study was approved by the regional ethics committee of Uppsala, Sweden.Accelerometer-based assessment of PA was monitored with the Actigraph GT3x activity monitor  worn around the waist for 7 days. Briefly, participants were instructed to wear the monitor during all waking hours (except water-based activities) and note non-wear time. Inclusion criteria were that the activity monitor was worn for a minimum of 4 days with at least 10 h of wear time per day. Non-wear time was defined as a minimum of 60 min of continuous zero counts. Sedentary wear time was defined as all <100 counts, and MVPA as >2,020 in accordance with previous research . Breaks Information on dietary habits was collected using a validated food frequency questionnaire . A dietaBlood samples were collected by venipuncture between 8.00 and 10.00 am after an overnight fast. For this study, six inflammatory biomarkers previously linked to metabolic syndrome were selected based on previous research . High-se® system . A clustered metabolic risk score was created based on the assessment of measured metabolic risk outcome variables . First, standardized values (z-scores) of each outcome variable were expressed. Z-scores on HDL-cholesterol were inverted before calculating the average z-score based on all standardized outcomes.Metabolic risk outcome variables included in the International Diabetes Federation (IDF) definition of the metabolic syndrome were assessed . Waist ct-test. To retrieve comparable effect outcomes from variables with different original units of measurement, all inflammatory biomarkers were standardized (z-score) before regression modeling. All variables were checked and transformed when necessary to fit a normal distribution. Prior to analysis, sedentary behaviors and MVPA were modeled in 30-min periods. All models were adjusted by accelerometer wear time. First, before adjusting for PA behaviors, linear associations between each inflammatory marker and time spent in sedentary behavior and break rate were assessed (Model 1). Second, linear regression models were conducted to determine the strength of associations between measured inflammatory biomarkers and sedentary behavior when adjusting for MVPA (Model 2) or total accelerometer counts (Model 3) and metabolic risk score (Model 4). All models were stratified by sex. Potential significant influences of age and dietary inflammatory score on inflammatory outcomes were first checked using simple linear regressions. As no significant associations were detected, age and dietary inflammatory score were omitted in final regression models in order to retain statistical power. Assumptions for regression models including linearity, homoscedasticity, and multicollinearity between independent variables were checked. Level of significance was set to p < 0.05. All statistical analyses were performed using SPSS version 26. A priori power calculation revealed a small to moderate effect size to be detected with a power of ≥80% given the current sample size and alpha set to 0.05.Data are presented as means ± SD. Differences between men and women were determined by independent sample p < 0.05) and in continuous time bouts of at least 10 min (p < 0.05) and 30 min (p < 0.05), respectively. Women also had significantly more breaks per sedentary hour  compared to their male counterparts (p < 0.05) (p < 0.05). There were no significant differences between men and women in levels of the clinically well-established inflammatory biomarkers CRP and fibrinogen.A total of 229 community-dwelling older adults (146 women and 83 men) with complete data on all variables were included in the final analysis. Eight women and 15 men had either incomplete accelerometer recordings, missing biological data, were current smokers or used prescribed anti-inflammatory medication. On average, participants wore the activity monitor for 6.1 ± 0.9 days with 14 ± 1.2 h per day, without differences between the sexes. Data on body composition, CRP and fibrinogen and sedentary patterns are shown in  < 0.05) . While ap < 0.05) and fibrinogen (p < 0.05) (p < 0.05) (p < 0.05). Importantly, all observed associations remained significant after further adjustment for time spent in MVPA. However, only the link between total accumulated sedentary time and fibrinogen remained after adjusting for total accelerometer counts instead of MVPA time (p < 0.05) (p < 0.05). Finally, no relationships with other inflammatory biomarkers were observed  . A posit < 0.05) . Besides < 0.05) . Moreoveobserved .p < 0.05) (p < 0.05), indicating a beneficial impact of breaking up sedentary activities on levels of this anti-inflammatory agent. Interestingly, adjustment for PA either by time in MVPA or total accelerometer counts did not attenuate the significant influence of sedentary behavior on IL-10 level (p < 0.05). Notably, no other biomarkers of inflammation were significantly associated with sedentary behaviors in the male participants  . Further10 level . Importaicipants .The present study revealed sex-specific links between sedentary time patterns and biomarkers of low-grade systemic inflammation. Higher accumulated amounts of sedentary time were related to higher levels of the pro-inflammatory biomarkers IL-6 and fibrinogen in women, whereas an inverse relationship with the anti-inflammatory biomarker IL-10 was observed in men. Interestingly, time spent in MVPA did not offset the detrimental impacts of accumulating excessive amounts of sedentary time in both sexes. However, adjustment for total PA volume attenuated observed links with IL-6 in women.It has been hypothesized that biological sex interacts with regulation of systemic inflammation, which should be considered when elucidating impacts of sedentariness on inflammatory status. Here we show detrimental sex-specific links for levels of IL-6, fibrinogen, and IL-10, which were generally confirmed by the association between a higher break rate and a more beneficial inflammatory profile. These findings are in accordance with previous observations highlighting stronger associations between sedentary time and levels of fibrinogen and IL-6 in women compared to men . This isAn important finding of the present study was that total daily PA rather than time in MVPA attenuates links between sedentary patterns and inflammation in older women. Generally, time spent in MVPA has been considered when exploring the impact of sedentary patterns on systemic inflammation . For insAnother important finding was the independent inverse relationship between sedentary patterns and IL-10 levels in men. This is in line with previous findings showing higher levels of IL-10 gene expression in active compared to sedentary older men . While aInterestingly, unlike previous studies, we did not observe a significant association between sedentary behavior and the pro-inflammatory biomarkers CRP, IL-18, and MCP-1 . There aAlthough sedentary behaviors lasting at least 30 min or longer are thought to be particularly detrimental to health, most of previous research supporting this hypothesis have been based on self-report measures, which is limited to cruder estimations of sedentary behavior compared to objective methods. Based on our objective assessment of sedentary patterns, significant associations were reported when analyzing time bouts lasting at least 10 min, while no corresponding links were observed for the 30-min bouts. A previous study investigating how to best capture prolonged sedentary behaviors when using accelerometers, including both ≥10- and ≥30-min bouts, concluded the ≥10-min bout to be an appropriate threshold to capture the prolonged nature of sedentary behavior and its relation to health outcomes . Thus, tWhile our cross-sectional analysis highlights important associations between sedentariness and systemic inflammation, direction of the relationships cannot be determined. The older men and women included in this study may not be representative of broader populations of older adults, including differences in ethnicity and health status. Nonetheless, reported time spent in sedentary behavior are similar to what others have reported in older adults . FurtherAlthough our study revealed sedentary pattern-related impacts on different pro- and anti-inflammatory biomarkers, the systemic inflammatory environment is likely influenced by additional mediators not included in the present work. Further research is warranted to uncover molecular mechanism underpinning the systemic inflammatory profiles in aging populations.In conclusion, our findings confirm the hypothesis of sex-specific routes by which sedentary patterns impact on pro- and anti-inflammatory biomarkers in older adults. The detrimental impact of sedentary patterns is partly explained by total amounts of daily PA rather than by sedentariness itself. These findings hold clinical and public health implications, by reinforcing efforts aiming to promote daily PA at the expense of less sedentary pursuits in older men and women. Future efforts should be put on elucidating molecular mechanisms underlying observed links revealed in this study.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Regional ethics committee of Uppsala, Sweden. The patients/participants provided their written informed consent to participate in this study.OB and AN: conception of the work, acquisition, analysis, and interpretation of data, drafting and revision of the work, and approval of final draft including agreement for accountability. FK: conception of the work, acquisition, analysis, and interpretation of data, revising and approval of final draft including agreement for accountability K-GP: acquisition of data, revision of manuscript, approval of final draft including agreement for accountability. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objective: To characterize the magnetic resonance imaging (MRI) features of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis and explore their clinical relevance.Methods: Patients with anti-LGI1 encephalitis who underwent MRI at our center were included in this study. Baseline and follow-up MRI characteristics were evaluated, and relationships between lesion location and clinical symptoms were analyzed. The extent of signal abnormalities within the lesion overlap region was measured and correlated with modified Rankin Scale scores and serum antibody titer.Results: Seventy-six patients were enrolled, of which 57 (75%) were classified as MR positive. Brain lesions were located in medial temporal lobe (MTL) (89%) and basal ganglia (BG) (28%). Hippocampus and amygdala were lesion hubs with more than 50% lesion overlap. BG lesions were found in 30% of patients with faciobrachial dystonic seizure (FBDS) and only 7% of patients without FBDS (p = 0.013). Meanwhile, MTL lesions were more commonly observed in patients with memory impairment . MRI features included hyperintensity and edema at baseline, as well as hypointensity and atrophy at follow-up. Correlations between signal intensity of lesion hubs  and modified Rankin Scale scores were found on T2  and diffusion-weighted imaging .Conclusion: MTL and BG are two important structures affected by anti-LGI1 encephalitis, and they are associated with distinctive symptoms. Our study provided evidence from Chinese patients that BG lesions are more commonly observed in patients with FBDS, potentially suggesting BG localization. Furthermore, in addition to supporting diagnosis, MRI has the potential to quantify disease severity. N-methyl-d-aspartate receptor (NMDAR) encephalitis (Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis was first reported in 2010 . We retrospectively reviewed patients' clinical data as well as their brain MRI results. Baseline MRI scans were performed on the first outpatient visit or upon admission. Follow-up imaging was acquired from 25 patients at a mean time of 28 months after initial disease onset. Baseline-modified Rankin Scale (mRS) scores were collected as a measurement of disease severity. The scale comprises seven levels of increasingly severe disability, from 0 to 6 see .MRI was performed with 3.0-T  or 1.5-T (GE Signa Excite) scanners with head-neck coils. Most MRI scans incorporated standard brain protocol sequences including fluid-attenuated inversion recovery (FLAIR) , T1-weighted imaging (T1WI) , T2-weighted imaging (T2WI) , diffusion-weighted imaging (DWI) , and in some cases contrast-enhanced T1WI . Slice thicknesses were 4–6.5 mm, and the fields of view were 200–240 mm.Two neuroradiologists, both blinded to patients' clinical details, reviewed the brain MR images to reach consensus. An MR was considered positive when both neuroradiologists identified a signal abnormality or volumetric change in any cortical region or subcortical nuclei; otherwise, the MR was considered negative. MR imaging features were visually assessed including lesion location and signal characteristics. We analyzed the relationship between location and clinical symptoms (memory impairment and FBDS). The time from disease onset to the presence of different MRI characteristics was recorded to explore the evolution of signal features overtime.To show the pattern of lesion distribution, we extracted each patient's lesion and mapped the images onto one brain. This procedure was referred to as lesion overlap mapping. The workflow for image processing is shown in Sratio = Slesion/Snormal, here Slesion and Snormal denote the average signal intensity of lesion and normal appearing tissue, respectively.In addition to visual assessment, we also attempted to quantify the extent of signal abnormalities. To achieve this goal, regions of interest (ROIs) were created from the overlap map for all MRI-positive patients to extract signal intensity. We set a threshold for the overlap map and defined areas with more than 50% overlap as lesion ROIs. We aimed to measure the signal intensity in the more commonly affected areas, which could be regarded as lesion hubs for anti-LGI1 encephalitis. To standardize the signal values among different patients, we also measured the signal intensity from tissue that appeared normal. The relative signal was calculated as 2 test or Fisher's exact test. The differences between the MR-positive and MR-negative group were analyzed using the χ2 test or Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. Spearman's correlation was used to test the correlation between signal values and mRS/serum antibody titer. False discovery rate was used to adjust for the multiple comparisons. We aimed to explore whether the extent of signal abnormalities was indicative of disease severity. The serum antibody titers were classified into four grades , with higher grade indicating higher concentration. A value of p < 0.05 was considered to indicate statistical significance.Statistical analysis was conducted using Statistical Package for the Social Sciences (SPSS) version 22.0 software. The associations between lesion locations and clinical symptoms were explored by χThis study was approved by the ethics committee of Peking Union Medical College Hospital (IRB no. JS-891). Written informed consent forms were waived for this retrospective design.Overall, 76 patients were included in this study. The demographic and clinical characteristics of these patients are listed in The lesion overlap map showed that, in addition to classic limbic system involvement, BG was another important target for anti-LGI1 encephalitis . SpecifiBecause brain lesions can be classified into two types according to the involvement of the MTL or BG, the signal patterns were evaluated separately. For MTL lesions, images usually presented as hypointensity on T1WI, and hyperintensity on T2WI, FLAIR, and DWI, accompanied by edema. Atrophy was usually observed in the late stage. Of 21 patients with follow-up imaging, brain MRI normalized in three patients (14%), nine patients (43%) developed atrophy, and 11 patients (52%) exhibited persistent high signal without loss of volume. Illustrative cases are shown in The signal patterns of BG lesions were more complex and could be mixed combinations of hypo- or hyperintensity on T1WI, T2WI, DWI, and FLAIR. However, it appeared that hyperintensity  usually only occurred in the early stage with a median time interval of 1–3 months after onset. In contrast, hypointensity  and atrophy usually presented in the chronic phase. Follow-up images were available in six patients. Of these, four patients (67%) exhibited persistent signal abnormalities without volume loss, and two patients (33%) developed atrophy. Illustrative cases are shown in p = 0.013). In addition, BG lesions were less common in patients with memory impairment (18%) compared with those without memory impairment (75%) (p = 0.037). MTL lesions were found in 70% of patients with memory impairment but were not found in any patients without memory impairment (p = 0.017). A comparison of lesion overlap maps for patients with and without specific symptoms could be found in To explore the relationship between lesion location and symptoms, we compared the lesion presentation frequency between patients with or without specific symptoms. As a result, BG lesions were more likely to be found in patients with FBDS (30%) compared with those without FBDS (7%)  and DWI   for the lesion hubs, then correlated with mRS scores and serum antibody titer, respectively. The results revealed correlations between relative signal intensity and mRS scores on T2WI (001) see . HoweverThe current study investigated brain MRI results of 76 patients with anti-LGI1 encephalitis and explored their clinical relevance. To the best of our knowledge, this is the largest study providing detailed descriptions of the MRI-based characteristics of Chinese patients. Moreover, in addition to visual assessment, we also tried to find disease-specific biomarkers through quantitative analysis. There are several major findings: first, brain lesions of patients with anti-LGI1 encephalitis were mainly located in MTL and BG as has been previously described , 20–22; Anti-LGI encephalitis exhibited classic limbic system involvement with its core hubs located in the hippocampus and amygdala. This finding is in accord with previous pathophysiological findings showing that the LGI1 protein is mainly expressed in the hippocampal region and temporal cortex . CorrespMore importantly, we have observed a correlation of BG lesions with FBDS. This finding may contribute to the understanding of the pathogenesis of FBDS which remains extensively debated. Increasing evidence tends to suggest basal ganglia localization for FBDS, because structural and functional changes in BG are more easily detected in subjects with FBDS , 21, 22.Anti-LGI encephalitis can mimic a variety of other pathological processes because of its diverse clinical features, presenting a diagnostic challenge for clinicians. This condition is commonly misdiagnosed as Creutzfeldt-Jakob disease and viral encephalitis , 28–31. The signal pattern of MTL lesions was typical for LE, which usually manifests as T2-FLAIR hyperintensity in the acute phase and mesial temporal sclerosis on follow-up imaging . The curFurthermore, the current findings have demonstrated that the extent of signal abnormality in lesion hubs was able to reflect disease severity. Specifically, signal values of T2 and DWI were positively correlated with mRS scores. Interestingly, decreased ADC values was not observed in cases with increased DWI. It appears that elevated DWI may have reflected the T2 “shine-through” effect but not restricted diffusion, as commonly seen in cases of abscess . Thus, eThe current study involved several limitations that should be considered. First, the imaging findings were likely to have reflected not only the primary pathological autoimmune inflammatory process but also alterations associated with immunotherapy and antiepileptic drug treatments. However, we were unable to disentangle these factors because of variation in disease duration and medical treatments among different patients. Second, because of the retrospective nature of the study, brain MRI was not regularly performed for all patients at follow-up and more advanced techniques, such as high-resolution MRI were not performed for calculating the exact volume of important structures. Advanced diffusion techniques such as diffusion tensor imaging , neuriteIn conclusion, the present study reviewed brain MRI results of patients with anti-LGI1 encephalitis and identified several characteristic radiological patterns. Classic limbic system involvement and the typical signal features on MTL supported the diagnosis of LE. BG was another important structure in the pathogenesis of anti-LGI1 encephalitis, which may be involved in the development of FBDS. Furthermore, MRI showed the potential to reflect disease severity, suggesting that it may be a useful biomarker for tracking disease-related changes.The original contributions generated for the study are included in the article/The studies involving human participants were reviewed and approved by the ethics committee of Peking Union Medical College Hospital (IRB no. JS-891). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.HG, WZ, and AQ contributed to the design of the study. XS, SF, TW, and HL performed the analysis. XS and SF wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Introduction: Surgical resection of brain tumors is often limited by adjacent critical structures such as blood vessels. Current intraoperative navigations systems are limited; most are based on two-dimensional (2D) guidance systems that require manual segmentation of any regions of interest . They additionally require time- and labor-intensive processing for any reconstruction steps. We aimed to develop a deep learning model for real-time fully automated segmentation of the intracranial vessels on preoperative non-angiogram imaging sequences.Methods: We identified 48 pediatric patients (10-months to 22-years old) with high resolution  isovolumetric, pre-operative T2 magnetic resonance images (MRIs). Twenty-eight patients had anatomically normal brains, and 20 patients had tumors or other lesions near the skull base. Manually segmented intracranial vessels  served as ground truth labels. Patients were divided into 80/5/15% training/validation/testing sets. A modified 2-D Unet convolutional neural network (CNN) architecture implemented with 5 layers was trained to maximize the Dice coefficient, a measure of the correct overlap between the predicted vessels and ground truth labels.Results: The model was able to delineate the intracranial vessels in a held-out test set of normal and tumor MRIs with an overall Dice coefficient of 0.75. While manual segmentation took 1–2 h per patient, model prediction took, on average, 8.3 s per patient.Conclusions: We present a deep learning model that can rapidly and automatically identify the intracranial vessels on pre-operative MRIs in patients with normal vascular anatomy and in patients with intracranial lesions. The methodology developed can be translated to other critical brain structures. This study will serve as a foundation for automated high-resolution ROI segmentation for three-dimensional (3D) modeling and integration into an augmented reality navigation platform. Brain tumors are often devastating, life threatening, and permanently affect quality of life. The mainstay of treatment for many brain tumors is surgical resection, with more extensive resections showing a clear benefit on survival . HoweverNeurosurgeons utilize intraoperative navigation systems when large tumors have severely distorted the intracranial arteries, as these systems are useful adjuncts for executing nuanced surgical plans, as well as confirming the extent of resection. However, standard intraoperative navigations systems are limited: they are based on two-dimensional 2D) representations of three-dimensional (3D) anatomy and provide guidance using flat screen monitor visualization. While some navigation systems have limited 3D reconstruction capabilities, most require manual segmentation of any regions of interest . Image-by-image identification of ROIs within a large series could include hundreds to thousands of individual images, each with multiple ROIs. This demarcation is time-consuming and labor intensive such that most neurosurgeons usually rely on quick 2D representations rather than forming 3D plans that are anatomically more accurate  as well as a board-certified pediatric neurosurgeon (SHC) and confirmed to have the requisite pre-surgical imaging protocol suitable for integration into a surgical navigation system.Stanford IRB-44851). Informed consent was obtained at the time of imaging acquisition but waived by the IRB for the retrospective review since images were de-identified immediately after collection and prior to analysis.Institutional review board (IRB) approval was obtained for the acquisition and analysis of all clinical and imaging data . The 3D isovolumetric isotropic T2-weighted MRI protocol comprised of Freq FOV 24; TR/TE 2500/MAX; ETL 100; slice thickness 0.5–1 mm; matrix (512 × 512); BW 62.50.The main intracranial arteries  were manually segmented by a neurosurgery resident (JLQ) on axial images from the level of the cavernous sinuses inferiorly to the frontal horns superiorly. Segmentations were confirmed by a board-certified pediatric neuroradiologist (KWY).DICOM images and their manual segmentations were processed using the Python programming language with the pydicom and SimpleITK packages . Images We used a modified U-net , which iMRIs were allocated into development  and held-out test sets using random stratified sampling within each group. The breakdown was 80/5% for the training/validation and 15% for the held out test set. The model was trained to minimize the generalized dice loss as described by Sudre et al. . The weil = label, p = predicted. The weight w = 1/n2, where n is the number of respective pixels (vessel or non-vessel) for that axial slice.Equation 1: Generalized dice loss (GDL) . SubscriWe assessed segmentation accuracy using the Dice coefficient (Equation 2) , a measuEquation 2: Dice coefficient . TP = trn = 1) since vessels may have been coagulated with subsequent angiogenesis; and one with a brainstem vascular lesion (n = 1) since they may have had obscured and potentially abnormal vessels. The final dataset included 48 patients aged 10-months to 22-years old (median = 9.5), with 21 girls and 27 boys. These comprised of 28 patients undergoing surgical planning for non-lesional epilepsy (23), evaluation of extracranial pathology (3), or concussion (2). We also included 20 patients with intracranial lesions, some of whom had significant distortion or encompassment of the intracranial vessels (15). Intracranial lesions included craniopharyngioma (4), ganglioglioma (4), pilocytic astrocytoma (3), ependymoma (1), oligodendroglioma (1), subependymal giant cell astrocytoma (1), tectal glioma (2), epidermoid cyst, (1), porencephalic cyst (1), and primitive neuroectodermal tumor (1). One patient had hemimegencephaly but was categorized with the “lesion” group due to distortion of the intracranial vasculature. All patients with intracranial lesions were imaged prior to surgical intervention. Six patients had also underwent vascular imaging , but all after their initial MRI. Patient demographics are shown in Patients undergoing evaluation at Lucile Packard Children's Hospital from 2011 to 2018 were included. A total of 50 patients were found to have high resolution, isovolumetric T2 MRIs. Isovolumetric T2 MRIs were chosen given the ability to reliably identify and visualize anatomical structures including the cerebral vasculature. The following two patients were excluded: one with prior tumor resection  were used to train the U-net. A validation set of 2 patients  was used to track training progress and check for overfitting. Example images of the original scan, ground truth label, model-generated segmentation, and overlaid figures are shown in In order to visualize the intracranial vessels in a manner similar to that of pre-operative planning systems, the axial slices were stacked to generate 3D projections of the vessels in patients with normal vasculature  and withOur results demonstrate the first application of a CNN to identify and segment the intracranial vasculature using non-contrast, pre-operative brain MRIs from children. The use of deep learning to fully automate intracranial vascular segmentation using standard of care brain MRI scans, without additional contrast or a vascular protocol, carries important clinical implications. These include more efficient segmentation outputs, time and cost savings, as well as the potential for real-time translation into safer surgical resection of tumors in close proximity to critical vascular structures, particularly at the skull base, brainstem, or peri-Sylvian regions of the brain.While some techniques for automated intra-operative brain volume rendering exist, most require extensive pre-processing steps, including skull-stripping . At presGiven that the MRI protocols used in surgical navigation systems are less sensitive to vascular delineation,  some invManual delineation and ROI generation by clinical experts remains the gold-standard for intracranial vessel segmentation. While thin-slice 3D MRI scans allow for superior 3D reconstructions for surgical navigation, they have many slices per scan, making manual delineation incredibly time consuming and clinically impractical. Therefore, some surgeons may choose to delineate ROIs on MRIs acquired using more conventional diagnostic protocols. However, due to technical differences in image angle, slice selection, and slice thickness, these ROIs may not accurately transfer onto the 3D reconstructions. Further, any manual delineation would be challenging to perform in real-time, such as during surgery using intra-operative MRIs.Various studies have examined automated and semi-automated vessel segmentation methods, from rule-based mathematical extraction algorithms to machine-learning techniques , 21. Onelearn to identify the most relevant features for model optimization. Various studies have shown the utility of CNNs, a form of deep learning, for vessel segmentation, in particular for retinal imaging (Deep learning, a task driven form of machine learning, has multiple advantages for clinical implementation. Rather than relying on hand-crafted features, deep learning algorithms  imaging . Another imaging . Livne e imaging  and can  imaging , 26.Given these weaknesses, we trained a U-net CNN to automate vascular segmentation on pre-operative scans, which allow for wider use of our model with more flexible clinical applications. These high-resolution, isotropic, isovolumetric T2-weighted MRI scans are acquired pre-operatively for mapping of brain tumors or seizure foci due to superior diagnostic capability for detecting small lesions as well as the potential for high-resolution reformatting in any plane . Unlike With our model, we noticed that segmentation was more accurate for delineating normal vasculature compared to vessels in patients with tumors. This was possibly due to vascular deformation by the tumor. Another possibility is that constriction of the vessels from the underlying mass diminished the overall vascular caliber, which decreases the number of pixels in the denominator of the Dice score on which the model is evaluated, making it quantitatively more sensitive to error. The model also tended to identify more false positives and have more artifacts as the vessels became more distal to the Circle of Willis. One source of false positives may stem from parasitic tumor vessel branches, which were not delineated in our manual ground truth labels that only included the main intracranial arteries. Significantly increasing the size of the training dataset, especially including patients with tumors, would allow the model to better learn which cerebral arteries are consistently represented, thus potentially decreasing the number of false positives.One major limitation in our study was the small sample size of our retrospective cohort. Despite our rather limited training set of 38 patients, our model was still able to generate relatively high fidelity segmentations of the major intracranial arteries on a held out test set of 8 patients, which were never seen by the model during the training phase. It is likely that more training data would lead to higher accuracy by the convolutional neural network. Since vascular imaging was not available for most of the patients in our study, we did not label our T2 scans using vascular imaging. However, our use of high-resolution, isotropic, isovolumetric scans permitted the best possible visualization of the vascular anatomy, which was labeled by a neurosurgery resident with oversight by a board-certified neuroradiologist, as manual delineation currently remains the gold standard for ROI identification in clinical practice. Future work could include more human labelers to address and to quantify the degree of inter-observer variability in identifying critical structures, as well as the integration of intraoperative MRI sequences to further facilitate the integration of this model into real-time neuronavigation.We demonstrate the feasibility and fidelity of a CNN model for segmentation of pediatric cerebral vasculature using a standard of care pre-operative MRI protocol that does not require contrast dye or additional vascular imaging sequences. In future work we hope to incorporate this model into neuronavigational systems for pre-operative planning and intraoperative navigation.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved the Stanford Institutional Review Board. Informed consent was obtained at the time of imaging acquisition but waived by the IRB for the retrospective review since images were de-identified immediately after collection and prior to analysis.JQ, LC, LK, SC, and KY: concept and design. JQ and LK: acquisition of data. LC: model design and development. JQ and LC: data analysis and data interpretation. JQ, LC, LK, GG, ME, SC, and KY: manuscript drafting and approval. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Research has shown that performance in visual domains depends on domain-specific cognitive and perceptual adaptations that result from extensive practice. However, less is known about processes and factors that underpin the acquisition of such adaptations. The present study investigated how prior experience, cognitive skills, task difficulty and practice effect eye-hand span (EHS) and performance in video gaming. Thirty-three participants played a platformer video game in a pre-test/practice/post-test experiment. Eye movements and keypresses were recorded. The results show that a short practice period improved performance but did not increase EHS. Instead, EHS was related to task difficulty. Furthermore, while EHS correlated with initial performance, this effect seemed to diminish after practice. Cognitive skills  predicted performance in some parts of the experiment. The study offers insights into the early development of visual adaptations and performance. Research on expertise has shown that performance invisual domains such as music, chess, sports, andmedicine depends on domain-specific cognitive and perceptualadaptations . HoweveResearch on musicians’ expertise in sight-readingoffers a particularly interesting parallel to the present study.Both jump-and-run platformer games and sight-readingrequire scanning of the incoming information and precisetiming of motor actions . FurtheIn music, eye-hand span is commonly expressedeither in milliseconds, notes or beats between the eyeposition and the currently played notes. For example, Truitt,Clifton, Pollatsek, and Rayner  found tIn a recent study, Rosemann et al. studied Although expertise research since decades has built astrong case for the domain-specificity of cognitive andperceptual adaptations , Dale aThe aim of the present study was to investigate howprior gaming experience, cognitive skills, task difficultyand practice are related with eye-hand span andperformance in the context of video gaming and early skilldevelopment. Moreover, as the design and researchquestions are informed by earlier research in the domain ofmusic  How do a short practice period and taskdifficulty influence performance and eye-hand span in aplatformer video game?(2) Does eye-hand span correlate with video gameperformance?(3) Are performance and eye-hand span related toprior gaming experience and cognitive skills?The 33 voluntary participants were young adults between 20 and 35 years of age . However, one maleparticipant was excluded from the analysis due to the fact thathe had played the stimulus game extensively prior to theexperiment and was clearly an outlier both in terms ofperformance and eye-hand span. Participants’ general,self-reported, video game experience (see table 1) variedbetween zero and 11520 hours . Informed consent wasobtained from each participant, and the participants werefree to withdraw from the study at any time.The study was conducted in the context of the videogame Geometry Dash (RobTop Games). The aim of thegame is to navigate a small square through a series ofobstacles by jumping over them (see figure 1). The onlycontrol is tapping the Spacebar key, which causes thesquare to jump vertically. Horizontally, the square staysin the same constant location in relation to the screen. Asthe game progresses, the obstacles become more complexand difficult to get through and require exact timing andmultiple jumps in quick succession. In this experiment,the participants played only the levels 1 and 2, which aregraded as easy by the game developer. However, thegame is relatively fast-paced . The oncoming obstacles moveapproximately at the speed of 880 pixels (px), or 250mm, per second. Consequently, each obstacle movesacross the whole screen in less than two seconds.In the normal mode of the game, the better oneperforms, the longer each game lasts. Therefore,performance was measured by calculating the mean time(milliseconds) for all played games in each performance testphase. However, the first two games of the pre-test wereexcluded from the data analysis to give the participanttime to familiarize themselves with the simple gamemechanics.Participants’ prior video gaming experience wasoperationalised by asking the participants about the numberof years they have played video games and about theaverage amount of hours they spend playing video gamesper day/week/month . These numbers were then multiplied into a variable“video game experience”.Furthermore, the participants’ cognitive skills wereassessed by using the D2 Concentration Endurance Test .The D2Table 2 presents the experimental procedure inchronological order. First, the participants were introduced tothe aims and to the procedure of the study. In addition tothe informed consent form, the participants filled in aquestionnaire including demographic questions and aself-assessment of video gaming experience.After completing the paper-and-pencil part, theparticipants were given a demonstration of the game,introducing them to the aim and functionality of the game. Theeye-tracker was calibrated before each test phase. In thepre-test (2 min), the participants played the game (Level1) in a normal mode, i.e. after each failure(playercontrolled square hits an obstacle) the game starts at thesame level from the beginning. During the practice phase(2 min), the participants played the game in practicemode which allows them to continue onwards from thelocation of the failure. The practice phase was kept shortas the pilot data collections showed that longer practiceperiods were frustrating to the participants. Finally,posttest1 (2 min) and post-test2 (2 min) were played in thenormal mode with the difference that in the post-test2, theparticipants played the Level 2, which they had notplayed or seen before. Post-test2 was administered tostudy how task difficulty affects performance and EHS.TMsoftware , which also recorded thekeypresses and screen activities. The head distance was set toapproximately 70 cm during each calibration, but no headrest was used. Eye movements were analysed usingBegazeTM software. Eye-hand span (EHS) was defined andmeasured for each keypress as the distance (in pixels)between the player-controlled square and eye position.Three recordings from two different participants had unusually low eyetracking ratios (below 80 %). After these were excludedfrom the data, the mean tracking ratio for the remainingdata was 92 % . This wasconsidered reasonable as the ratio is for the wholerecording, including the short periods before and after eachexperiment (10 – 15 seconds) when the experimenter wasstarting and closing the game that was used in theexperiment.Eye movements were recorded using a SMI 250Hzred Eye Tracker with an accuracy of 0.5 degrees and1680 X 1050 px monitor resolution and the relatedExperiment CenterThe statistical analysis was carried out using the IBMSPSS Statistics 24 software. Based on the Shapiro-Wilktest (p < .05) and visual inspection of Q-Q plots, many ofthe variables deviated from the normal distribution(Table 3). Therefore, non-parametric statistical analyseswere used. Differences in performance and EHS betweenthe pre-test and the post-tests were analysed with theFriedman test, post hoc Wilcoxon signed-rank tests andIndependent-Samples Mann Whitney U-test. Therelationship between the eye-hand span, performance,cognitive skills and prior gaming experience was analysedusing Spearman’s rho correlation. Bonferroni correctionwas used for multiple correlations. However, as this is anexploratory study, original p values are reported andvalues that were not statistically significant afterBonferroni correction are marked with #.Table 3 shows the descriptive data for all measuredvariables. The performance difference between thepretest, post-test1 and post-test2 was statistically significant,X² = 48.07, p < .001.Wilcoxon post hoc tests showed that after the practicephase, the average performance in the post-test1  was significantly higher than in the pre-test, which, in turn, was higher thanin the post-test2 . Consideringthe fact that by post-test2 the participants already hadmore experience playing the game than in the beginning,it seems reasonable to conclude that, compared to Level1, Level 2 (post-test2) was significantly more difficult.The mean EHS differed between the threemeasurement points, X² = 8.30, p = .016. However,posthoc test revealed that the difference between pre-test (M= 186 px) and post-test1 (M = 192 px) was notstatistically significant (p = .468). The mean EHS in post-test2 (M= 147 px) was lower than in pre-test and post-test1 . The range of the meanEHS from 147 px to 192 px corresponds to 41-54 mmdistance on screen, approximately 4 degrees viewingangle and latency of 170-220 milliseconds.In summary, performance and EHS follow a similarpattern. Practice increases the mean length of playedgames (performance) and EHS. However, for EHS thisincrease was only marginal and not statisticallysignificant. In post-test2, both performance and EHS droppedbelow the pre-test level.s = .59, p < .001). After the practice period(post-test1), the correlation was noticeably lower . Post-test2 did not have a statisticallysignificant correlation with the corresponding EHS.Additionally, it is noteworthy that while both measures(performance and EHS) had reasonably high correlationsbetween different phases of the experiment, the pattern issomewhat different:The relationship between EHS and performance grewweaker as the experiment advanced. The correlationbetween EHS and performance was the strongest in thepre-test . The relationship between prior gamingexperience and performance was strongest when theparticipants were playing a level that was new to them.Furthermore, D2 accuracy score correlated withperformance in post-test2  and TMT (partB) correlated negatively with pre-test  and post-test2  performance. Thecorrelation is negative as the TMT test is scored using thetime it took the participants to finish the tasks.Neither the prior video gaming experience, the D2Concentration Endurance Test nor the Trail Making Test(TMT) had any statistically significant correlations withany of the EHS measures. However, prior video gamingexperience correlated with performance . Thisindicates that for more experienced video game players, theEHS was less likely to increase as a result of practice. Afurther analysis was conducted by dividing theparticipants into groups based on whether their EHS increased(n = 14) or decreased (n = 15). Mann-Whitney U-testshowed that the groups did not differ in terms of videogame experience or increase in performance.Finally, to study if the cognitive skills and priorgaming experience are related to effectiveness of practice,changes in EHS and performance between pre-test andpost-test1 were calculated by subtracting the post-test1values from pre-test values (EHS and performance).While there were no statistically significant correlationsbetween changes in performance (pre-test to post-test1),cognitive skills and video game experience, prior videogame experience correlated negatively with changes inEHS  whenthe participants were playing a level that was new to them(pre-test and post-test2). Yet, the effect was smaller afterpractice (post-test1). Concentration endurance  was positively related to performance in the lastphase of the experiment and the Trail Making Test , that measures working memory, mentalflexibility and executive functioning, correlated with pre-test andpost-test2 performance.In terms of EHS, the current results converge withresults obtained earlier in the domain of music . EHS seIn addition to similarities, there are interestingdifferences between the results of the current study and thestudy conducted by Rosemann et al. . DespitThe questions whether video gaming as an activity isrelated to more general improvements in perceptual skillsand whether EHS is a valid measure of these skillsremain open. Regarding video gaming and generalperceptual skills, the current data showed no relationshipbetween prior video gaming experience and EHS cf.. There Finally, the cognitive skills that were assessed in thecurrent study were not related to the participants’ EHS.While Rosemann et al.  found aIt should be noted that although the present study hasmany similarities to the Rosemann et al.  study,The present study extends the research on EHS to anew domain, video gaming, and offers insights into theearly development of EHS and performance and howthese are related practice, task difficulty, cognitive skillsand prior experience. The results highlight the need forfurther studies on the dynamic nature of skilldevelopment in visual domains.http://biblio.unibe.ch/portale/elibrary/BOP/jemr/ethics.html and that there is no conflict of interest regarding thepublication of this paper.The authors declare that the contents of the article arein agreement with the ethics described in