Comment on "Does the 5-2-1 criteria identify patients with advanced Parkinson's disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries".

The 5-2-1 criteria are intended to help general neurologists identify patients with advanced Parkinson's disease who may benefit from treatment optimisation, such as with a device-aided therapy. Although the 5-2-1 criteria claim to address an unmet need, we urge readers to cautiously interpret the results of this validation study.

Implications of interhospital patient transfers for emergency medical services transportation systems in the Netherlands: a retrospective study.

OBJECTIVES: Interhospital patient transfers have become routine. Known drivers are access to specialty care and non-clinical reasons, such as limited capacity. While emergency medical services (EMS) providers act as main patient transfer operators, the impact of interhospital transfers on EMS service demand and fleet management remains understudied. This study aims to identify patterns in regional interhospital patient transfer volumes and their spatial distribution, and to discuss their potential implications for EMS service demand and fleet management. DESIGN: A retrospective study was performed analysing EMS transport data from the province of Drenthe in the Netherlands between 2013 and 2019 and public hospital listings. Yearly volume changes in urgent and planned interhospital transfers were quantified. Further network analysis, including geomapping, was used to study how transfer volumes and their spatial distribution relate to hospital specialisation, and servicing multihospital systems. Organisational data were considered for relating transfer patterns to fleet changes. SETTING: EMS in the province of Drenthe, the Netherlands, 492 167 inhabitants. PARTICIPANTS: Analyses are based on routinely collected patient data from EMS records, entailing all 248 114 transports (137 168 patients) of the Drenthe EMS provider (2013-2019). From these interhospital transports were selected (24 311 transports). RESULTS: Interhospital transfers represented a considerable (9.8%) and increasing share of transports (from 8.6% in 2013 to 11.3% in 2019). Most transfers were related to multihospital systems (47.3%, 11 509 transports), resulting in a considerable growth of planned EMS transports (from 2093 in 2013 to 3511 in 2019). Geomapping suggests increasing transfer distances and diminishing resource efficiencies due to lacking follow-up rides. Organisational data clarify how EMS fleets were adjusted by expanding resources and reorganising fleet operation. CONCLUSIONS: Emerging interhospital network transfers play an important role in EMS service demand. Increased interhospital transport volumes and geographical spread require a redesign of current EMS fleets and management along regional lines.

Cohort profile: The ENTWINE iCohort study, a multinational longitudinal web-based study of informal care.

Informal care is a key pillar of long-term care provision across Europe and will likely play an even greater role in the future. Thus, research that enhances our understanding of caregiving experiences becomes increasingly relevant. The ENTWINE iCohort Study examines the personal, psychological, social, economic, and geographic factors that shape caregiving experiences. Here, we present the baseline cohort of the study and describe its design, recruitment methods, data collection procedures, measures, and early baseline findings. The study was conducted in nine countries: Germany, Greece, Ireland, Israel, Italy, the Netherlands, Poland, Sweden, and the United Kingdom. The study comprised a web-based longitudinal survey (baseline + 6-month follow-up) and optional weekly diary assessments conducted separately with caregivers and care recipients. From 14 August 2020 to 31 August 2021, 1872 caregivers and 402 care recipients were enrolled at baseline. Participants were recruited via Facebook and, to a lesser extent, via the study website or caregiver/patient organisations. Caregiver participants were predominantly female (87%) and primary caregivers (82%), with a median age of 55 years. A large proportion (80%) held at least post-secondary education, and two-thirds were married/partnered. Over half of the caregivers were employed (53%) and caring for a person with multiple chronic conditions (56%), and nearly three-quarters were caring for either a parent (42%) or a spouse/partner (32%). About three-quarters of care recipient participants were female (77%), not employed (74%), and had at least post-secondary education (77%), with a median age of 55 years. Over half of the care recipients were married/partnered (59%), receiving care primarily from their spouses/partners (61%), and diagnosed with multiple chronic conditions (57%). This study examining numerous potential influences on caregiving experiences provides an opportunity to better understand the multidimensional nature of these experiences. Such data could have implications for developing caregiving services and policies, and for future informal care research.

The Economic Costs of Informal Care: Estimates from a National Cross-Sectional Survey in The Netherlands.

Faced with an unprecedented demand for long-term care, European health care systems are moving towards mixed care models, where the welfare state and informal caregivers share care responsibilities. While informal care is often viewed as a means of alleviating pressure on public care, it comes with significant economic costs for caregivers, their employers, and society at large. This study uses nationally representative data to estimate the total direct (informal care time and out-of-pocket costs) and indirect (productivity) economic costs of informal care in the Netherlands in 2019. Informal care time costs are estimated using the opportunity cost and the proxy good methods. Indirect costs are estimated using the human capital and friction cost approaches. Our results reveal the considerable annual societal cost of informal care in the Netherlands, ranging between €17.5 billion and €30.1 billion, depending on the valuation approach. These costs are equivalent to 2.15% and 3.71% of Dutch GDP in 2019, comparable to the public expenditure on long-term care in that year. Female caregivers account for slightly more than half (53%-57%) of the total costs. Around 57%-88% of these costs are in the form of informal care time. The main driver of indirect costs is the temporary cessation of work, which comprises 12%-17% of the total costs. Findings corroborate that substantial resources, yet thus far largely disregarded, are spent on informal care even in a country with a relatively generous public long-term care system.

Cost-effectiveness of CT perfusion for the detection of large vessel occlusion acute ischemic stroke followed by endovascular treatment: a model-based health economic evaluation study.

OBJECTIVES: CT perfusion (CTP) has been suggested to increase the rate of large vessel occlusion (LVO) detection in patients suspected of acute ischemic stroke (AIS) if used in addition to a standard diagnostic imaging regime of CT angiography (CTA) and non-contrast CT (NCCT). The aim of this study was to estimate the costs and health effects of additional CTP for endovascular treatment (EVT)-eligible occlusion detection using model-based analyses. METHODS: In this Dutch, nationwide retrospective cohort study with model-based health economic evaluation, data from 701 EVT-treated patients with available CTP results were included (January 2018-March 2022; trialregister.nl:NL7974). We compared a cohort undergoing NCCT, CTA, and CTP (NCCT + CTA + CTP) with a generated counterfactual where NCCT and CTA (NCCT + CTA) was used for LVO detection. The NCCT + CTA strategy was simulated using diagnostic accuracy values and EVT effects from the literature. A Markov model was used to simulate 10-year follow-up. We adopted a healthcare payer perspective for costs in euros and health gains in quality-adjusted life years (QALYs). The primary outcome was the net monetary benefit (NMB) at a willingness to pay of €80,000; secondary outcomes were the difference between LVO detection strategies in QALYs (ΔQALY) and costs (ΔCosts) per LVO patient. RESULTS: We included 701 patients (median age: 72, IQR: [62-81]) years). Per LVO patient, CTP-based occlusion detection resulted in cost savings (ΔCosts median: € - 2671, IQR: [€ - 4721; € - 731]), a health gain (ΔQALY median: 0.073, IQR: [0.044; 0.104]), and a positive NMB (median: €8436, IQR: [5565; 11,876]) per LVO patient. CONCLUSION: CTP-based screening of suspected stroke patients for an endovascular treatment eligible large vessel occlusion was cost-effective. CLINICAL RELEVANCE STATEMENT: Although CTP-based patient selection for endovascular treatment has been recently suggested to result in worse patient outcomes after ischemic stroke, an alternative CTP-based screening for endovascular treatable occlusions is cost-effective. KEY POINTS: • Using CT perfusion to detect an endovascular treatment-eligible occlusions resulted in a health gain and cost savings during 10 years of follow-up. • Depending on the screening costs related to the number of patients needed to image with CT perfusion, cost savings could be considerable (median: € - 3857, IQR: [€ - 5907; € - 1916] per patient). • As the gain in quality adjusted life years was most affected by the sensitivity of CT perfusion-based occlusion detection, additional studies for the diagnostic accuracy of CT perfusion for occlusion detection are required.

Costs and health effects of CT perfusion-based selection for endovascular thrombectomy within 6 hours of stroke onset: a model-based health economic evaluation.

BACKGROUND: Although CT perfusion (CTP) is often incorporated in acute stroke workflows, it remains largely unclear what the associated costs and health implications are in the long run of CTP-based patient selection for endovascular treatment (EVT) in patients presenting within 6 hours after symptom onset with a large vessel occlusion. METHODS: Patients with a large vessel occlusion were included from a Dutch nationwide cohort (n=703) if CTP imaging was performed before EVT within 6 hours after stroke onset. Simulated cost and health effects during 5 and 10 years follow-up were compared between CTP based patient selection for EVT and providing EVT to all patients. Outcome measures were the net monetary benefit at a willingness-to-pay of €80 000 per quality-adjusted life year, incremental cost-effectiveness ratio), difference in costs from a healthcare payer perspective (ΔCosts) and quality-adjusted life years (ΔQALY) per 1000 patients for 1000 model iterations as outcomes. RESULTS: Compared with treating all patients, CTP-based selection for EVT at the optimised ischaemic core volume (ICV≥110 mL) or core-penumbra mismatch ratio (MMR≤1.4) thresholds resulted in losses of health (median ΔQALYs for ICV≥110 mL: -3.3 (IQR: -5.9 to -1.1), for MMR≤1.4: 0.0 (IQR: -1.3 to 0.0)) with median ΔCosts for ICV≥110 mL of -€348 966 (IQR: -€712 406 to -€51 158) and for MMR≤1.4 of €266 513 (IQR: €229 403 to €380 110)) per 1000 patients. Sensitivity analyses did not yield any scenarios for CTP-based selection of patients for EVT that were cost-effective for improving health, including patients aged ≥80 years CONCLUSION: In EVT-eligible patients presenting within 6 hours after symptom onset, excluding patients based on CTP parameters was not cost-effective and could potentially harm patients.

Cost-effectiveness of tenecteplase versus alteplase for acute ischemic stroke.

INTRODUCTION: Alteplase is widely used as an intravenous thrombolytic drug in acute ischemic stroke (AIS). Recently however, tenecteplase, a modified form of tissue plasminogen activator, has been shown to increase early recanalization rate and has proven to be non-inferior with a similar safety profile compared to alteplase. This study aims to evaluate the cost-effectiveness of 0.25 mg/kg tenecteplase versus 0.9 mg/kg alteplase for intravenous thrombolysis in AIS patients from the Dutch healthcare payer perspective. METHODS: A Markov decision-analytic model was constructed to assess total costs, total quality-adjusted life year (QALY), an incremental cost-effectiveness ratio, and incremental net monetary benefit (INMB) of two treatments at willingness-to-pay (WTP) thresholds of €50,000/QALY and €80,000/QALY over a 10-year time horizon. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted to test the robustness of results. Clinical data were obtained from large randomized controlled trials and real-world data. RESULTS: Treatment with tenecteplase saved €21 per patient while gaining 0.05 QALYs, resulting in INMB of €2381, clearly rendering tenecteplase cost-effective compared to alteplase. Importantly, tenecteplase remained the cost-effective alternative in all scenarios, including AIS patients due to large vessel occlusion (LVO). Probabilistic sensitivity analysis proved tenecteplase to be cost-effective with a 71.0% probability at a WTP threshold of €50,000/QALY. CONCLUSIONS: Tenecteplase treatment was cost-effective for all AIS patients (including AIS patients with LVO) compared to alteplase. The finding supports the broader use of tenecteplase in acute stroke care, as health outcomes improve at acceptable costs while having practical advantages, and a similar safety profile.

'Drive the doctor' for endovascular thrombectomy in a rural area: a simulation study.

BACKGROUND: Patients who present in a primary stroke center (PSC) with ischemic stroke are usually transferred to a comprehensive stroke center (CSC) in case of a large vessel occlusion (LVO) for endovascular thrombectomy (EVT) treatment, the so-called 'drip-and-ship' (DS) model. The 'drive-the-doctor' (DD) model modifies the DS model by allowing mobile interventionalists (MIs) to transfer to an upgraded PSC acting as a thrombectomy capable stroke center (TSC), instead of transferring patients to a CSC. Using simulation we estimated time savings and impact on clinical outcome of DD in a rural region. METHODS: Data from EVT patients in northern Netherlands was prospectively collected in the MR CLEAN Registry between July 2014 - November 2017. A Monte Carlo simulation model of DS patients served as baseline model. Scenarios included regional spread of TSCs, pre-hospital patient routing to 'the nearest PSC' or 'nearest TSC', MI's notification after LVO confirmation or earlier prehospital, and MI's transport modalities. Primary outcomes are onset to groin puncture (OTG) and predicted probability of favorable outcome (PPFO) (mRS 0-2). RESULTS: Combining all scenarios OTG would be reduced by 28-58 min and PPFO would be increased by 3.4-7.1%. Best performing and acceptable scenario was a combination of 3 TSCs, prehospital patient routing based on the RACE scale, MI notification after LVO confirmation and MI's transfer by ambulance. OTG would reduce by 48 min and PPFO would increase by 5.9%. CONCLUSIONS: A DD model is a feasible scenario to optimize acute stroke services for EVT eligible patients in rural regions. Key design decisions in implementing the DD model for a specific region are regional spread of TSCs, patient routing strategy, and MI's notification moment and transport modality.

Cost-Effectiveness of Four Tobacco Control Interventions in Mongolia.

INTRODUCTION: The aim of this study is to quantify the cost-effectiveness of four tobacco control interventions: Tobacco taxation, mass media campaigns, school programs, and cessation support, and to illustrate how available evaluation tools can be adapted to the local setting. AIMS AND METHODS: We used the dynamic population health modeling-health impact assessment tool to project the future smoking prevalence associated with the interventions and to simulate the resulting smoking-related disease burden over time. Applying the most recent available national Mongolian data as input, the costs and effects of four interventions were compared to a business-as-usual scenario, resulting in costs per life year gained and per disability-adjusted life years (DALYs) averted. RESULTS: Three years after implementation, all interventions reduce the prevalence of current smoking, with the strongest reduction observed with the increase in tobacco tax (5.1% points), followed by mass media campaigns (1.6% points), school programs (1.3% points), and cessation support interventions (0.6% points). School programs were a cost-saving tobacco control intervention compared to current practice in Mongolia, while the other programs resulted in additional costs compared to business as usual. Compared to the World Health Organization (WHO) thresholds, all interventions would be considered "very cost-effective" in terms of cost per DALY averted (below US$ 4295 per DALY averted) in Mongolia. CONCLUSIONS: Large-scale interventions such as taxation and mass media campaigns result in both cost-effectiveness and important health benefits in relation to intervention costs. Reducing the prevalence of smoking among the male population would be particularly worthwhile in Mongolia. IMPLICATIONS: This study shows that in Mongolia school programs were a cost-saving intervention, while the cost-effectiveness ratios were US$ 25 per disability-adjusted life year (DALY) averted for mass media campaigns, US$ 74 for taxation, and US$ 1961 for cessation support interventions. Compared to the WHO thresholds, all interventions would be considered "very cost-effective" in terms of expenses per DALY averted (

Simulation modelling to study the impact of adding comprehensive stroke centres. Can we deliver endovascular thrombectomy sooner?

OBJECTIVES: Regional accessibility and distribution of endovascular thrombectomy (EVT) capable facilities, that is, comprehensive stroke centres (CSCs), may significantly influence time to treatment. We analysed the impact of adding CSCs in the north of the Netherlands, a region with roughly 1.7 million inhabitants currently served by one CSC and eight primary stroke centres (PSCs). DESIGN: Monte Carlo simulation modelling was used to establish new CSCs in our region by hypothetically upgrading existing PSCs to CSCs and ensuing adjustments in health services set-up. SETTING: One CSC and eight PSCs in the north of the Netherlands. PARTICIPANTS: 165 patients with acute stroke treated with EVT and underwent interhospital transfer between PSC and CSC (drip and ship patients). PRIMARY AND SECONDARY OUTCOMES: Time from onset to groin (OTG) puncture and predicted probability of favourable outcome (modified Rankin Scale 0-2) after 90 days. Sensitivity analyses were performed to assess uncertainty in workflow efficiency of CSCs. RESULTS: Adding one or two CSCs would reduce the OTG time up to approximately 17 min and increases the predicted probability of favourable outcome by approximately 2%. Sensitivity analyses revealed that 'slow-acting' CSCs may reduce OTG by 3-5 min compared with 24-32 min for 'fast-acting' CSCs. CONCLUSIONS: This study suggests that adding one or two CSCs in the north of the Netherlands would have modest impact. Improving workflow efficiencies seems to be more potent when aiming to improve existing acute stroke care systems.

Cost-effectiveness of Direct Transfer to Angiography Suite of Patients With Suspected Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Patients with acute ischemic stroke due to large vessel occlusion (LVO) deemed eligible for endovascular thrombectomy (EVT) are transferred from the emergency room to the angiography suite to undergo the procedure. Recently, the strategy of direct transfer of patients with suspected LVO to the angiography suite (DTAS) has been shown to improve functional outcomes. This study aims to evaluate the cost-effectiveness of the DTAS strategy vs initial transfer of patients with suspected LVO (Rapid Arterial Occlusion Evaluation score >4 and NIH Stroke Scale >10) to the emergency room (ITER). METHODS: A decision-analytic Markov model was developed to estimate the cost-effectiveness of the DTAS strategy vs the ITER strategy from a Dutch health care perspective with a 10-year time horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER) using Dutch thresholds of $59,135 (€50,000) and $94,616 (€80,000) per quality-adjusted life year (QALY). Uncertainty of input parameters was assessed using 1-way sensitivity analysis, scenario analysis, and probabilistic sensitivity analysis. RESULTS: The DTAS strategy yielded 0.65 additional QALYs at an additional $16,089, resulting in an ICER of $24,925/QALY compared with the ITER strategy. The ICER varied from $27,169 to $38,325/QALY across different scenarios. The probabilistic sensitivity analysis showed that the DTAS strategy had a 91.8% and 97.0% likelihood of being cost-effective at a decision threshold of $59,135/QALY and $94,616/QALY, respectively. DISCUSSION: The cost-effectiveness of the DTAS strategy over ITER is robust for patients with suspected LVO. Together with recently published clinical results, this means that implementation of the DTAS strategy may be considered to improve the workflow and outcome of EVT.

Tools and criteria to select patients with advanced Parkinson's disease for device-aided therapies: a narrative review.

This article provides an overview of the various screening and selection tools which have been developed over the past 25 years to identify patients with Parkinson's disease (PD) possibly eligible for device-aided therapies (DATs). For the available screening tools, we describe the target therapies (subtypes of DAT), development methods, validation data, and their use in clinical practice. In addition, the historical background and potential utility of these screening tools are discussed. The challenges in developing and validating these tools are also addressed, taking into account the differences in population, the local health care organization, and resource availability.

Timely referral for device-aided therapy in Parkinson's disease. Development of a screening tool.

BACKGROUND: Timely referral of Parkinson's disease (PD) patients to specialized centers for treatment with device-aided therapies (DAT) is suboptimal. OBJECTIVE: To develop a screening tool for timely referral for DAT in PD and to compare the tool with the published 5-2-1 criteria. METHODS: A cross-sectional, observational study was performed in 8 hospitals in the catchment area of a specialized movement disorder center in the Northern part of the Netherlands. The target population comprised PD patients not yet on DAT visiting the outpatient clinic of participating hospitals. The primary outcome was apparent eligibility for referral for DAT based on consensus by a panel of 5 experts in the field of DAT. Multivariable logistic regression modelling was used to develop a screening tool for eligibility for referral for DAT. Potential predictors were patient and disease characteristics as observed by attending neurologists. RESULTS: In total, 259 consecutive PD patients were included, of whom 17 were deemed eligible for referral for DAT (point prevalence: 6.6%). Presence of response fluctuations and troublesome dyskinesias were the strongest independent predictors of being considered eligible. Both variables were included in the final model, as well as levodopa equivalent daily dose. Decision curve analysis revealed the new model outperforms the 5-2-1 criteria. A simple chart was constructed to provide guidance for referral. Discrimination of this simplified scoring system proved excellent (AUC after bootstrapping: 0.97). CONCLUSIONS: Awaiting external validation, the developed screening tool already appears promising for timely referral and subsequent treatment with DAT in patients with PD.

Cost-effectiveness of improvement strategies for reperfusion treatments in acute ischemic stroke: a systematic review.

BACKGROUND: Reducing delays along the acute stroke pathway significantly improves clinical outcomes for acute ischemic stroke patients eligible for reperfusion treatments. The economic impact of different strategies reducing onset to treatment (OTT) is crucial information for stakeholders in acute stroke management. This systematic review aimed to provide an overview on the cost-effectiveness of several strategies to reduce OTT. METHODS: A comprehensive literature search was conducted in EMBASE, PubMed, and Web of Science until January 2022. Studies were included if they reported 1/ stroke patients treated with intravenous thrombolysis and/or endovascular thrombectomy, 2/ full economic evaluation, and 3/ strategies to reduce OTT. The Consolidated Health Economic Evaluation Reporting Standards statement was applied to assess the reporting quality. RESULTS: Twenty studies met the inclusion criteria, of which thirteen were based on cost-utility analysis with the incremental cost-effectiveness ratio per quality-adjusted life year gained as the primary outcome. Studies were performed in twelve countries focusing on four main strategies: educational interventions, organizational models, healthcare delivery infrastructure, and workflow improvements. Sixteen studies showed that the strategies concerning educational interventions, telemedicine between hospitals, mobile stroke units, and workflow improvements, were cost-effective in different settings. The healthcare perspective was predominantly used, and the most common types of models were decision trees, Markov models and simulation models. Overall, fourteen studies were rated as having high reporting quality (79%-94%). CONCLUSIONS: A wide range of strategies aimed at reducing OTT is cost-effective in acute stroke care treatment. Existing pathways and local characteristics need to be taken along in assessing proposed improvements.

Cost-effectiveness of CT perfusion for patients with acute ischemic stroke (CLEOPATRA)-Study protocol for a healthcare evaluation study.

Introduction: Computed tomography perfusion (CTP) is variably considered to assess eligibility for endovascular thrombectomy (EVT) in acute ischemic (AIS) stroke patients. Although CTP is recommended for patient selection in later (6-24 h) time window, it is currently not recommended in the earlier (0-6 h) time window and the costs and health effects of including CTP for EVT selection remain unknown. We aim to estimate the costs and health effects of using CTP for EVT selection in AIS patients compared to conventional selection. Patients and methods: CLEOPATRA is a healthcare evaluation study using clinical and imaging data from multiple, prospective EVT trials and registries in both the earlier and later time windows. To study the long-term health and cost effects, we will construct a ("Markov") health state transition model simulating the clinical outcome over a 5-year follow-up period for CTP-based and conventional selection for EVT. Clinical data acquired within the current study and estimates from the literature will be used as input for probabilities of events, costs, and Quality-Adjusted Life Years (QALYs) per modified Rankin Scale (mRS) subscore. Primary outcome for the cost-effectiveness analysis will be the Incremental Cost-Effectiveness Ratio (ICER) in terms of costs per QALY gained over the simulated follow-up period. Study outcomes: Outcome measures will be reported as cumulative values over a 5-year follow-up period. Discussion: This study will provide preliminary insight into costs and health effects of including CTP in the selection for EVT for AIS patients, presenting between 0 and 24 h after time last known well. The results may be used to develop recommendations and inform further implementation projects and studies.

Expediting workflow in the acute stroke pathway for endovascular thrombectomy in the northern Netherlands: a simulation model.

OBJECTIVE: The objective of this study is to identify barriers for the timely delivery of endovascular thrombectomy (EVT) and to investigate the effects of potential workflow improvements in the acute stroke pathway. DESIGN: Hospital data prospectively collected in the MR CLEAN Registry were linked to emergency medical services data for each EVT patient and used to build two Monte Carlo simulation models. The 'mothership (MS) model', reflecting patients who arrived directly at the comprehensive stroke centre (CSC); and the 'drip and ship' (DS) model, reflecting patients who were transferred to the CSC from primary stroke centres (PSCs). SETTING: Northern region of the Netherlands. One CSC provides EVT, and its catchment area includes eight PSCs. PARTICIPANTS: 248 patients who were treated with EVT between July 2014 and November 2017. OUTCOME MEASURES: The main outcome measures were total delay from stroke onset until groin puncture, functional independence at 90 days (modified Rankin Scale 0-2) and mortality. RESULTS: Barriers identified included fast-track emergency department routing, prealert for transfer to the CSC, reduced handover time between PSC and ambulance, direct transfer from CSC arrival to angiography suite entry, and reducing time to groin puncture. Taken together, all workflow improvements could potentially reduce the time from onset to groin puncture by 59 min for the MS model and 61 min for the DS model. These improvements could thus result in more patients-3.7% MS and 7.4% DS-regaining functional independence after 90 days, in addition to decreasing mortality by 3.0% and 5.0%, respectively. CONCLUSIONS: In our region, the proposed workflow improvements might reduce time to treatment by about 1 hour and increase the number of patients regaining functional independence by 6%. Simulation modelling is useful for assessing the potential effects of interventions aimed at reducing time from onset to EVT.

Letter to the editor, "Validation and clinical value of the MANAGE-PD tool: A clinician-reported tool to identify Parkinson's disease patients inadequately controlled on oral medications".

The MANAGE-PD tool may help general neurologists in deciding whether a patient with advanced Parkinson's disease should be referred for an advanced therapy. Although the development and clinical validation of MANAGE-PD would appear to serve an important need, we urge the reader to be aware of several methodological concerns.

A Multinational Longitudinal Study Incorporating Intensive Methods to Examine Caregiver Experiences in the Context of Chronic Health Conditions: Protocol of the ENTWINE-iCohort.

Informal caregivers are those who provide unpaid care to a relative or friend with a chronic illness, disability or other long-lasting health or care need. Providing informal care in the context of chronic health conditions presents a significant global challenge. Examination of the determinants of informal caregivers' behaviour, especially in terms of motivations and willingness to provide/receive care, is crucial to understanding the nature of caregiver and care recipient experiences. A large group of international researchers have co-operated to execute the ENTWINE iCohort-a multinational, transdisciplinary, longitudinal study incorporating intensive methods to examine caregiver experiences in the context of chronic health conditions. The aim of ENTWINE-iCohort is to investigate the broad spectrum of factors, i.e., cultural, personal, geographical, relational, psychological, and economic that may affect motivations, willingness to provide or receive care, among diverse groups of informal caregivers and their care recipients, in different countries that have different care systems. Study questionnaires will be disseminated on-line in nine countries: Germany, Greece, Ireland, Italy, Israel, the Netherlands, Poland, Sweden, and the UK. Cross-sectional and longitudinal multivariate analysis, including intensive longitudinal and dyadic data analysis will be applied to examine the relative contribution of the above factors to caregiver or care recipient wellbeing.