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Background: Dementia patients frequently depend on caregivers. Agitation is a common behavioral dementia symptom particularly burdensome to patients and caregivers. Objective: To assess the association of agitation severity with non-professional caregiver hours, burden, health status, and productivity. Secondarily, to assess the association of agitation severity with these outcomes for patients receiving remote (not living with the patient) and proximate (living with the patient) caregiving. Methods: A retrospective analysis of physician and non-professional caregiver-reported data from a US point-in-time survey. Patients were aged ≥50 years, with early cognitive impairment or dementia. Regression analyses compared outcomes by agitation severity; covariates included age, sex, and clinical characteristics. Results: Data were included for 1,349 patients (non-agitated n = 656, agitated n = 693; no care n = 305, remote care n = 248, proximate care n = 691; unknown care n = 105). Greater agitation was significantly associated (p

The pattern-match safety problem is to verify that a given functional program will never crash due to non-exhaustive patterns in its function definitions. We present a refinement type system that can be used to solve this problem. The system extends ML-style type systems with algebraic datatypes by a limited form of structural subtyping and environment-level intersection. We describe a fully automatic, sound and complete type inference procedure for this system which, under reasonable assumptions, is worst-case linear-time in the program size. Compositionality is essential to obtaining this complexity guarantee. A prototype implementation for Haskell is able to analyse a selection of packages from the Hackage database in a few hundred milliseconds.

Objective This study evaluated work and activity impairment in patients with multiple sclerosis (MS) treated with ocrelizumab (OCR) versus other disease-modifying therapies (DMTs). Methods Data were obtained from the Adelphi Real World Disease Specific Programme for Multiple Sclerosis. Patients with relapsing–remitting or secondary progressive MS who completed surveys in 2018 and 2019 and received ≥ 6 months of an eligible therapy, including OCR, injectable therapy, and oral therapy, were included. Outcomes were assessed using the patient-reported Work Productivity and Activity Impairment questionnaire. Doubly robust estimation, which combined propensity score weighting and regression modeling, was used to compare treatments, controlling for baseline clinical and demographic characteristics. Results This study included 630 patients (OCR, n = 90; injectable DMT, n = 224; oral DMT, n = 316) with a mean (standard deviation) age of 42 (11) years. A greater proportion of OCR-treated patients had an Expanded Disability Status Scale score of ≥ 3 at treatment initiation compared with those receiving oral and injectable DMTs (51 vs. 15% and 15%, respectively), and a smaller proportion of OCR-treated patients received treatment for ≥ 1 year (43 vs. 90% and 92%, respectively). OCR-treated patients had higher odds of employment [odds ratio (95% confidence interval) 3.4 (1.5–7.7) vs. oral DMT, 5.6 (2.6–12.0) vs. injectable DMT], lower overall work productivity loss [difference (95% confidence interval) − 10.0% (− 6.1 to − 15.0%) vs. oral DMT, − 13.0% (− 8.5 to − 17.0%) vs. injectable DMT] and lower activity impairment [difference (95% confidence interval) − 11% (− 7.1 to − 16.0%) vs. oral DMT, − 9.7% (− 5.0 to − 14.0%) vs. injectable DMT]. Conclusion This real-world evidence suggests that patients with MS treated with OCR experience lower work and activity impairment than patients treated with other DMTs. Electronic supplementary material The online version of this article (10.1007/s40120-020-00224-1) contains supplementary material, which is available to authorized users., Plain Language Summary Multiple sclerosis (MS) is the most common progressive neurological disease in young adults. It typically starts between the ages of 20 and 40 years—arguably some of the most productive years of an individual’s life—and it has a large impact on many aspects of everyday life for the rest of a person’s life. The reduction in the ability to do routine activities, including working, results in a large economic burden. Disease-modifying treatments (DMTs) available for MS, particularly high-efficacy DMTs, have been shown to improve work productivity. This study looked at work and activity impairment using the Work Productivity and Activity Impairment Questionnaire in patients with MS who were treated with ocrelizumab (OCR) or other DMTs for ≥ 6 months. A total of 630 patients with relapsing–remitting MS (RRMS) or secondary progressive MS (SPMS) from the Adelphi Real World Disease Specific Programme for Multiple Sclerosis were included in the study, including 90, 316 and 224 patients who completed ≥ 6 months of treatment with OCR, oral or injectable therapy. Compared with patients receiving oral or injectable DMTs, those receiving OCR had higher odds of employment [odds ratio (OR) vs. oral DMT 3.4; OR vs. injectable DMT 5.6], lower overall work productivity impairment (difference vs. oral DMT − 10%; difference vs. injectable DMT − 13%) and lower activity impairment (difference vs. oral DMT − 11%; difference vs. injectable DMT − 9.7%). These findings in patients with RRMS or SPMS being treated in the real world suggest that OCR may reduce the impact of MS disease on work productivity more than other DMTs. Electronic supplementary material The online version of this article (10.1007/s40120-020-00224-1) contains supplementary material, which is available to authorized users.

ObjectiveTo evaluate the contribution of MRI activity and relapses in defining disease activity in Secondary progressive multiple sclerosis (SPMS) patients by analysing real-world data from Adelphi real-world MS Disease Specific Programme (Adelphi-MS-DSP) and to understand whether active SPMS (aSPMS) and non-active SPMC (naSPMS) are mutually exclusive groups in EXPAND.MethodsAdelphi-MS-DSP was a non-interventional, multinational real-world study (N=37,318). Patients were categorised into aSPMS (⩾1 new lesion on the most recent MRI and/or ⩾1 relapse in the last 12-months) and naSPMS groups. In EXPAND, disease activity was defined as relapses in the 2-years before screening and with/without ⩾1 gadolinium-enhancing (Gd+) T1 lesion at baseline. Demographics, MRI and relapse status were analysed descriptively.ResultsSPMS from the Adelphi-MS-DSP were categorised as aSPMS (n=1889) and naSPMS (n=665). Disease activity for aSPMS was based on MRI lesions (59.1%), relapses (12.6%), and both (28.3%). In EXPAND, 52.6% of patients (n/N=866/1645) who had no relapse in the 2-years prior to screening and no Gd+ T1 lesions at baseline were categorised under naSPMS; of these who were on placebo, 52.7% experienced on-study relapse and/or MRI activity.ConclusionsIn both real-world and clinical studies, MRI activity appears to be a more sensitive measure of disease activity versus relapses. Funding: Novartis Pharma AG, Basel, Switzerland.

IntroductionApproximately 34%-65% of people with multiple sclerosis (pwMS) develop cognitive impair- ment (CI). CI often encompasses information processing speed, memory problems, difficulty concentrat- ing, and problems using executive functions effectively. This study explores the perception of the presence of CI from the perspectives of pwMS and neurologists.MethodsUS, UK and EU retrospective data analysis from the 2011-2019 Adelphi Multiple Sclerosis Disease- Specific Programme (MS-DSP). The MS-DSP is a database where neurologists provide data on the next 10 pwMS to have a consultation, patient record form (PRF), integrated with pwMS self-reported data, patient self-completion form (PSC). Neurologists and pwMS were asked about the presence of problems concentrating.Results25,374 pwMS had a PRF. 11,220 pwMS had a PRF and PSC, of these 4294 answered the cognition section, with 62% (n=2,643) reporting CI (mild 36.8%, moderate 18.6, or extreme 6.1% problems concen- trating) in the past two weeks. For the same pwMS, neurologists reported 27% (n=1,158) currently having CI (mild 19.9%, moderate 6.8%, or severe 0.3% problems concentrating).ConclusionsA clear discordance is observed between neurologists and pwMS on their perception of the presence and severity of CI with neurologists clearly underestimating the existence. Funding: Novartis Pharma AG, Basel, Switzerland.

Introduction Making Informed Decisions to Aid Timely Management of Parkinson's Disease (MANAGE-PD) is a clinician-reported tool designed to facilitate timely identification and management of patients with advancing Parkinson's disease (PD) with suboptimal symptom control while on standard therapy. The objective of this study was to evaluate the validity and clinical value of the tool. Methods Driven by structured inputs from a steering committee and panel of PD experts, the tool was developed to classify patients into 3 categories. Validity and clinical value were elucidated using a two-pronged approach: (i) hypothetical patient vignettes (n = 10) developed based on the MANAGE-PD tool and rated by 17 PD specialists and 400 general neurologists (GN) and (ii) patients with PD (n = 2546) managed in real-world clinical settings. Vignette validity was based on concordance between PD experts’ clinical judgement and MANAGE-PD vignette categorization. Patient-level data was used for known-group comparisons (validity) and discordant pair analysis (clinical value). Results The tool demonstrated strong validity and clinical value among PD specialists (intraclass coefficient [ICC] 0.843; Fleiss weighted kappa [ƙweighted] 0.79) and GN (ICC 0.690; ƙweighted 0.65) using patient vignettes. MANAGE-PD also demonstrated real-world validity and clinical value based on ability to identify patients with incrementally higher clinical, economic, and humanistic PD burden across categories of the tool (p Conclusions MANAGE-PD demonstrated robust validity and clinical value in identifying patients with suboptimal PD symptom control. Clinical use of MANAGE-PD may complement treatment decision-making and facilitate timely and comprehensive management of patients with advancing PD.

Introduction Dimethyl fumarate (DMF) is a novel oral therapy used for the treatment of relapse-remitting multiple sclerosis (RRMS). In two 2-year pivotal Phase 3 trials in patients with RRMS, DMF significantly reduced disease activity based on both clinical and magnetic resonance imaging (MRI) findings and demonstrated an acceptable safety profile. However, there is currently a lack of comparative data which explore the relationship between work productivity and health-related quality of life (HRQoL) outcomes in RRMS and how these differ among RRMS therapies, including DMF. Methods We explored this relationship through patient-reported data from the EuroQol Five-Dimensions (EQ-5D) tool, Work Productivity and Activity Impairment Questionnaire (WPAI), and the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) using the Adelphi MS DSP® dataset. Results Our data demonstrated that patients receiving DMF experienced better outcomes, relative to patients receiving beta (β)interferons or glatiramer acetate, in all WPAI subscales [overall; average treatment effect (ATE) −13.92, 95% confidence interval (CI) −18.87 to −7.08; p

Background There is an unmet need for a tool that helps to evaluate patients who are at risk of progressing from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS). A new tool supporting the evaluation of early signs suggestive of progression in multiple sclerosis (MS) has been developed. In the initial stage, concepts relevant to progression were identified using a mixed method approach involving regression on data from a real-world observational study and qualitative research with patients and physicians. The tool was drafted in a questionnaire format to assess these variables. Objective This study aimed to develop the scoring algorithm for the tool, using both quantitative and qualitative research methods. Methods The draft scoring algorithm was developed using two approaches: quantitative analysis of real-world data and qualitative analysis based on physician interviews and ranking and weighting exercises. Variables that were included in the draft tool and regarded as most clinically relevant were selected for inclusion in a multiple logistic regression. The analyses were run using physician-reported data and patient-reported data. Subsequently, a ranking and weighting exercise was conducted with 8 experienced neurologists as part of semistructured interviews. Physicians were presented with the variables included in the draft tool and were asked to rank them in order of strength of contribution to progression and assign a weight by providing a percentage of the overall contribution. Physicians were also asked to explain their ranking and weighting choices. Concordance between physicians was explored. Results Multiple logistic regression identified age, MS disease activity, and Expanded Disability Status Scale score as the most significant physician-reported predictors of progression to SPMS. Patient age, mobility, and self-care were identified as the strongest patient-reported predictors of progression to SPMS. In physician interviews, the variables ranked and weighted as most important were stability or worsening of symptoms, intermittent or persistent symptoms, and presence of ambulatory and cognitive symptoms. Across all physicians, the level of concordance was 0.278 (P Conclusions This study further confirms the need for a tool to provide a consistent, comprehensive approach across physicians to support the early evaluation of signs indicative of progression to SPMS. The novel and comprehensive approach to develop the draft scoring algorithm triangulates data obtained from ranking and weighting exercises, qualitative interviews, and a real-world observational study. Variables that go beyond the clinically most obvious impairment in lower limbs have been identified as relevant subtle/sensitive signs suggestive of progressive disease.

BACKGROUND Alzheimer's disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer's Disease Assessment Scale-Cognition subscale (ADAS-Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials. OBJECTIVE This study evaluated the relationship between ADAS-Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU)-measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world. METHODS A retrospective observational survey of physicians and their consulting patients with multiple ADAS-Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS-Cog rate of change, baseline ADAS-Cog, and their interaction included as exposure variables. RESULTS 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS-Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p

Implementation of guidelines can improve clinical practice. The aim in this study was to investigate whether neurologists in Germany adhered to the national Parkinson’s disease guideline. Data were obtained from a cross-sectional survey of 60 neurologists. Analyses were performed on 320 patients with idiopathic Parkinson’s disease with either low grades of functional impairment (Hoehn and Yahr stage I) or higher grades of functional impairment (stage II–V) but without motor complications. The sample was divided into four groups depending on age and grade of functional impairment. For each group, a biometric parameter on the use of dopamine agonists and L-dopa was defined based on the guideline. In patients aged

Background Multiple sclerosis (MS) is a chronic progressive neurological disease and the majority of patients will experience some degree of impaired mobility. We evaluated the prevalence, severity and burden of walking and mobility problems (WMPs) in 5 European countries. Methods This was a cross-sectional, patient record-based study involving 340 neurologists who completed detailed patient record forms (PRF) for patients (>18 years) attending their clinic with MS. Patients were also invited to complete a questionnaire (PSC). Information collected included demographics, disease characteristics, work productivity, quality of life (QoL; EuroQol-5D and Hamburg Quality of Life Questionnaire Multiple Sclerosis [HAQUAMS]) and mobility (subjective patient-reported and objectively measured using the timed 25 foot walk test [T25FW]). Relationships between WMPs and disease and other characteristics were examined using Chi square tests. Analysis of variance was used to examine relationships between mobility measures and work productivity. Results Records were available for 3572 patients of whom 2171 also completed a PSC. WMPs were regarded as the most bothersome symptom by almost half of patients who responded (43%; 291/683). There was a clear, independent and strong directional relationship between severity of WMPs (subjective and objective) and healthcare resource utilisation. Patients with longer T25FW times (indicating greater walking impairment) were significantly more likely to require additional caregiver support (p < 0.0001), visit a variety of healthcare professionals including their primary care physicians (p = 0.0044) and require more long-term non-disease modifying drugs (p = 0.0001). A similar pattern was observed when subjective reporting of the severity of WMPs was considered. Work productivity was also markedly impacted by the presence of WMPs with fewer patients working full time and a reduction in weekly working hours as T25FW times and the subjective severity of WMPs increased. Conclusions In Europe, WMPs in MS represent a considerable personal and social burden both financially and in terms of quality of life. Interventions to improve mobility could have significant benefits for patients and society as a whole.

Background Multiple sclerosis (MS) is a chronic progressive condition affecting the central nervous system. Progression of MS results in increased level of disability and most patients will eventually experience some degree of functional impairment and impaired mobility. Costs and burdens escalate as MS disability increases. However, there is a lack of recent data on the impact of MS disability on the cost and burden among patients in the US. Methods Data for this study were drawn from a real world, cross-sectional survey undertaken between 2013 and 2014. Neurologists completed detailed patient report forms (PRF) for the most recent consulting patients with MS (age >18 years). Patient’s perceptions of their diagnosis and health-related quality of life (HRQoL) were collected through a patient self-completion questionnaire (PSC). Regression analysis was used to evaluate the relationship between disability (determined by latest Expanded Disability Status Scale [EDSS] score) and current relapse and health care resource utilization, health care costs, HRQoL and work productivity. Results PRF data were collected for 715 patients (335 also completed a PSC). Patients with higher disability scores (EDSS 3–5 and >5 vs 5 groups, respectively; $51,692 and $58,648 for non-relapse and relapse groups, respectively. Conclusions For MS patients in the US, health resource utilization and healthcare care costs increase with progression of disability. As the disability worsens, patients also exhibit diminished HRQoL and lower work productivity. There is a need for treatments that slow down or delay disability progression among MS patients.