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. PARTICIPANTS: 155 healthcare professionals who had previously participated in courses in improvement science. RESULTS: The covariate patient involvement was significantly related to a perceived strengthened patient role. There was also a significant interaction effect between degree of patient involvement and professionals' experience in the area of improvement science on a strengthened patient role. The result shows that there is a relationship between the perceived level of patient involvement in improvements and professionals' perceptions of a strengthened patient role. In this study, the covariate, perceived patient involvement, was significantly related to experiences of more equal relationships between patients and healthcare professionals. There was also a significant interaction effect between the degree of patient involvement and professionals' experience in the area of improvement science, for a more equal relationship between patients and healthcare professionals. CONCLUSION: Increased patient involvement in QI is a means of strengthening the patient role and supporting a more equal relation between patients and healthcare professionals. Furthermore, empirical evidence shows that the healthcare professionals' experiences in the area of improvement science support a strengthened patient role and a more equal power relationship, but for this to happen, the mindset of professionals is key. Future research is needed to capture and investigate the experiences from patients and relatives about being involved in QI in healthcare, and to study the effects on quality in care processes.

Limited value of sputum culture to guide antibiotic treatment in a Danish emergency department.

INTRODUCTION: Antibiotics resistance is increasing worldwide. The Region of Southern Denmark developed an antibiotic stewardship to reduce the use of broad-spectrum antibiotics in hospitals including microbiological diagnostics of sputum samples. The aim of this study was to evaluate the implementation of the stewardship in the emergency department (ED) concerning management of pulmonary infections. The objectives were: 1) to investigate whether the empirical therapy was prescribed correctly, 2) to identify the quality and results of pre-antibiotic sputum collection and 3) to investigate whether the antibiotic treatment was revised based on the microbiological results. METHODS: This was a quality assessment study. Patient files from patients discharged with either pneumonia or acute exacerbation of chronic pulmonary disease were reviewed, and written feedback was provided to the doctors, focusing on the regional guideline. RESULTS: Among the 257 medical records audited, the guideline was followed in 89% of the cases. Pre-antibiotic sputum samples were collected from 47% of the patients and 79% of these had sufficient quality for cultivation. None of the empirical antibiotic treatments were revised based on the microbiological results but some were revised based on other clinical parameters. CONCLUSIONS: Sputum samples had no clinical value for adjustment of the antibiotic treatment. Improvements of sputum sample collection and faster microbiological diagnostics are needed for sputum analysis to have any impact on the antibiotic treatment of patients with a pulmonary infection in the ED. FUNDING: none. TRIAL REGISTRATION: not relevant.

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 SGSH 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. There is currently no available treatment against MPS IIIA. In the present study, a chemically modified recombinant human sulfamidase (CM-rhSulfamidase) with disrupted glycans showed reduced glycan receptor mediated endocytosis, indicating a non-receptor mediated uptake in MPS IIIA patient fibroblasts. Intracellular enzymatic activity and stability was not affected by chemical modification. After intravenous (i.v.) administration in mice, CM-rhSulfamidase showed a prolonged exposure in plasma and distributed to the brain, present both in vascular profiles and in brain parenchyma. Repeated weekly i.v. administration resulted in a dose- and time-dependent reduction of HS in CNS compartments in a mouse model of MPS IIIA. The reduction in HS was paralleled by improvements in lysosomal pathology and neuroinflammation. Behavioral deficits in the MPS IIIA mouse model were apparent in the domains of exploratory behavior, neuromuscular function, social- and learning abilities. CM-rhSulfamidase treatment improved activity in the open field test, endurance in the wire hanging test, sociability in the three-chamber test, whereas other test parameters trended towards improvements. The unique properties of CM-rhSulfamidase described here strongly support the normalization of clinical symptoms, and this candidate drug is therefore currently undergoing clinical studies evaluating safety and efficacy in patients with MPS IIIA.

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

Aim: 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). Materials & methods: Two LC-MS/MS methods were adapted from literature methodology, one to measure HS metabolites (HSmet), the other to measure digests of HS after heparinase treatment (HSdig). Results: The HSmet and HSdig methods showed similar relative reduction of HS in brain after CM-rhSulfamidase administration to MPS IIIA mice and the reduction was reflected also in CSF. Conclusion: The results of the two methods correlated and therefore the HSdig method can be used in clinical studies to determine HS levels in CSF from patients with MPS IIIA.

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. Thus, the purpose of this study was to identify the phase of an improvement cycle in which patient involvement had the highest impact on radicality of improvement. DESIGN: An exploratory cross-sectional survey was used. SETTING AND METHODS: A questionnaire was completed by 155 Swedish healthcare professionals (response rate 34%) who had trained and had experience in patient involvement in quality improvement. Based on their replies, the impact of patient involvement on radicality in various phases of the improvement cycle was modelled using the partial least squares method. RESULTS: Patient involvement in quality improvement might help to identify and realise innovative solutions; however, there is variation in the impact of patient involvement on perceived radicality depending on the phase in which patients become involved. The highest impact on radicality was observed in the phases of capture experiences and taking action, while a moderate impact was observed in the evaluate phase. The lowest impact was observed in the identify and prioritise phase. CONCLUSIONS: Involving patients in improvement projects can enhance the quality of care and help to identify radically new ways of delivering care. This study shows that it is possible to suggest at what point in an improvement cycle patient involvement has the highest impact, which will enable more efficient use of the resources available for patient involvement.

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. METHODS: Quantitative study of all 835 closed patient complaints during 2013 at three mid-sized hospitals in Sweden. The complaints were categorisation based on perceived quality theory and analysed using a probabilistic graphical model. The findings were validated through qualitative interviews. FINDINGS: Female patients were more likely than male patients to report dissatisfaction with interpersonal issues, whereas male patients were more likely to report dissatisfaction with administration. If a complaint from a male patient had been reported by a relative, the matter was more likely to be interpersonal. Improvement suggestions were predominantly reported by staff. However, patients and relatives proved more likely than staff to report improvement suggestions when dissatisfied with interpersonal matters. CONCLUSION: Using a Bayesian network, this article suggests that complaints in health care should be more holistically understood and the factors should be viewed as interconnected. This article addresses complaints as an important source of identifying not only perceived healthcare deficiencies and sex disparities, but also improvement suggestions.

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. METHODS: This paper is based on interviews with parents participating in two experience-based co-design projects in a Swedish hospital that included qualitative content analysis of data from 12 parent interviews in paediatric care. RESULTS: Health care professionals often overemphasize their own significance for value creation in care processes and underappreciate parents' ability to influence and contribute to better quality. However, quality is not based solely on how professionals accomplish their task, but is co-created by health care professionals and parents. Consequently, assessment of quality outcomes also must include parents' ability and context. CONCLUSIONS: This paper questions current models of quality dimensions in health care, and suggests additional sub-dimensions, such as family quality and involvement quality. RELEVANCE TO CLINICAL PRACTICE: This paper underscores the importance of involving parents in health care improvements with health care professionals to capture as many dimensions of quality as possible.

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

Aggregation of amyloid beta (Aß) peptides and the subsequent neural plaque formation is a central aspect of Alzheimer's disease. Various strategies to reduce Aß load in the brain are therefore intensely pursued. It has been hypothesized that reducing Aß peptides in the periphery, that is in organs outside the brain, would be a way to diminish Aß levels and plaque load in the brain. In this report, we put this peripheral sink hypothesis to test by investigating how selective inhibition of Aß production in the periphery using a ß-secretase (BACE)1 inhibitor or reduced BACE1 gene dosage affects Aß load in the brain. Selective inhibition of peripheral BACE1 activity in wild-type mice or mice over-expressing amyloid precursor protein (APPswe transgenic mice; Tg2576) reduced Aß levels in the periphery but not in the brain, not even after chronic treatment over several months. In contrast, a BACE1 inhibitor with improved brain disposition reduced Aß levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, displayed a 62% reduction in plasma Aß40, whereas brain Aß40 was only lowered by 11%. These data suggest that reduction of Aß in the periphery is not sufficient to reduce brain Aß levels and that BACE1 is not the rate-limiting enzyme for Aß processing in the brain. This provides evidence against the peripheral sink hypothesis and suggests that a decrease in Aß via BACE1 inhibition would need to be carried out in the brain. Aggregation of amyloid beta (Aß) peptides in the brain is a central aspect of Alzheimer's disease. In this study, we demonstrate that inhibition of Aß formation by BACE1 inhibitors needs to be carried out in the brain and that reduction of Aß in the periphery is not sufficient to reduce brain Aß levels. This information is useful for developing future Aß-targeting therapies for Alzheimer's disease.

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. Healthcare staff and patient experiences with patient processes differ, and a collaborative approach is needed to capture all areas needing improvement. RESEARCH LIMITATIONS/IMPLICATIONS: The conclusions are drawn from a project with few participants in a context that probably influenced the results. In contrast, other studies in the same area confirm the results. PRACTICAL IMPLICATIONS: The study outcomes have direct implications for healthcare professionals who can learn from patients involved in quality improvements such as this experience-based co-design (EBCD) project. ORIGINALITY/VALUE: The paper contributes to limited studies on EBCD involving patients in healthcare quality improvements.

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

Aß, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). ß-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aß peptides. Small molecule BACE1 inhibitors are expected to decrease Aß-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aß production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.

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

γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid ß (Aß) 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 Aß production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aß levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.

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

ß-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 ß peptide (Aß) species. Because cerebral deposition of Aß 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. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aß and sAPPß release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aß levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aß in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.

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. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300µmol/kg (R)-25 and efflux inhibitor GF120918 the brain Aß40 level was reduced by 17% and the plasma Aß40 level by 76%.

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. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation.