Determinants of health-related quality of life of patients with focal epilepsy: A systematic literature review.

Objective: Focal epilepsy can have significant negative impacts on a person's health-related quality of life (HRQoL). Although studies have been published on HRQoL in persons with focal epilepsy (PWFE), determinants of HRQoL have not been comprehensively examined. This systematic literature review (SLR) queried existing literature to identify aspects associated with HRQoL in PWFE without focus on resective epilepsy surgery, with an interest in identifying modifiable determinants for medical/nonmedical interventions.

The impact of anti-inflammatory therapy on Parkinson's disease incidence: A retrospective cohort study.

Background: Previous research suggests shared pathophysiology between Parkinson's Disease (PD) and autoimmune disorders, with inflammation reduction as a potential PD intervention. The impact of anti-tumor necrosis factor (anti-TNF) and anti-interleukin (IL)-17 drugs on PD development has yielded conflicting results.

Objectives: The study investigated the association between PD incidence and immunosuppressive anti-inflammatory drugs in patients with autoimmune diseases (rheumatoid arthritis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, psoriasis/psoriatic arthritis).

Development of a General Composite Scale (GENCOMS) for Progressive Neurodegenerative Diseases and Implications for the Assessment of Disease-Modifying Therapies.

Introduction: The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression.

Psychometric Validation of the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) in Patients With Spinocerebellar Ataxia.

This study aimed to generate evidence to support psychometric validity of the modified functional Scale for the Assessment and Rating of Ataxia (f-SARA) among patients with spinocerebellar ataxia (SCA). Psychometric measurement properties and minimal change thresholds of the f-SARA were evaluated using data from a cohort of SCA subjects (recruited at Massachusetts General Hospital [MGH]; n = 33) and data from a phase 3 trial of troriluzole in adults with SCA (NCT03701399 [Study 206]; n = 217), including a subset of patients with the SCA3 genotype (n = 89). f-SARA item ceiling effects were absent within the MGH cohort, while floor effects were present.

Content Validity of the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Instrument in Spinocerebellar Ataxia.

The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA.

Development and Validation of SCACOMS, a Composite Scale for Assessing Disease Progression and Treatment Effects in Spinocerebellar Ataxia.

Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763).

Psychometric properties of the Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment (ADCS-MCI-ADL) scale: a post hoc analysis of the ADCS ADC-008 trial.

Background: The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale for use in Mild Cognitive Impairment (MCI), the ADCS-ADL-MCI, is an evaluation scale with information provided by an informant/caregiver to describe the functional impairment of patients with MCI. As the ADCS-ADL-MCI has yet to undergo a full psychometric evaluation, this study aimed to evaluate the measurement properties of the ADCS-ADL-MCI in subjects with amnestic MCI.

Methods: Measurement properties, including item-level analysis, internal consistency reliability, test-retest reliability, construct validity (convergent/discriminant, known-groups validity), and responsiveness were evaluated using data from the ADCS ADC-008 trial, a 36-month, multicenter, placebo-controlled study in 769 subjects with amnestic MCI (defined by clinical criteria and a global clinical dementia rating, CDR, score of 0.

Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimer's Disease.

Introduction: Insight into the relationship between concepts that matter to the people affected by Alzheimer's disease (AD) and the clinical outcome assessments (COAs) commonly used in AD clinical studies is limited. Phases 1 and 2 of the What Matters Most (WMM) study series identified and quantitatively confirmed 42 treatment-related outcomes that are important to people affected by AD.

Methods: We compared WMM concepts rated as "very important" or higher to items included in COAs used commonly in AD studies.

Assessing What Matters to People Affected by Alzheimer's Disease: A Quantitative Analysis.

Introduction: In this phase of the ongoing What Matters Most study series, designed to evaluate concepts that are meaningful to people affected by Alzheimer's disease (AD), we quantified the importance of symptoms, impacts, and outcomes of AD to people at risk for or with AD and care partners of people with AD.

Methods: We administered a web-based survey to individuals at risk for or with AD (Group 1: unimpaired cognition with evidence of AD pathology; Group 2: AD risk factors and subjective cognitive complaints/mild cognitive impairment; Group 3: mild AD) and to care partners of individuals with moderate AD (Group 4) or severe AD (Group 5). Respondents rated the importance of 42 symptoms, impacts, and outcomes on a scale ranging from 1 ("not at all important") to 5 ("extremely important").

Ataxia Rating Scales Reflect Patient Experience: an Examination of the Relationship Between Clinician Assessments of Cerebellar Ataxia and Patient-Reported Outcomes.

Ataxia rating scales are observer administered clinical outcome assessments (COAs) of the cerebellar motor syndrome. It is not known whether these COAs mirror patient experience of their disease. Here we test the hypothesis that ataxia COAs are related to and reflect patient reported symptoms and impact of illness.

Health economic modeling for Alzheimer's disease: Expert perspectives.

The successful development of an economic model for the evaluation of future Alzheimer's disease (AD) interventions is critical to accurately inform policy makers and payers. As our understanding of AD expands, this becomes an increasingly complex and challenging goal. Advances in diagnostic techniques for AD and the prospect of disease-modifying treatments raise an urgent need to define specifications for future economic models and to ensure that the necessary data to populate them are available.

Identification of cognitively impaired patients at risk for development of Alzheimer's disease dementia: an analysis of US Medicare claims data.

Background: Identifying factors associated with transitioning from mild cognitive impairment (MCI) to dementia due to Alzheimer's disease (AD dementia) or dementia due to any cause (all-cause dementia) may inform economic assessments of disease and early care planning.

Research Design And Methods: A multivariate logistic regression approach identified potential predictors of progression to AD dementia or all-cause dementia in individuals with MCI or cognitive impairment (CI). Eligible patients and variables of interest were identified using claims data from the Medicare Advantage Patient Database, by Optum.

Economic and caregiver impact of Alzheimer's disease across the disease spectrum: a cohort study.

Background: Alzheimer's disease (AD) substantially increases health-related costs. This study investigates direct medical costs and characterizes the caregiver burden across AD stages.

Methods: This study analyzed data from the French Primary Health Insurance Fund claims database and reflected this public payer perspective.

Estimating Progression Rates Across the Spectrum of Alzheimer's Disease for Amyloid-Positive Individuals Using National Alzheimer's Coordinating Center Data.

Introduction: Published estimates of Alzheimer's disease (AD) progression do not capture the full disease continuum. This study provides transition probabilities of individuals with amyloid-β (Aβ+) pathology across the disease continuum.

Methods: Patient-level longitudinal data from the National Alzheimer's Coordinating Center were used to estimate progression rates.

Health-related quality of life in people with predementia Alzheimer's disease, mild cognitive impairment or dementia measured with preference-based instruments: a systematic literature review.

Background: Obtaining reliable estimates of the health-related quality of life (HR-QoL) of people with predementia Alzheimer's disease [AD] (preclinical or prodromal AD), mild cognitive impairment (MCI) and dementia is essential for economic evaluations of related health interventions.

Aims: To provide an overview of which quality of life instruments are being used to assess HR-QoL in people with predementia AD, MCI or dementia; and, to summarise their reported HR-QoL levels at each stage of the disease and by type of respondent.

Methods: We systematically searched for and reviewed eligible studies published between January 1990 and the end of April 2017 which reported HR-QoL for people with predementia AD, MCI or dementia.

The incidence of mild cognitive impairment: A systematic review and data synthesis.

Introduction: Incidence estimates of mild cognitive impairment (MCI) range widely. We obtained contemporary age-specific MCI incidence rates and examined sources of heterogeneity.

Methods: We conducted a systematic review of population-based studies from the Americas, Europe, and Australia using restrictive inclusion criteria to limit heterogeneity.

What outcomes are important to patients with mild cognitive impairment or Alzheimer's disease, their caregivers, and health-care professionals? A systematic review.

Introduction: Clinical trials involving patients with Alzheimer's disease (AD) continue to try to identify disease-modifying treatments. Although trials are designed to meet regulatory and registration requirements, many do not measure outcomes of the disease most relevant to key stakeholders.

Methods: A systematic review sought research that elicited information from people with AD, their caregivers, and health-care professionals on which outcomes of the disease were important.

Challenges for Optimizing Real-World Evidence in Alzheimer's Disease: The ROADMAP Project.

ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer's disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit.

Measuring quality of life of people with predementia and dementia and their caregivers: a systematic review protocol.

Introduction: Dementia is the fastest growing major cause of disability globally and may have a profound impact on the health-related quality of life (HRQoL) of both the patient with dementia and those who care for them. This review aims to systematically identify and synthesise the measurements of HRQoL for people with, and their caregivers across the full spectrum of, dementia from its preceding stage of predementia to end of life.

Methods And Analysis: A systematic literature review was conducted in Medical Literature Analysis and Retrieval System Online , ExcerptaMedicadataBASE, Cochrane Database of Systematic Reviews , Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, National Health Service Economic Evaluation Database and PsycINFO between January 1990 and the end of April 2017.

Resource utilisation and costs in predementia and dementia: a systematic review protocol.

Introduction: Dementia is the fastest growing major cause of disability globally with a mounting social and financial impact for patients and their families but also to health and social care systems. This review aims to systematically synthesise evidence on the utilisation of resources and costs incurred by patients and their caregivers and by health and social care services across the full spectrum of dementia, from its preceding preclinical stage to end of life. The main drivers of resources used and costs will also be identified.

Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.

One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR.

Examination of hospital length of stay in Canada among patients with acute bacterial skin and skin structure infection caused by methicillin-resistant Staphylococcus aureus.

Purpose: Skin infections, particularly those caused by resistant pathogens, represent a clinical burden. Hospitalization associated with acute bacterial skin and skin structure infections (ABSSSI) caused by methicillin-resistant Staphylococcus aureus (MRSA) is a major contributor to the economic burden of the disease. This study was conducted to provide current, real-world data on hospitalization patterns for patients with ABSSSI caused by MRSA across multiple geographic regions in Canada.

Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.