MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

Introduction: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides.

Methods: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ, the pathogenic self-aggregating species of Aβ.

Results: MEDI1814 reduces free Aβ without impacting Aβ in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration.

Introduction of a Novel Patient Safety Advisory: Evaluation of Perceived Information With a Modified QPP Questionnaire-A Case-Control Study.

Objectives: Adverse events (AEs) may result in serious injuries or death. AEs occur in approximately 9.2% of hospitalizations, with a potential preventability of 43.

Exploring power shifts as an enabler for a strengthened patient role in quality improvements: a Swedish survey study.

Objectives: This study examined the relationship between professionals' perceptions of a strengthened role for the patient and of patient involvement in quality improvement (QI) and whether professionals' experiences in improvement science were a moderator on such a relationship.

Design: From a predominantly close-ended, 44-item questionnaire, 4 questions specifically concerning professionals' perception on patient involvement in QI were analysed.

Setting: Three Swedish regions.

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) characterized by severe central nervous system (CNS) degeneration. The disease is caused by mutations in the gene coding for the lysosomal enzyme sulfamidase. Sulfamidase deficiency leads to accumulation of heparan sulfate (HS), which triggers aberrant cellular function, inflammation and eventually cell death.

Robust LC-MS/MS methods for analysis of heparan sulfate levels in CSF and brain for application in studies of MPS IIIA.

Accumulation of heparan sulfate (HS) is associated with the neurodegenerative disorder Mucopolysaccharidosis type IIIA (MPS IIIA). Here, we compare HS levels in brain and cerebrospinal fluid (CSF) of MPS IIIA mice after treatment with a chemically modified sulfamidase (CM-rhSulfamidase). Two LC-MS/MS methods were adapted from literature methodology, one to measure HS metabolites (HS), the other to measure digests of HS after heparinase treatment (HS).

Exploring the phase for highest impact on radicality: a cross-sectional study of patient involvement in quality improvement in Swedish healthcare.

Objectives: Involving patients in quality improvement is often suggested as a critical step for improving healthcare processes. However, this comes with challenges related to resources, tokenism, validity and competence. Therefore, to optimise the use of available resources, there is a need to understand at what stage in the improvement cycle patient involvement is most beneficial.

Exploring complaints by female and male patients at Swedish hospitals using a probabilistic graphical model.

Background: Patients' complaints have been highlighted as important for constructively improving healthcare services. In so doing, it may be important to identify disparities in experiences based on patients' demographics, such as sex.

Aim: To explore hospital recorded complaints addressing potential sex differences and whether complaints were reported by the patient or a relative.

Designing quality of care--contributions from parents: Parents' experiences of care processes in paediatric care and their contribution to improvements of the care process in collaboration with healthcare professionals.

Aims And Objectives: The aim of this article was to explore whether current quality dimensions for health care services are sufficient to capture how parents perceive and contribute to quality of health care.

Background: New quality improvement initiatives that actively involve patients must be examined with a critical view on established quality dimensions to ensure that these measures support patient involvement.

Design: This paper used a qualitative and descriptive design.

Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter β-amyloid levels in the CNS.

Aggregation of amyloid beta (Aβ) peptides and the subsequent neural plaque formation is a central aspect of Alzheimer's disease. Various strategies to reduce Aβ load in the brain are therefore intensely pursued. It has been hypothesized that reducing Aβ peptides in the periphery, that is in organs outside the brain, would be a way to diminish Aβ levels and plaque load in the brain.

Improvements in neonatal care; using experience-based co-design.

Purpose: The purpose of this paper is to identify and improve patient care processes by collaborating patients, relatives and healthcare professionals.

Design/methodology/approach: To identify and improve patient care processes by collaborating patients, relatives and healthcare professionals.

Findings: Healthcare problems captured from collaboration between patients and healthcare professionals fall into simple, complicated and complex problems.

AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice.

Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD.

Alzheimer's disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aβ peptide-lowering strategy.

γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro.

Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.

β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1.

Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy.

The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy.

2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation.

Myeloperoxidase (MPO) is a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO.