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Background We sought to understand the impact of the COVID-19 pandemic on lipid-lowering therapy prescribing as a potential cause of the excess cardiovascular mortality seen post-pandemic in England. We examined temporal changes over 3 years in the prescribing of high-intensity and non-high-intensity statin therapy and ezetimibe. Sources of data We utilized data available via the National Health Service (NHS) Business Services Authority (NHSBSA) Information Services Data Warehouse, extracting 3 monthly data from October 2018 to December 2021 on high- and low-intensity statin and ezetimibe prescribing, (commencement, cessation or continuation) through each time period of study and those before, and after, the period of interest. Areas of agreement Optimizing lipid management is a key component of the NHS Long Term Plan ambition to reduce deaths from cardiovascular disease, stroke and dementia. Areas of controversy The COVID-19 pandemic and associated lockdown have seen a significant reduction in prescribing of lipid-lowering therapies. If cardiovascular risk is not to worsen in the forthcoming years, urgent action is needed to ensure that the impact of the pandemic upon optimization of cholesterol and the historical undertreatment of cholesterol is reversed and improved. Areas timely for developing research Prescription data available via NHSBSA can support our understanding of the implications of policy and behaviour and highlight the impact of guidelines in practise. Growing points Understanding the impact of the COVID-19 pandemic upon cholesterol management and the opportunities for newer lipid-lowering therapies delivered using a population health approach have the potential to enhance lipid-lowering and improve cardiovascular mortality and morbidity and reduce health inequalities.

Background Intravenous thrombolysis and intra-arterial thrombectomy are proven emergency treatments for acute ischaemic stroke, but they require rapid delivery to selected patients within specialist services. National audit data have shown that treatment provision is suboptimal. Objectives The aims were to (1) determine the content, clinical effectiveness and day 90 cost-effectiveness of an enhanced paramedic assessment designed to facilitate thrombolysis delivery in hospital and (2) model thrombectomy service configuration options with optimal activity and cost-effectiveness informed by expert and public views. Design A mixed-methods approach was employed between 2014 and 2019. Systematic reviews examined enhanced paramedic roles and thrombectomy effectiveness. Professional and service user groups developed a thrombolysis-focused Paramedic Acute Stroke Treatment Assessment, which was evaluated in a pragmatic multicentre cluster randomised controlled trial and parallel process evaluation. Clinicians, patients, carers and the public were surveyed regarding thrombectomy service configuration. A decision tree was constructed from published data to estimate thrombectomy eligibility of the UK stroke population. A matching discrete-event simulation predicted patient benefits and financial consequences from increasing the number of centres. Setting The paramedic assessment trial was hosted by three regional ambulance services (in north-east England, north-west England and Wales) serving 15 hospitals. Participants A total of 103 health-care representatives and 20 public representatives assisted in the development of the paramedic assessment. The trial enrolled 1214 stroke patients within 4 hours of symptom onset. Thrombectomy service provision was informed by a Delphi exercise with 64 stroke specialists and neuroradiologists, and surveys of 147 patients and 105 public respondents. Interventions The paramedic assessment comprised additional pre-hospital information collection, structured hospital handover, practical assistance up to 15 minutes post handover, a pre-departure care checklist and clinician feedback. Main outcome measures The primary outcome was the proportion of patients receiving thrombolysis. Secondary outcomes included day 90 health (poor status was a modified Rankin Scale score of > 2). Economic outputs reported the number of cases treated and cost-effectiveness using quality-adjusted life-years and Great British pounds. Data sources National registry data from the Sentinel Stroke National Audit Programme and the Scottish Stroke Care Audit were used. Review methods Systematic searches of electronic bibliographies were used to identify relevant literature. Study inclusion and data extraction processes were described using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results The paramedic assessment trial found a clinically important but statistically non-significant reduction in thrombolysis among intervention patients, compared with standard care patients [197/500 (39.4%) vs. 319/714 (44.7%), respectively] (adjusted odds ratio 0.81, 95% confidence interval 0.61 to 1.08; p = 0.15). The rate of poor health outcomes was not significantly different, but was lower in the intervention group than in the standard care group [313/489 (64.0%) vs. 461/690 (66.8%), respectively] (adjusted odds ratio 0.86, 95% confidence interval 0.60 to 1.2; p = 0.39). There was no difference in the quality-adjusted life-years gained between the groups (0.005, 95% confidence interval –0.004 to 0.015), but total costs were significantly lower for patients in the intervention group than for those in the standard care group (–£1086, 95% confidence interval –£2236 to –£13). It has been estimated that, in the UK, 10,140–11,530 patients per year (i.e. 12% of stroke admissions) are eligible for thrombectomy. Meta-analysis of published data confirmed that thrombectomy-treated patients were significantly more likely to be functionally independent than patients receiving standard care (odds ratio 2.39, 95% confidence interval 1.88 to 3.04; n = 1841). Expert consensus and most public survey respondents favoured selective secondary transfer for accessing thrombectomy at regional neuroscience centres. The discrete-event simulation model suggested that six new English centres might generate 190 quality-adjusted life-years (95% confidence interval –6 to 399 quality-adjusted life-years) and a saving of £1,864,000 per year (95% confidence interval –£1,204,000 to £5,017,000 saving per year). The total mean thrombectomy cost up to 72 hours was £12,440, mostly attributable to the consumables. There was no significant cost difference between direct admission and secondary transfer (mean difference –£368, 95% confidence interval –£1016 to £279; p = 0.26). Limitations Evidence for paramedic assessment fidelity was limited and group allocation could not be masked. Thrombectomy surveys represented respondent views only. Simulation models assumed that populations were consistent with published meta-analyses, included limited parameters reflecting underlying data sets and did not consider the capital costs of setting up new services. Conclusions Paramedic assessment did not increase the proportion of patients receiving thrombolysis, but outcomes were consistent with improved cost-effectiveness at day 90, possibly reflecting better informed treatment decisions and/or adherence to clinical guidelines. However, the health difference was non-significant, small and short term. Approximately 12% of stroke patients are suitable for thrombectomy and widespread provision is likely to generate health and resource gains. Clinician and public views support secondary transfer to access treatment. Future work Further evaluation of emergency care pathways will determine whether or not enhanced paramedic assessment improves hospital guideline compliance. Validation of the simulation model post reconfiguration will improve precision and describe wider resource implications. Trial registration This trial is registered as ISRCTN12418919 and the systematic review protocols are registered as PROSPERO CRD42014010785 and PROSPERO CRD42015016649. Funding The project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 10, No. 4. See the NIHR Journals Library website for further project information.

ObjectiveTo evaluate the effectiveness and cost-effectiveness of the National PReCePT Programme (NPP) in increasing use of magnesium sulfate (MgSO4) in preterm births.DesignBefore-and-after study.SettingMaternity units (N=137) within NHS England and the Academic Health Science Network (AHSN) in 2018.ParticipantsBabies born ≤30 weeks’ gestation admitted to neonatal units in England.InterventionsThe NPP was a quality improvement (QI) intervention including the PReCePT (Preventing Cerebral Palsy in Pre Term labour) QI toolkit and materials (preterm labour proforma, staff training presentations, parent leaflet, posters for the unit and learning log), regional AHSN-level support, and up to 90 hours funded backfill for a midwife ‘champion’ to lead implementation.Main outcome measuresMgSO4uptake post implementation was compared with pre-NPP implementation uptake. Implementation and lifetime costs were estimated.ResultsCompared with pre-implementation estimates, the average MgSO4uptake for babies born ≤30 weeks’ gestation, in 137 maternity units in England, increased by 6.3 percentage points (95% CI 2.6 to 10.0 percentage points) to 83.1% post implementation, accounting for unit size, maternal, baby and maternity unit factors, time trends, and AHSN. Further adjustment for early/late initiation of NPP activities increased the estimate to 9.5 percentage points (95% CI 4.3 to 14.7 percentage points). From a societal and lifetime perspective, the health gains and cost savings associated with the NPP effectiveness generated a net monetary benefit of £866 per preterm baby and the probability of the NPP being cost-effective was greater than 95%.ConclusionThis national QI programme was effective and cost-effective. National programmes delivered via coordinated regional clinical networks can accelerate uptake of evidence-based therapies in perinatal care.

Background: Prehospital care including recognition of stroke symptoms by the public and professionals combined with an efficient and effective emergency medical service (EMS) is essential to increase access to effective acute stroke care. We undertook a survey to document the status of stroke prehospital care globally. Methods: A survey was distributed via email to the World Stroke Organisation (WSO) members. Information was sought on the current status of stroke prehospital delay globally including 1) ambulance availability and whether payment for use is required, 2) ambulance response times and the proportion of patients arriving at hospital by ambulance, 3) the proportion of patients arriving within 3 hours and more than 24 hours after symptom, 4) whether stroke care training of paramedics, call handlers and primary care staff, 5) availability of specialist centers, and 6) the proportion of patients taken to specialist centers. Respondents were also asked to identify the top three changes in prehospital care that would benefit their population. Data were analysed descriptively at both country and continent level. Results: Responses were received from 116 individuals in 43 countries, with a response rate of 4.7%. Most respondents (90%) reported access to ambulances but 40% of respondents reported payment was required by the patient. Where an ambulance service was available (105 respondents) 37% of respondents reported that less than 50% of patients used an ambulance and 12% less than 20% of patients used an ambulance. Large variations in ambulance response times were reported both within and between countries. Most of the participating High-Income Countries (HIC) offered a service used by patients, but this was rarely the case for the Low and Middle Income Countries (LMIC). Time to admission was often much longer in LMIC and there was less access to stroke training for EMS and primary care staff. Conclusions: Significant deficiencies in stroke prehospital care exist globally especially in LMIC. In all countries there are opportunities to improve the quality of the service in ways that would likely result in improved outcomes after acute stroke.

ObjectiveTo evaluate the effectiveness and cost-effectiveness of the National PreCePT Programme (NPP) in increasing magnesium sulphate (MgSO4) in pre-term births.DesignA quasi-experimental before-and-after designSettingMaternity units within NHS England and the AHSN network in 2018.ParticipantsMaternity units in England (n=137) who participated in the NPP.InterventionsNPP support which included the PReCePT QI toolkit and materials (pre-term labour proforma, staff training presentations, parent leaflet, posters for the unit, learning log), regional AHSN level support, and up to 90 hours funded backfill for a midwife ‘champion’ to lead implementation.Main outcome measuresMgSO4 post-implementation uptake compared to pre-implementation uptake. Implementation and lifetime costs were estimated.ResultsCompared to pre-implementation estimates, the average MgSO4 uptake in 137 maternity units in England increased by 6.3 percentage points (95% CI 2.6 to 10.0 percentage points) to 83.1% post-implementation, accounting for unit size, maternal, baby, and maternity unit factors, time trends, and AHSN. Further adjustment for early or late initiation of NPP activities increased the estimate to 9.5 percentage points (95% CI 4.3 to 14.7 percentage points). From a societal and lifetime perspective, the health gains and cost-savings associated with the NPP effectiveness generated a net monetary benefit of £866 per preterm baby and the probability of the NPP being cost-effective was greater than 95%.ConclusionThis national QI programme was effective and cost-effective. National programmes delivered via coordinated regional clinical networks can accelerate uptake of evidence-based therapies in perinatal care.WHAT IS ALREADY KNOWN ON THIS TOPICSince 2015 the UK National Institute for Health and Care Excellence (NICE) has recommended administration of Magnesium Sulphate (MgSO4) for fetal neuroprotection in very preterm deliveries as a core part of maternity care. By 2017, only two-thirds of all eligible women in England were being given MgSO4, with wide regional variation. The PReCePT pilot study showed an increase in uptake from 21% (2012-2013) to 88% after the introduction of the tool in2015 in 5 units. The National PReCePT Programme (NPP) was rolled out in 2018 by the national network of Academic Health Science Networks with a target to increase MgSO4 administration in England to 85% by 2020.WHAT THIS STUDY ADDSThe study has shown that the nationwide implementation of the NPP, which provided a Quality Improvement (QI) toolkit and materials, cross unit AHSN regional level support, and funded backfill for a unit midwife ‘champion’ through local regional support was effective and cost-effective. Scaling-up of network supported QI programmes at national level can accelerate uptake of new therapies and promote improvements in perinatal care delivery.

BackgroundLoss of arm function is common after stroke. Robot-assisted training may improve arm outcomes.ObjectiveThe objectives were to determine the clinical effectiveness and cost-effectiveness of robot-assisted training, compared with an enhanced upper limb therapy programme and with usual care.DesignThis was a pragmatic, observer-blind, multicentre randomised controlled trial with embedded health economic and process evaluations.SettingThe trial was set in four NHS trial centres.ParticipantsPatients with moderate or severe upper limb functional limitation, between 1 week and 5 years following first stroke, were recruited.InterventionsRobot-assisted training using the Massachusetts Institute of Technology-Manus robotic gym system (InMotion commercial version, Interactive Motion Technologies, Inc., Watertown, MA, USA), an enhanced upper limb therapy programme comprising repetitive functional task practice, and usual care.Main outcome measuresThe primary outcome was upper limb functional recovery ‘success’ (assessed using the Action Research Arm Test) at 3 months. Secondary outcomes at 3 and 6 months were the Action Research Arm Test results, upper limb impairment (measured using the Fugl-Meyer Assessment), activities of daily living (measured using the Barthel Activities of Daily Living Index), quality of life (measured using the Stroke Impact Scale), resource use costs and quality-adjusted life-years.ResultsA total of 770 participants were randomised (robot-assisted training,n = 257; enhanced upper limb therapy,n = 259; usual care,n = 254). Upper limb functional recovery ‘success’ was achieved in the robot-assisted training [103/232 (44%)], enhanced upper limb therapy [118/234 (50%)] and usual care groups [85/203 (42%)]. These differences were not statistically significant; the adjusted odds ratios were as follows: robot-assisted training versus usual care, 1.2 (98.33% confidence interval 0.7 to 2.0); enhanced upper limb therapy versus usual care, 1.5 (98.33% confidence interval 0.9 to 2.5); and robot-assisted training versus enhanced upper limb therapy, 0.8 (98.33% confidence interval 0.5 to 1.3). The robot-assisted training group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale) than the usual care group at 3 and 6 months. The enhanced upper limb therapy group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale), better mobility (as measured by the Stroke Impact Scale mobility domain) and better performance in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the usual care group, at 3 months. The robot-assisted training group performed less well in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the enhanced upper limb therapy group at 3 months. No other differences were clinically important and statistically significant. Participants found the robot-assisted training and the enhanced upper limb therapy group programmes acceptable. Neither intervention, as provided in this trial, was cost-effective at current National Institute for Health and Care Excellence willingness-to-pay thresholds for a quality-adjusted life-year.ConclusionsRobot-assisted training did not improve upper limb function compared with usual care. Although robot-assisted training improved upper limb impairment, this did not translate into improvements in other outcomes. Enhanced upper limb therapy resulted in potentially important improvements on upper limb impairment, in performance of activities of daily living, and in mobility. Neither intervention was cost-effective.Future workFurther research is needed to find ways to translate the improvements in upper limb impairment seen with robot-assisted training into improvements in upper limb function and activities of daily living. Innovations to make rehabilitation programmes more cost-effective are required.LimitationsPragmatic inclusion criteria led to the recruitment of some participants with little prospect of recovery. The attrition rate was higher in the usual care group than in the robot-assisted training or enhanced upper limb therapy groups, and differential attrition is a potential source of bias. Obtaining accurate information about the usual care that participants were receiving was a challenge.Trial registrationCurrent Controlled Trials ISRCTN69371850.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 54. See the NIHR Journals Library website for further project information.

Objective: To report the fidelity of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after stroke (RATULS) randomized controlled trial, the types of goals selected and the proportion of goals achieved. Design: Descriptive analysis of data on fidelity, goal selection and achievement from an intervention group within a randomized controlled trial. Setting: Out-patient stroke rehabilitation within four UK NHS centres. Subjects: 259 participants with moderate-severe upper limb activity limitation (Action Research Arm Test 0–39) between one week and five years post first stroke. Intervention: The enhanced upper limb therapy programme aimed to provide 36 one-hour sessions, including 45 minutes of face-to-face therapy focusing on personal goals, over 12 weeks. Results: 7877/9324 (84%) sessions were attended; a median of 34 [IQR 29–36] per participant. A median of 127 [IQR 70–190] repetitions were achieved per participant per session attended. Based upon the Canadian Occupational Performance Measure, goal categories were: self-care 1449/2664 (54%); productivity 374/2664 (14%); leisure 180/2664 (7%) and ‘other’ 661/2664 (25%). For the 2051/2664 goals for which data were available, 1287 (51%) were achieved, ranging between 27% by participants more than 12 months post stroke with baseline Action Research Arm Test scores 0–7, and 88% by those less than three months after stroke with scores 8–19. Conclusions: Intervention fidelity was high. Goals relating to self-care were most commonly selected. The proportion of goals achieved varied, depending on time post stroke and baseline arm activity limitation.

Background Study was a PROBE design phase II randomized controlled trial (RCT). We assessed trial feasibility and technical efficacy and safety of two novel thrombectomy devices – ERIC (a retriever device) and SOFIA (a distal access catheter) – used alone or in combination depending on operator preference. Methods Four UK neuroscience centers enrolled adults with proximal large artery occlusion (LAO) stroke on imaging where arterial puncture was achievable within 5.5 hours (8.5 hours for posterior circulation) of symptom onset; National Institutes of Health Stroke Scale (NIHSS) ≥6 with limited ischemic change on CT imaging. Randomization was 2:1 into intervention arm (ERIC and/or SOFIA). Patients and core lab were blinded to allocation. Primary outcome was independent core lab adjudication of reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) scale). Secondary outcomes were modified Rankin score (mRS) at 90 and 365 days (independence and shift analysis), 30-day mortality, symptomatic intracranial hemorrhage (sICH), procedural complications and NIHSS change. Results Sixty-six patients were enrolled. TICI 2B/3 reperfusion was achieved in 72% in intervention compared with 90% in control arm on intention to treat (ITT) analysis (P=0.2) and 78% compared with 86% on per protocol analysis (P=0.7). Functional independence at 90 days was 40% (intervention) compared with 43% (control) on ITT analysis (P=1.0). sICH rates were low at 0% and 5%, respectively (P=0.3). The 30-day mortality was 9% intervention compared with 14% control (P=0.7). Conclusions Study indicated feasibility of a phase II RCT trial approach for assessing new thrombectomy devices. In a broad LAO stroke population ERIC and SOFIA were not statistically different from control devices. Larger trials are needed.

Introduction Approaches to economic evaluations of stroke therapies are varied and inconsistently described. An objective of the European Stroke Organisation (ESO) Health Economics Working Group is to standardise and improve the economic evaluations of interventions for stroke. Methods The ESO Health Economics Working Group and additional experts were contacted to develop a protocol and a guidance document for data collection for economic evaluations of stroke therapies. A modified Delphi approach, including a survey and consensus processes, was used to agree on content. We also asked the participants about resources that could be shared to improve economic evaluations of interventions for stroke. Results Of 28 experts invited, 16 (57%) completed the initial survey, with representation from universities, government, and industry. More than half of the survey respondents endorsed 13 specific items to include in a standard resource use questionnaire. Preferred functional/quality of life outcome measures to use for economic evaluations were the modified Rankin Scale (14 respondents, 88%) and the EQ-5D instrument (11 respondents, 69%). Of the 12 respondents who had access to data used in economic evaluations, 10 (83%) indicated a willingness to share data. A protocol template and a guidance document for data collection were developed and are presented in this article. Conclusion The protocol template and guidance document for data collection will support a more standardised and transparent approach for economic evaluations of stroke care.

Supplemental Digital Content is available in the text., Background and Purpose— There is limited evidence to guide rehabilitation to meet the longer term needs of stroke survivors. The clinical effectiveness and cost-effectiveness of an extended stroke rehabilitation service (EXTRAS) provided following early supported discharge were determined. Methods— EXTRAS was a pragmatic parallel-group observer-blind randomized controlled trial involving 19 UK centers. Patients with stroke were individually randomized to receive EXTRAS or usual care at discharge from early supported discharge. Five EXTRAS reviews were provided by an early supported discharge team member between one and 18 months, usually by telephone. Reviews consisted of a semi-structured interview assessing progress, rehabilitation needs, and service provision, with goal setting and action planning. The primary outcome was performance in extended activities of daily living (Nottingham EADL Scale) at 24 months post-randomization. The Nottingham EADL Scale is scored 0 to 66, with higher scores indicating better performance in these activities. Cost-effectiveness was estimated using resource utilization costs and Quality Adjusted Life Years. Analyses were intention to treat. Results— Between January 9, 2013 and October 26, 2015, 573 participants were randomized (EXTRAS, n=285; usual care, n=288). Mean 24 month Nottingham EADL Scale scores were EXTRAS (n=219) 40.0 (SD 18.1) and usual care (n=231) 37.2 (SD 18.5) giving an adjusted mean difference of 1.8 (95% CI, –0.7 to 4.2). 1155/1338 (86%) of expected EXTRAS reviews were undertaken. Over 24 months, the mean cost of resource utilization was lower in the intervention group: –£311 (–$450 [95% CI, −£3292 to £2787; −$4764 to $4033]). EXTRAS provided more Quality Adjusted Life Years (0.07 [95% CI, 0.01 to 0.12]). At current conventional thresholds of willingness to pay (£20 000 [$28 940] per Quality Adjusted Life Years), there was a 90% chance that EXTRAS could be considered cost-effective. Conclusions— EXTRAS did not significantly improve stroke survivors’ performance in extended activities of daily living. However, given the impact on costs and Quality Adjusted Life Years, EXTRAS may be an affordable addition to improve stroke care. Clinical Trial Registration— URL: www.isrctn.com. Unique identifier: ISRCTN45203373.

Background We have previously modelled that the optimal number of comprehensive stroke centres (CSC) providing endovascular thrombectomy (EVT) in England would be 30 (net 6 new centres). We now estimate the relative effectiveness and cost-effectiveness of increasing the number of centres from 24 to 30. Methods We constructed a discrete event simulation (DES) to estimate the effectiveness and lifetime cost-effectiveness (from a payer perspective) using 1 year’s incidence of stroke in England. 2000 iterations of the simulation were performed comparing baseline 24 centres to 30. Results Of 80,800 patients admitted to hospital with acute stroke/year, 21,740 would be affected by the service reconfiguration. The median time to treatment for eligible early presenters ( Conclusion Changes in acute stroke service configuration will produce clinical and cost benefits when the time taken for patients to receive treatment is reduced. Benefits are highly likely to be cost saving over 5 years before any capital investment above £8 million is required.

Background and Objectives:Diffusion tensor imaging (DTI) networks integrate damage from a variety of pathological processes in cerebral small vessel disease (SVD) and may be a sensitive marker to detect treatment effects. We determined whether brain network analysis could detect treatment effects in the PRESERVE trial dataset, in which intensive versus standard blood pressure (BP) lowering was compared. The primary endpoint of DTI had not shown treatment differences.Methods:Subjects with lacunar stroke were randomised to standard (systolic 130-140 mmHg), or intensive (systolic Results:Data were available in 82 subjects; standard n=40 (mean age 66.3±1.5), intensive n=42 (69.6±1.0). Mean (SD) systolic blood pressure was reduced by 13(14) and 23(23) mmHg in the standard and intensive groups respectively (PDiscussion:Brain network analysis may be a sensitive surrogate marker in trials in small vessel disease. This work suggests that measures of brain network efficiency may be more sensitive to the effects of blood pressure control treatment than conventional DTI metrics.Trial Registration Information:The trial is registered with the ISRCTN Registry (ISRCTN37694103; //doi.org/10.1186/ISRCTN37694103) and the NIHR Clinical Research Network (CRN 10962; //public-odp.nihr.ac.uk/QvAJAXZfc/opendoc.htm?document=crncc_users%5Cfind%20a%20clinical%20research%20study.qvw&lang=en-US&host=QVS%40crn-prod-odp-pu&anonymous=true)Classification of Evidence:This study provides Class II evidence that intensive BP lowering in patients with small vessel disease results in improved brain network function when assessed by DTI based brain network metrics.