Concordance between patient- and physician-reported Myasthenia Gravis Activities of Daily Living (MG-ADL) scores.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is a neuromuscular disease characterized by abnormal skeletal muscle fatiguability. The MG Activities of Daily Living (MG-ADL) scale assesses eight symptoms and is often used as primary endpoint in MG clinical trials where it is completed by neurologists. However, in observational studies, patients frequently complete the MG-ADL scale independently of their neurologist. In this study we aimed to assess the concordance between self- and physician-reported MG-ADL scores. METHODS: An international observational study was conducted among adult patients with MG scheduled for a routine visit or who entered the hospital via emergency services. Consenting patients and physicians completed the MG-ADL. Concordance between assessments was calculated using Gwet's agreement coefficient (Gwet's AC) for the MG-ADL individual items and the intraclass correlation coefficient (ICC) for the MG-ADL total score. RESULTS: Data were collected from 137 patients (63% female; mean age, 57.7 years). Physicians assessed the patient's symptoms as slightly more severe (8.1 vs 7.5 MG-ADL total score, respectively), corresponding to a difference of 0.6 on a range from 0 to 24. The ICC for the MG-ADL total score between the patient and the physician assessment was 0.94 (95% confidence interval, 0.89 to 0.95), showing excellent concordance. Gwet's AC showed substantial to almost perfect agreement for all items, except eyelid droop, for which the agreement was moderate. DISCUSSION: Our results demonstrate that patients and neurologists have a concordant assessment of the patient's MG symptoms when using the MG-ADL scale. This evidence supports patient self-administration of the MG-ADL in clinical practice and research.

Exploration of the Reasons Why Health State Valuation Differs for Children Compared With Adults: A Mixed Methods Approach.

OBJECTIVES: Evidence comparing utilities for adults and children consistently report higher utility values for child health states. This study investigates the reasons why child health states are valued differently. METHODS: A total of 80 respondents (United Kingdom, Belgium, The Netherlands) participated in 1.5-hour face-to-face interviews. Respondents valued 4 health states from 2 perspectives (8-year-old child, 40-year-old adult) using visual analog scale and time trade-off. A total of 32 respondents participated in think-aloud interviews. Audio recordings were analyzed by 2 independent coders using NVIVO software. Statements, nodes, and themes were reviewed cyclically until consensus was reached. RESULTS: Qualitative results: a total of 5 themes were identified in the data regarding child and adult valuation-intergenerational responsibility and dependency (childhood is crucial for forming life skills based on new experiences; adulthood is an important time to take care of the family), staying alive is important (life is worth living even with impaired health-related quality of life (HRQoL), for children and adults), awareness of poor HRQoL and ability to make decisions (children have difficulties comprehending poor HRQoL and their parents make their healthcare decision; adults can assess their own HRQoL and decide for themselves), coping ability (children are flexible and resilient; adults have experience with dealing with difficulties), and practical organization of care (children are cared for by their parents; adults are able to organize and pay for care). Mixed methods: comparing qualitative statements with respondents' higher utilities for child health states confirmed concordance between results. CONCLUSIONS: Quality-adjusted life-years are interpreted differently for children and adults. Child-specific value sets are needed to reflect society's preferences and to adequately conduct health technology assessment of pediatric treatments.

Evaluation of the cost-effectiveness of dexrazoxane for the prevention of anthracycline-related cardiotoxicity in children with sarcoma and haematologic malignancies: a European perspective.

BACKGROUND: Anthracycline-treated childhood cancer survivors are at higher risk of cardiotoxicity, especially with cumulative doses received above 250 mg/m2. Dexrazoxane is the only option recommended for cardiotoxicity prevention in high-risk patients supported by randomised trials but its cost-effectiveness in paediatric cancer patients has not been established. METHODS: A cost-effectiveness model applicable to different national healthcare system perspectives, which simulates 10,000 patients with either sarcoma or haematologic malignancies, based upon baseline characteristics including gender, age at diagnosis, cumulative anthracycline dose and exposure to chest irradiation. Risk equations for developing congestive heart failure and death from recurrence of the original cancer, secondary malignant neoplasms, cardiac death, pulmonary death, and death from other causes were derived from published literature. These are applied to the individual simulated patients and time until development of these events was determined. The treatment effect of dexrazoxane on the risk of CHF or death was based upon a meta-analysis of randomised and non-randomised dexrazoxane studies in each tumour type. The model includes country specific data for drug and administration costs, all aspects of heart failure diagnosis and management, and death due to different causes for each of the five countries considered; France, Germany, the UK, Italy, and Spain. RESULTS: Dexrazoxane treatment resulted in a mean QALY benefit across the five countries ranging from 0.530 to 0.683 per dexrazoxane-treated patient. Dexrazoxane was cost-effective for paediatric patients receiving anthracycline treatment for sarcoma and for haematologic malignancies, irrespective of the cumulative anthracycline dose received. The Incremental Cost Effectiveness Ratio (ICER) was favourable in all countries irrespective of anthracycline dose for both sarcoma and haematological malignancies (range: dominant to €2196). Individual ICER varied considerably according to country with dominance demonstrated for dexrazoxane in Spain and Italy and ratios approximately double the European average in the UK and Germany. CONCLUSIONS: Dexrazoxane is a highly cost-effective therapy for the prevention of anthracycline cardiotoxicity in paediatric patients with sarcoma or haematological malignancies in Europe, irrespective of the healthcare system in which they receive treatment. These benefits persist when patients who receive doses of anthracycline > 250 mg/m2 are included in the model.

The combined impact of dependency on caregivers, disability, and coping strategy on quality of life after ischemic stroke.

BACKGROUND: To estimate the additional impact of coping and of being dependent on caregivers, over and above the large effects of disability on utility after ischemic stroke. METHODS: A total of 539 patients were recruited into an observational, retrospective study when returning for a check-up between 3 and 36 months after an ischemic stroke. Patients' modified Rankin Scale (mRS), dependency on caregivers, the Brandtstädter and Renner Coping questionnaire (with summary scores: Tenacity of Goal Pursuit (TGP) and Flexible Goal Adjustment (FGA) coping styles), EQ-5D-3 L and co-morbidities were evaluated. RESULTS: In multivariable regression, greater disability (mRS) resulted in large utility losses, between 0.06 for mRS 1 to 0.65 for mRS 5 (p < 0.0001). Dependency on caregivers caused an additional dis-utility of 0.104 (p = 0.0006) which varied by mRS (0.044, 0.060, 0.083, 0.115, 0.150 and 0.173 for mRS 0-5). The effect of coping on utility varied by coping style, by the disability level of the patient and by his or her dependency on caregivers. FGA coping was associated with additional increases in utility (p < 0.0001) over and above the effect of disability and dependency, whereas TGA had no significant impact. FGA coping was associated with larger utility changes among more disabled patients (0.018 to 0.105 additional utility, for mRS 0 to mRS 5 respectively). Dependent patients had more to gain from FGA coping than patients who function independently of caregivers: utility gains were between 0.049 and 0.072 for moderate to high levels of FGA coping. In contrast, the same positive evolution in FGA coping resulted in 0.039 and 0.057 utility gain among independent patients. Finally, we found that important stroke risk factors and co-morbidities, such as diabetes and atrial fibrillation, were not predictors of EQ-5D utility in a multivariable setting. CONCLUSIONS: This study suggests that treatment strategies targeting flexible coping styles and decreasing dependency on caregivers may lead to significant gains in quality of life above and beyond treatment strategies that solely target disability.

What Impact Does Venous Thromboembolism and Bleeding Have on Cancer Patients' Quality of Life?

BACKGROUND: Venous thromboembolism (VTE) is common in cancer patients and its treatment is associated with a high risk of recurrent VTE (rVTE) and bleeding. OBJECTIVES: To analyze data from the Comparison of Acute Treatments in Cancer Hemostasis (CATCH) trial to describe the impact of rVTE and bleeding events on health-related quality of life. METHODS: The three-level EuroQol five-dimensional questionnaire (EQ-5D) data were collected monthly for up to 7 months in patients starting anticoagulation for newly diagnosed VTE. Analyses were designed to describe the impact of rVTE and bleeding on EQ-5D scores while controlling for effects of covariates such as background and clinical variables and longitudinal changes. A repeated-measures model with specification of the variance-covariance matrix to characterize the intrapatient correlation was used to estimate the utility values. The impact of an rVTE or a bleeding event was assumed to be reflected in the utility value when it occurred within 2 weeks from a planned data collection point. RESULTS: Data were available from 883 patients. A total of 76 rVTE and 159 bleeding events occurred during follow-up. rVTE had a significant impact on EQ-5D scores, with a decrement of -0.075 on the basis of our reference case (male, no metastasis, Eastern Cooperative Oncology Group score = 1, Western European), but different patients might have different decrements. Bleeding events had a smaller (nonstatistically significant) impact on EQ-5D scores. CONCLUSIONS: This data set study has quantified the decline in EQ-5D scores associated with experiencing rVTE or bleeding events in cancer patients. These results indicate the net gain in quality of life and impact on cost-effectiveness of secondary VTE prevention.

Hospital financing of ischaemic stroke: determinants of funding and usefulness of DRG subcategories based on severity of illness.

BACKGROUND: Several Western and Arab countries, as well as over 30 States in the US are using the "All-Patient Refined Diagnosis-Related Groups" (APR-DRGs) with four severity-of-illness (SOI) subcategories as a model for hospital funding. The aim of this study is to verify whether this is an adequate model for funding stroke hospital admissions, and to explore which risk factors and complications may influence the amount of funding. METHODS: A bottom-up analysis of 2496 ischaemic stroke admissions in Belgium compares detailed in-hospital resource use (including length of stay, imaging, lab tests, visits and drugs) per SOI category and calculates total hospitalisation costs. A second analysis examines the relationship between the type and location of the index stroke, medical risk factors, patient characteristics, comorbidities and in-hospital complications on the one hand, and the funding level received by the hospital on the other hand. This dataset included 2513 hospitalisations reporting on 35,195 secondary diagnosis codes, all medically coded with the International Classification of Disease (ICD-9). RESULTS: Total costs per admission increased by SOI (€3710-€16,735), with severe patients costing proportionally more in bed days (86%), and milder patients costing more in medical imaging (24%). In all resource categories (bed days, medications, visits and imaging and laboratory tests), the absolute utilisation rate was higher among severe patients, but also showed more variability. SOI 1-2 was associated with vague, non-specific stroke-related ICD-9 codes as primary diagnosis (71-81% of hospitalisations). 24% hospitalisations had, in addition to the primary diagnosis, other stroke-related codes as secondary diagnoses. Presence of lung infections, intracranial bleeding, severe kidney disease, and do-not-resuscitate status were each associated with extreme SOI (p < 0.0001). CONCLUSIONS: APR-DRG with SOI subclassification is a useful funding model as it clusters stroke patients in homogenous groups in terms of resource use. The data on medical care utilisation can be used with unit costs from other countries with similar healthcare set-ups to 1) assess stroke-related hospital funding versus actual costs; 2) inform economic models on stroke prevention and treatment. The data on diagnosis codes can be used to 3) understand which factors influence hospital funding; 4) raise awareness about medical coding practices.

Association Between Myasthenia Gravis-Activities of Daily Living (MG-ADL) and EQ-5D-5L Utility Values: The Additional Effect of Efgartigimod on Utilities.

INTRODUCTION: For patients with generalized myasthenia gravis (gMG), the association between symptom severity, often measured with the Myasthenia Gravis Activities of Daily Living (MG-ADL) instrument, and utility values is unknown. METHODS: Data was analyzed from the phase 3 ADAPT trial, which included adult patients with gMG randomly assigned to treatment with efgartigimod + conventional therapy (EFG + CT) or placebo + CT (PBO + CT). MG-ADL total symptom scores and the EQ-5D-5L, a measure of health-related quality of life (HRQoL), were collected biweekly up to 26 weeks. Utility values were derived from the EQ-5D-5L data with the United Kingdom value set. Descriptive statistics were reported for MG-ADL and EQ-5D-5L at baseline and follow-up. A normal identity-link regression model estimated the association between utility and the eight MG-ADL items. A generalized estimating equations (GEE) model was estimated to predict utility based on the patient's MG-ADL score and treatment received. RESULTS: A total of 167 patients (84 EFG + CT, 83 PBO + CT) contributed 167 baseline and 2867 follow-up measurements of MG-ADL and EQ-5D-5L. EFG + CT-treated patients experienced more improvements than PBO + CT-treated patients in most MG-ADL items and EQ-5D-5L dimensions, with the largest improvements observed in chewing, brushing teeth/combing hair, eyelid droop (MG-ADL); self-care, usual activities, mobility (EQ-5D-5L). The regression model indicated that individual MG-ADL items contributed differently to utility values, with the largest impact from brushing teeth/combing hair, rising from a chair, chewing, and breathing. The GEE model showed that each unit improvement in MG-ADL led to a statistically significant utility increase of 0.0233 (p < 0.001). In addition, a statistically significant improvement of 0.0598 (p = 0.0079) in utility was found for patients in the EFG + CT group compared to the PBO + CT group. CONCLUSION: Among patients with gMG, improvements in MG-ADL were significantly associated with higher utility values. MG-ADL scores alone were not sufficient to capture the utility gained from efgartigimod therapy.

Patient-reported burden of myasthenia gravis: baseline results of the international prospective, observational, longitudinal real-world digital study MyRealWorld-MG.

OBJECTIVES: Myasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain detailed knowledge of the impact of MG on HRQoL in a broad population from the perspective of the patient. DESIGN: Prospective, observational, digital, longitudinal real-world study. SETTING: Adult patients with MG from seven countries (USA, Japan, Germany, UK, Italy, Spain and Canada) downloaded a mobile application onto their phones and entered data about themselves and their MG. OUTCOME MEASURES: Data was collected using the following general and disease-specific patient-reported outcome measurements: EuroQol 5 Domains Health-Related Quality of Life Questionnaire (EQ-5D-5L), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Quality of Life 15-item revised scale (MG-QoL-15r), Hospital Anxiety and Depression Scale (HADS) and Health Utilities Index III (HUI3). Patients were categorised by their self-assessed Myasthenia Gravis Foundation of America (MGFA) class (I-V). RESULTS: Baseline results of 841 participants (mean age 47 years, 70% women) are reported . The distribution across the MGFA classes was: 13.9%, 31.0%, 38.1%, 15.5% and 1.6% for classes I-V. The MGFA class was a strong predictor of all aspects of HRQoL, measured with disease-specific and with generic instruments. The domains in which patients with MG most frequently mentioned problems were usual activities, anxiety and depression, tiredness, breathing and vision. The mean total MG-ADL Score was positively associated with increasing MGFA classes: 2.7, 4.4, 6.3 and 8.4 for MGFA classes I-IV. Mean baseline EQ-5D-5L utility was also associated with MGFA classes and was 0.817, 0.766, 0.648 and 0.530 for MGFA class I-IV. CONCLUSIONS: MG has a large impact on key aspects of health and HRQoL. The impact of this disease increases substantially with increasing disease severity.

Genome-wide discovery of functional transcription factor binding sites by comparative genomics: the case of Stat3.

The identification of direct targets of transcription factors is a key problem in the study of gene regulatory networks. However, the use of high throughput experimental methods, such as ChIP-chip and ChIP-sequencing, is limited by their high cost and strong dependence on cellular type and context. We developed a computational method for the genome-wide identification of functional transcription factor binding sites based on positional weight matrices, comparative genomics, and gene expression profiling. The method was applied to Stat3, a transcription factor playing crucial roles in inflammation, immunity and oncogenesis, and able to induce distinct subsets of target genes in different cell types or conditions. A newly generated positional weight matrix enabled us to assign affinity scores of high specificity, as measured by EMSA competition assays. Phylogenetic conservation with 7 vertebrate species was used to select the binding sites most likely to be functional. Validation was carried out on predicted sites within genes identified as differentially expressed in the presence or absence of Stat3 by microarray analysis. Twelve of the fourteen sites tested were bound by Stat3 in vivo, as assessed by Chromatin Immunoprecipitation, allowing us to identify 9 Stat3 transcriptional targets. Given its high validation rate, and the availability of large transcription factor-dependent gene expression datasets obtained under diverse experimental conditions, our approach appears to be a valid alternative to high-throughput experimental assays for the discovery of novel direct targets of transcription factors.

Exploring the Comparability of Face-to-Face Versus Video Conference-Based Composite Time Trade-Off Interviews: Insights from EQ-5D-Y-3L Valuation Studies in Belgium and Spain.

BACKGROUND: Face-to-face interviews are recommended for the collection of composite time trade-off (cTTO) data. The coronavirus disease 2019 (COVID-19) social distancing measures made researchers consider videoconferencing interviews as an alternative mode of administration, but little evidence about the implementation of videoconferencing in valuation studies is available. This study provides insights into the effect of videoconferencing on the quality of data, evaluating interviewers' and respondents' engagement level in videoconferences compared with face-to-face interviews. METHODS: We used cTTO data collected in Belgium and Spain following the EQ-5D-Y-3L valuation protocol. Due to the COVID-19 pandemic, both projects interrupted the face-to-face data collection before reaching the target sample. The remaining interviews were conducted by videoconference. We compared both modes of administration in terms of interviewers' engagement (task duration and number of moves in each example) and respondents' engagement (task duration and proportions of specific response values, in half-year units). To minimise interviewers' learning effects, we split our sample into three groups: (1) first 20 interviews conducted face-to-face; (2) subsequent interviews conducted face-to-face; and (3) videoconferencing interviews. RESULTS: The comparison between videoconferencing and subsequent face-to-face interviews showed the interviewer's engagement was not affected by the mode of administration as almost no significant results were found either in the task duration or the numbers of moves shown in the examples. Similarly, none of the respondents' task duration or proportion of specific responses or half-year units were affected by the mode of administration in either of the two countries. CONCLUSIONS: No evidence suggested that the quality of cTTO data is reduced when using videoconferencing compared with face-to-face interviews.

Thrombectomy is a cost-saving procedure up to 24 h after onset.

INTRODUCTION AND AIM: The treatment of ischemic stroke due to large-vessel occlusion has been revolutionized by mechanical thrombectomy (MT), as multiple trials have consistently shown improved functional outcomes compared to standard medical management both in the early and late time windows after symptom onset. However, MT is an interventional procedure that is more costly than best supportive care (BSC). METHODS: We set out to study the cost-utility and budget impact of MT + BSC versus BSC alone for large-vessel occlusion using a combined decision tree and Markov model. The analysis was conducted from a Belgian payer perspective over a lifetime horizon, and health states were defined by the modified Rankin Scale (mRS). The treatment effect of MT + BSC combined clinical outcomes from all published early and late treatment window studies showing improved mRS after 90 days. Resource use and utilities were informed by an observational Belgian study of 569 stroke patients. Long-term mRS transitions were sourced from the Oxford Vascular study. RESULTS: MT + BSC generated 1.31 additional quality-adjusted life years and resulted in cost savings of €10,216 per patient over lifetime. Deterministic sensitivity analyses demonstrated dominance of MT over a wide range of parameter inputs. In a Belgian setting, adding MT to BSC within an early time window for 1575 eligible stroke patients every year produced cost savings between €6.3 million (year 1) and €14.6 million (year 5), or a total cost saving of €56.2 million over 5 years. CONCLUSION: Mechanical thrombectomy is a highly cost-effective treatment for ischemic stroke patients, providing quality-adjusted survival at lower health care cost, both when given in an early time window, as well as in a late time window.

An EQ-5D-Y-3L Value Set for Belgium.

BACKGROUND: In Belgium, a value set for children and adolescents for a generic health-related quality-of-life measure is not available. To inform drug pricing and make resource allocation decisions for children and adolescents, national tax-payers' preferences for youth health states should be known. OBJECTIVE: We aimed to obtain a value set for EQ-5D-Y-3L in Belgium, following the international youth valuation protocol for data collection. METHODS: Composite Time Trade-Off interviews were conducted in a sample of 200 adults, either face to face or via video conferencing. Another sample of 1000 adults completed an online discrete choice experiment survey. All adults were asked to take the perspective of a 10-year-old child for both methods. Both samples were representative for Belgium in terms of age, sex and region. A latent class analysis was selected to obtain the relative importance of the five dimensions and their levels based on the discrete choice experiment data, which were anchored with the composite Time Trade-Off censored value for the worst health state (33333). RESULTS: Preferences from Belgian adults revealed a mean censored value for 33333 for children and adolescents of - 0.475. All the estimated coefficients of the model with 4 latent classes were statistically significant and showed higher disutility as severity levels increase. The most important health dimension was pain/discomfort, followed by feeling sad/worried/unhappy. CONCLUSIONS: This study presents the Belgian EQ-5D-Y-3L value set, which will be included in the Belgian pharmacoeconomic guidelines. The value set enables the calculation of quality-adjusted life-years in children and adolescents, allowing a cost-effectiveness evaluation of health technologies and their youth-specific price setting.

The activity of aminoacyl-tRNA synthetase-interacting multi-functional protein 1 (AIMP1) on endothelial cells is mediated by the assembly of a cytoskeletal protein complex.

AIMP1 was first found as a factor associated with the aminoacyl-tRNA synthetase (ARS) complex. However, it is also secreted and acts on different target cells such as endothelial cells, macrophages, and fibroblasts as an extracellular regulator, respectively, of angiogenesis, inflammatory responses and dermal regeneration. AIMP1 has also been reported to suppress in vivo tumor growth. In this study, we investigated the signaling pathways activated by exogenous AIMP1 in an in vitro endothelial model. AIMP1 decreases EC viability through an α5ß1 integrin-dependent mechanism and inhibits cell adhesion, is internalized and shows an asymmetric pattern of distribution and accumulation in cell protrusions. Experiments of affinity purification, pull down, and co-immunoprecipitation showed that AIMP1 interacts with four cytoskeletal proteins (filamin-A, α-tubulin, vinculin, and cingulin). α-Tubulin also gets phosphorylated upon cell treatment with AIMP1 and colocalization between AIMP1 and filamin-A as well as between AIMP1 and cingulin was observed through immunofluorescence assays. In this work, we propose that AIMP1 effect on EC adhesion is mediated by the assembly of a cytoskeletal protein complex on the cytosolic face of the cell membrane which could regulate cellular architecture maintenance and remodeling. Moreover, this activity is able to indirectly influence cell viability.

Methylphenidate delivery mechanisms for the treatment of children with attention deficit hyperactivity disorder: heterogeneity in parent preferences.

OBJECTIVES: Extended-release therapies avoid the need for children with attention-deficit/hyperactivity disorder (ADHD) to take medication at school. Recently a transdermal delivery system has been developed which can allow symptom control all day long but with greater dosing flexibility. This study explored the parents' preferences regarding oral and transdermal therapy. METHODS: A nonsystematic and qualitative literature review and in-depth interviews with parents and physicians helped identify salient treatment attributes for a discrete choice experiment. Treatment attributes included mode of administration (tablet or transdermal), speed of onset (30-90 min); duration (lasts until 3-9 pm) and ability to tailor the drug to different needs (no flexibility, limited flexibility, easy to adjust to different days). A convenience sample of parents of children treated for ADHD (n = 200) were recruited using a recruitment agency. Data were analyzed using generalized estimating equations (GEE). RESULTS: Parents' preferred once-a-day oral therapy (odds ratio [OR] = 1.76 [95 percent confidence interval {CI}, 1.43 - 2.18]); rapid speed of onset (OR = 1.22 [95 percent CI, 1.07 - 1.39]), and symptom control until 9 pm (OR = 3.79 [95 percent CI, 2.98 - 4.82]). Analyses identified that 30 percent of parents preferred transdermal treatment and this subgroup preferred treatments with a fast onset of action. CONCLUSIONS: This survey demonstrates that parents of ADHD children have different preferences for the ADHD treatments prescribed for their children. A distinct subgroup of parents prefer the transdermal therapy. These parents were less likely to be working and so monitoring compliance and doing after school activities may have been easier.

Cost of hospitalization for cerebrovascular disorders in Belgium.

BACKGROUND: There is only scarce information on the incidence and costs of stroke in Belgium. Knowledge of these figures permits targeted allocation of resources and aids cost efficacy estimates. METHODS: We analysed a nationwide administrative database used for reimbursement of hospitals in Belgium. This database allows analysis of the rate of all hospital admissions for TIA, acute ischemic stroke, intracranial hemorrhage and carotid surgery or angioplasty. We compared the costs of hospitalization for stroke and related disorders with the costs of hospitalization for coronary artery disease. RESULTS: There were 32970 admissions for stroke related disorders in 2007 at a cost of 191.6 million EUROS. There was a decline of 4.7% of the rate of hospitalization for stroke and associated disorders over the period 2002-2007. Despite this decline the total costs did not diminish substantially. In 2007 stroke and related disorders accounted for 2.0% of all Belgian hospitalizations, whereas coronary artery disease hospitalization accounted for 4.4%. The length of stay was longer for stroke and associated disorders. The average cost of hospitalizations in 2007 for stroke related disorders was 6188 EURO and the average cost of coronary artery related disorders was 5026 EURO. CONCLUSION: The cost of hospitalization for stroke and related disorders is high. Although coronary artery disease is more frequent and has a larger impact on the health care expenditures, the average cost per hospitalization is higher for stroke and related diseases. This is mainly due to the longer hospitalization duration for stroke.

Estimating health state utilities in hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocyti.c lymphohistiocytosis (HLH) is a rare and severe disorder characterized by abnormal activation of the immune system. Primary HLH causes prolonged fever, spleen and liver enlargement, and organ dysfunction, usually in infancy and early childhood and is fatal if left untreated. As effective treatment options emerge, such as emapalumab-lzsg, Health Technology Assessment bodies around the world will assess them in terms of cost-effectiveness. This study was designed to estimate quality of life weights (utilities) for such analyses. METHODS: Vignettes were developed describing HLH treatment related health states. Health states included active HLH, HLH plus neurological symptoms, receiving chemotherapy, undergoing stem cell transplant (SCT), graft versus host disease (GVHD), cure and end of life care. The vignettes were based on information from in depth interviews with clinical specialists; and qualitative research with four parents of children with primary HLH aged between 1 and 18 years old. The vignettes were then assessed in time trade off (TTO) interviews with members of the UK general public in one on one face to face interviews with trained, experienced interviewers. Preference data were analysed using the generalised estimating equations framework. RESULTS: Detailed qualitative data captured the substantial burden of this disease for young children. One hundred participants completed the TTO interviews. The utility score for Active HLH was estimated as 0.32 (95% CI, 0.24 to 0.39). Values for other states were HLH plus neurological symptoms (0.27, 95%CI 0.18-0.35), receiving chemotherapy (0.26, 95%CI 0.17-0.34), undergoing SCT (0.18, 95%CI 0.07-0.28), GVHD (0.07, 95%CI -0.04-0.17), cure (0.72, 95%CI 0.67-0.77) and end of life care (- 0.17, 95%CI -0.27- -0.07). CONCLUSIONS: This study has estimated utility weights for seven different HLH related states which are based on detailed input from carers and physicians and have good face validity. There are few other options for collecting these data in an ultra-rare setting.

Patient-reportedimpact of myasthenia gravis in the real world: protocol for a digital observational study (MyRealWorld MG).

INTRODUCTION: Myasthenia gravis (MG) is a rare, chronic, autoimmune disease, mediated by immunoglobulin G antibodies, which causes debilitating muscle weakness. As with most rare diseases, there is little patient-reported data with which to understand and address patient needs. This study explores the impact of MG in the real world from the patient perspective. METHODS AND ANALYSIS: This is a 2-year prospective, observational, digital, longitudinal study of adults with MG, resident in the following countries: the USA, Japan, Germany, France, the UK, Italy, Spain, Canada and Belgium. The planned sample size is 2000. Recruitment will be community based, via patient advocacy groups, social media and word of mouth. Participants will use a smartphone application (app) to check eligibility, provide consent and contribute data. Planned data entry is as follows: (1) personal profile on enrollment-covering demographics, MG characteristics and previous care; (2) monthly event tracker-current treatments, healthcare visits, treatment-related adverse events, productivity losses; (3) monthly selection of validated generic and disease-specific patient-reported outcomes instruments: EQ-5D-5L, Myasthenia Gravis Activities of Daily Living, Myasthenia Gravis Quality of Life 15-item revised scale, Hospital Anxiety and Depression Scale and Health Utilities Index III. Analyses are planned for when the study has been running in most countries for approximately 6, 12, 18 and 24 months. ETHICS AND DISSEMINATION: The study protocol has been reviewed and granted ethics approval by Salus IRB for participants resident in the following countries: Germany, the UK and the US. Local ethics approval is being sought for the following study countries: Belgium, Canada, France, Italy, Japan and Spain. Study results will be communicated to the public and participants via conference presentations and journal publications, as well as regular email, social media and in-application communication. TRIAL REGISTRATION NUMBER: NCT04176211.

The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/STAT3 and Wnt-1 pathways.

STAT3 (signal transducer and activator of transcription 3) is a transcription factor activated by cytokines, growth factors and oncogenes, whose activity is required for cell survival/proliferation of a wide variety of primary tumours and tumour cell lines. Prominent among its multiple effects on tumour cells is the stimulation of cell migration and metastasis, whose functional mechanisms are however not completely characterized. RhoU/Wrch1 (Wnt-responsive Cdc42 homologue) is an atypical Rho GTPase thought to be constitutively bound to GTP. RhoU was first identified as a Wnt-1-inducible mRNA and subsequently shown to act on the actin cytoskeleton by stimulating filopodia formation and stress fibre dissolution. It was in addition recently shown to localize to focal adhesions and to Src-induced podosomes and enhance cell migration. RhoU overexpression in mammary epithelial cells stimulates quiescent cells to re-enter the cell cycle and morphologically phenocopies Wnt-1-dependent transformation. In the present study we show that Wnt-1-mediated RhoU induction occurs at the transcriptional level. Moreover, we demonstrate that RhoU can also be induced by gp130 cytokines via STAT3, and we identify two functional STAT3-binding sites on the mouse RhoU promoter. RhoU induction by Wnt-1 is independent of beta-catenin, but does not involve STAT3. Rather, it is mediated by the Wnt/planar cell polarity pathway through the activation of JNK (c-Jun N-terminal kinase). Both the so-called non-canonical Wnt pathway and STAT3 are therefore able to induce RhoU, which in turn may be involved in mediating their effects on cell migration.

The relationship between Home-time, quality of life and costs after ischemic stroke: the impact of the need for mobility aids, home and car modifications on Home-time.

Purpose: Home-time (the number of days spent at home during the first 3 months after stroke) shows a strong association with the modified Rankin scale (mRS). We studied whether Home-time was also a determinant of quality-of-life and medical care costs after ischemic stroke, and assessed factors delaying discharge home.Materials and methods: Five hundred and sixty nine patients participated in a retrospective study when returning for an in-person visit after an ischemic stroke. Home-time, mRS, EQ-5D-3L, inpatient and outpatient resource utilization, use of mobility aids, changes to home and car, comorbidities were recorded.Results: Each additional Home-time day was significantly associated with an increase in utility of 0.0056 (p < 0.0001) and an in- and outpatient cost saving of $99 (p = 0.0158). Requiring extra material support significantly decreased Home-time by 76 days (including: requiring home changes: -68 days, car alterations: -49 days, needing a wheelchair: -80 days or walker: -71 days, needing bed or bath rails: -79 days). This univariable effect was confirmed in multivariable analysis when comparing with patients having the same disability level without requiring material support.Conclusions: Home-time is a stroke outcome associated with disease severity, healthcare costs and patient wellbeing. Streamlining the discharge process for those requiring extra material support may lead to cost savings and higher quality-of-life.Implications for rehabilitationDelays in discharge from the acute hospital or rehabilitation facility are incurred when patients need extra material support in order to return home.Staff from the discharging facility should assist families by giving timely information on the availability and the cost of wheel chairs and walkers; and explaining and planning the need of a stair lift, bed and bath rails as well as car modifications.Planning the discharge process with the families will lead to a more rapid return home and will result in reduced overall health care costs and higher quality of life for the patients.

Cost-effectiveness of warfarin: trial versus "real-world" stroke prevention in atrial fibrillation.

BACKGROUND AND PURPOSE: Previous cost-effectiveness analyses analyzed warfarin for stroke prevention in randomized trial settings. Given the complexities of warfarin treatment, cost-effectiveness should be examined within a real-world setting. METHODS: Our model followed patients with atrial fibrillation at moderate to high risk of stroke through primary and recurrent ischemic stroke, hemorrhages--intracranial and extracranial, and the resulting disability. Four scenarios were examined: (1) all patients start on warfarin with perfect control, that is, international normalized ratio (INR) values always within range; (2) all patients start on warfarin with trial-like control, where INR can fall outside the recommended range; (3) all patients start on warfarin with real-world INR control; and (4) real-world prescription (and control) of warfarin, aspirin, or neither for warfarin-eligible patients. Reported warfarin discontinuation rates were used. Main outcomes were total number of events, quality adjusted life years, and costs in a US setting. RESULTS: The total number of primary and recurrent ischemic strokes in a 1,000-patient cohort (age 70 years, lifetime analysis) was 626, 832, 984, and 1,171 in scenarios 1 to 4, respectively. The corresponding mean quality adjusted life years per patient were 7.21, 6.92, 6.75, and 6.67 for scenarios 1 to 4, respectively. Costs per patient were $68,039, $77,764, $84,518, and $87,248 in scenarios 1 to 4, respectively. If "perfect" adherence to warfarin was assumed, except for discontinuations for clinical reasons, strokes would decrease to 503, 737, 909, and 1,120 in scenarios 1 to 4, respectively. CONCLUSIONS: Clinical and cost outcomes are strongly dependent on the quality of anticoagulation and rates of warfarin discontinuation. Clinicians should work to improve both. Policy makers should use real-world INR control and warfarin discontinuation rates when assessing cost-effectiveness.