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Purpose: Furoscix® (subcutaneous furosemide) is administered using a wearable On-Body Infusor (OBI) and is approved for the treatment of congestion associated with heart failure (HF). The purpose of this study was to assess the safe and effective use of the OBI and Instructions for Use (IFU) by patients with HF, caregivers, and healthcare practitioners (HCPs). Methods: Sixty participants (patients, n=30; caregivers, n=15; HCPs, n=15) were evaluated on completion of OBI use tasks and IFU knowledge tasks in a simulated use environment. Fifteen of the patients received OBI/IFU training before evaluation. Results: Overall, 893/900 (99.2%) use tasks and 2211/2220 (99.6%) knowledge tasks were completed successfully, without differences due to training. The most common (n=6) use error was failure to wipe skin or cartridge tip with an alcohol wipe. Errors were due to forgetfulness/misinterpretation rather than IFU clarity. Conclusion: The subcutaneous furosemide OBI can be safely and effectively used by patients, caregivers, and HCPs, regardless of training.
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Our qualitative analysis of interviews with remote Australian healthcare professionals found that they require reliable, local antimicrobial resistance (AMR) data reflecting the geographical diversity of the population they serve. The optimal use of AMR data must consider challenges within this setting, including high staff turnover, limited diagnostic capacity, and antibiotic shortages.
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Cerebral small vessel disease (SVD) is a major cause of cognitive impairment in older people. As secondary endpoints in a phase-2 randomised clinical trial, we tested the effects of single administration of a widely-used PDE5 inhibitor, tadalafil, on cognitive performance in older people with SVD. In a double-blinded, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥ 7 days apart (randomised to order of treatment). The Montreal Cognitive Assessment (MOCA) was administered at baseline, alongside a measure to estimate optimal intellectual ability (Test of Premorbid Function). Then, before and after treatment, a battery of neuropsychological tests was administered, assessing aspects of attention, information processing speed, working memory and executive function. Sixty-five participants were recruited and 55 completed the protocol (N = 55, age: 66.8 (8.6) years, range 52-87; 15/40 female/male). Median MOCA score was 26 (IQR: 23, 27], range 15-30). No significant treatment effects were seen in any of the neuropsychological tests. There was a trend towards improved performance on Digit Span Forward (treatment effect 0.37, C.I. 0.01, 0.72; P = 0.0521). We did not identify significant treatment effects of single-administration tadalafil on neuropsychological performance in older people with SVD. The trend observed on Digit Span Forward may help to inform future studies. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00123456, https://eudract.ema.europa.eu. Unique identifier: 2015-001,235-20NCT00123456.
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INTRODUCTION: This study aimed to identify opportunities for clinical decision support targeting medication safety in remote primary care, by investigating the relationship between clinical workflows, health system priorities, cognitive tasks, and reasoning processes in the context of medicines used in people with chronic kidney disease (CKD). METHODS: This qualitative study involved one-on-one, semistructured interviews. The participants were healthcare professionals employed in a clinical or managerial capacity with clinical work experience in a remote health setting for at least 1 year. RESULTS: Twenty-five clinicians were interviewed. Of these, four were rural medical practitioners, nine were remote area nurses, eight were Aboriginal health practitioners, and four were pharmacists. Four major themes were identified from the interviews: (1) the need for a clinical decision support system to support a sustainable remote health workforce, as clinicians were "constantly stretched" and problems may "fall through the cracks"; (2) reliance on digital health technologies, as medical staff are often not physically available and clinicians-on-duty usually "flick an email and give a call so that I can actually talk it through to our GP"; (3) knowledge gaps, as "it takes a lot of mental space" to know each patient's renal function and their medication history, and clinicians believe "mistakes can be made"; and (4) multiple risk factors impacting CKD management, including clinical, social and behavioural determinants. CONCLUSIONS: The high prevalence of CKD and reliance on digital health systems in remote primary health settings can make a clinical decision support system valuable for supporting clinicians who may not have extensive experience in managing medicines for people with CKD.
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In 2016, the U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and state partners investigated nine Listeria monocytogenes infections linked to frozen vegetables. The investigation began with two environmental L. monocytogenes isolates recovered from Manufacturer A, primarily a processor of frozen onions, that were a match by whole genome sequencing (WGS) to eight clinical isolates and historical onion isolates with limited collection details. Epidemiologic information, product distribution, and laboratory evidence linked suspect food items, including products sourced from Manufacturer B, also a manufacturer of frozen vegetable/fruit products, with an additional illness. The environmental isolates were obtained during investigations at Manufacturers A and B. State and federal partners interviewed ill people, analyzed shopper card data, and collected household and retail samples. Nine ill persons between 2013 and 2016 were reported in four states. Of four ill people with information available, frozen vegetable consumption was reported by three, with shopper cards confirming purchases of Manufacturer B brands. Two identified outbreak strains of L. monocytogenes (Outbreak Strain 1 and Outbreak Strain 2) were a match to environmental isolates from Manufacturer A and/or isolates from frozen vegetables recovered from open and unopened product samples sourced from Manufacturer B; the investigation resulted in extensive voluntary recalls. The close genetic relationship between isolates helped investigators determine the source of the outbreak and take steps to protect public health. This is the first known multistate outbreak of listeriosis in the United States linked to frozen vegetables and highlights the significance of sampling and WGS analyses when there is limited epidemiologic information. Additionally, this investigation emphasizes the need for further research regarding food safety risks associated with frozen foods.
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Doenças Transmitidas por Alimentos , Listeria monocytogenes , Listeriose , Humanos , Estados Unidos , Verduras , Doenças Transmitidas por Alimentos/epidemiologia , Microbiologia de Alimentos , Listeriose/epidemiologia , Surtos de Doenças , CebolasRESUMO
BACKGROUND: Aboriginal Australians are reported to have a high burden of chronic airway diseases. However, prescribing patterns and related outcomes of airway directed inhaled pharmacotherapy, (short-acting beta agonists (SABA), short-acting muscarinic antagonists (SAMA), long-acting ß-agonists (LABA), long-acting muscarinic antagonists (LAMA) and inhaled corticosteroids (ICS)) among Aboriginal Australian patients with chronic airway disease have been sparsely reported in the past. METHODS: A retrospective cohort study was conducted, using clinical, spirometry data, chest radiology, primary healthcare (PHC) presentations and hospital admission rates among Aboriginal patients identified to have been prescribed inhaled pharmacotherapy in remote and rural communities referred to the respiratory specialist service in the Top End, Northern Territory of Australia. RESULTS: Of the 372 identified active patients, 346 (93%) had inhaled pharmacotherapy prescribed (64% female, median age 57.7 years). ICS was the most common prescription (72% of the total cohort) and was recorded to be prescribed in 76% of patients with bronchiectasis, and 80% of patients with asthma or chronic obstructive pulmonary disease (COPD). Fifty-eight percent of patients had a respiratory hospital admission and 57% had a recorded PHC presentation for a respiratory issue during the study period, with a higher rate of hospital admissions among patients prescribed ICS compared with those on SAMA/SABA or LAMA/LABA without ICS (median rate (per person per year) 0.42 vs 0.21 and 0.21 (p=0.004). Regression models demonstrated that presence of COPD or bronchiectasis alongside ICS was associated with significantly increased hospitalisation rates (1.01 admissions/person/year (95% CI 0.15 to 1.87) and 0.71 admissions/person/year (95% CI 0.23 to 1.18) against patients without COPD/bronchiectasis, respectively). CONCLUSIONS: This study demonstrates that among Aboriginal patients with chronic airway diseases, ICS is the most common inhaled pharmacotherapy prescribed. Although LAMA/LABA and concurrent ICS use may be appropriate among patients with asthma and COPD, the use of ICS may have detrimental effects among those with underlying bronchiectasis either in isolation or concurrent COPD and bronchiectasis, potentially leading to higher hospital admission rates.
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Asma , Bronquiectasia , Doença Pulmonar Obstrutiva Crônica , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Northern Territory/epidemiologia , Povos Aborígenes Australianos e Ilhéus do Estreito de Torres , Antagonistas Muscarínicos/uso terapêutico , Estudos Retrospectivos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
BACKGROUND: In children, chronic wet cough may be a sign of underlying lung disease, including protracted bacterial bronchitis (PBB) and bronchiectasis. Chronic (> 4 weeks in duration) wet cough (without indicators pointing to alternative causes) that responds to antibiotic treatment is diagnostic of PBB. Timely recognition and management of PBB can prevent disease progression to irreversible bronchiectasis with lifelong consequences. However, detection and management require timely health-seeking by carers and effective management by clinicians. We aim to improve (a) carer health-seeking for chronic wet cough in their child and (b) management of chronic wet cough in children by clinicians. We hypothesise that implementing a culturally integrated program, which is informed by barriers and facilitators identified by carers and health practitioners, will result in improved lung health of First Nations children, and in the future, a reduced the burden of bronchiectasis through the prevention of the progression of protracted bacterial bronchitis to bronchiectasis. METHODS: This study is a multi-centre, pseudorandomised, stepped wedge design. The intervention is the implementation of a program. The program has two components: a knowledge dissemination component and an implementation component. The implementation is adapted to each study site using a combined Aboriginal Participatory Action Research and an Implementation Science approach, guided by the Consolidated Framework of Implementation Research. There are three categories of outcome measures related to (i) health (ii) cost, and (iii) implementation. We will measure health-seeking as the proportion of parents seeking help for their child in a 6-month period before the intervention and the same 6-month period (i.e., the same six calendar months) thereafter. The parent-proxy, Cough-specific Quality of Life (PC-QoL) will be the primary health-related outcome measure. DISCUSSION: We hypothesise that a tailored intervention at each site will result in improved health-seeking for carers of children with a chronic wet cough and improved clinician management of chronic wet cough. In addition, we expect this will result in improved lung health outcomes for children with a chronic wet cough. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; ACTRN12622000430730 , registered 16 March 2022, Retrospectively registered.
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Infecções Bacterianas , Bronquiectasia , Bronquite Crônica , Bronquite , Criança , Humanos , Tosse/diagnóstico , Qualidade de Vida , Bronquite/diagnóstico , Ciência da Implementação , Austrália , Doença Crônica , Infecções Bacterianas/diagnóstico , Bronquiectasia/complicações , Bronquite Crônica/complicações , Avaliação de Resultados em Cuidados de Saúde , Estudos Multicêntricos como AssuntoRESUMO
INTRODUCTION: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. METHODS: In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling. RESULTS: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed. DISCUSSION: This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.
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Disfunção Cognitiva , Humanos , Idoso , Tadalafila/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Método Duplo-CegoRESUMO
Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter.Here we quantified test-retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days).Test-retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM).We conclude that pCASL has high test-retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint.All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015).
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Leucoaraiose , Substância Branca , Idoso , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular/fisiologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Reprodutibilidade dos Testes , Marcadores de Spin , Substância Branca/diagnóstico por imagemRESUMO
INTRODUCTION: Delivering health services and improving health outcomes of the 1.3 million people residing in northern Australia, a region spanning 3 million km2 across the three jurisdictions of Western Australia, Northern Territory and Queensland, presents specific challenges. This review addresses a need for systems level analysis of the issues influencing the coverage, quality and responsiveness of health services across this region by examining the available published literature and identifying key policy-relevant gaps. METHODS: A scoping review design was adopted with searches incorporating both peer-reviewed and grey literature (eg strategy documents, annual reports and budgets). Grey literature was predominantly sourced from websites of key organisations in the three northern jurisdictions, with peer-reviewed literature sourced from electronic database searches and reference lists. Key articles and documents were also contributed by health sector experts. Findings were synthesised and reported narratively using the WHO health system 'building blocks' to categorise the data. RESULTS: From the total of 324 documents and data sources included in the review following screening and eligibility assessment, 197 were peer-reviewed journal articles and 127 were grey literature. Numerous health sector actors across the north - comprising planning bodies, universities and training organisations, peak bodies and providers - deliver primary, secondary and tertiary healthcare and workforce education and training in highly diverse contexts of care. Despite many exemplar health service and workforce models in the north, this synthesis describes a highly fragmented sector with many and disjointed stakeholders and funding sources. While the many strengths of the northern health system include expertise in training and supporting a fit-for-purpose health workforce, health systems in the north are struggling to meet the health needs of highly distributed populations with poorly targeted resources and ill-suited funding models. Ageing of the population and rising rates of chronic disease and mental health issues, underpinned by complex social, cultural and environmental determinants of health, continue to compound these challenges. CONCLUSION: Policy goals about developing northern Australia economically need to build from a foundation of a healthy and productive population. Improving health outcomes in the north requires political commitment, local leadership and targeted investment to improve health service delivery, workforce stability and evidence-based strengthening of community-led comprehensive primary health care. This requires intersectoral collaboration across many organisations and the three jurisdictions, drawing from previous collaborative experiences. Further evaluative research, linking structure to process and outcomes, and responding to changes in the healthcare landscape such as the rapid emergence of digital technologies, is needed across a range of policy areas to support these efforts.
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Serviços de Saúde Rural , Atenção à Saúde , Mão de Obra em Saúde , Humanos , Northern Territory , Recursos HumanosRESUMO
OBJECTIVE: This review will systematically examine the qualitative literature reporting on strategies that have been used (or could be developed) by health care services to integrate pharmacists into a multidisciplinary health care team. INTRODUCTION: Delivery models of pharmaceutical care have been developed, trialed and refined since this concept was first defined more than 30 years ago. Delivery models that integrate pharmacists within a multidisciplinary team allow pharmacists to play a pivotal role in improving health outcomes for patients and contributing to patient self-management. Systematic reviews clearly demonstrate the effectiveness of these models; however, the attitudes, beliefs, expectations, understandings, perceptions and experiences of these multidisciplinary teams is less clear. INCLUSION CRITERIA: The populations of interest in this review are health care providers, including hospital specialists, general practitioners, nurses, health workers, pharmacists, allied health workers, aged care workers, Indigenous health workers and health promotion workers. The phenomena of interest are attitudes, beliefs, expectations, understandings, perceptions and experiences of the populations of interest arising from experiencing, developing or implementing strategies that have or could support the integration of pharmacists into multidisciplinary health care teams. METHODS: The databases to be searched include PubMed, Cochrane, EBSCO (CINAHL), Embase, MedNar, Trove and Australian Indigenous Health Infonet. Studies published from 2011 onwards and in English will be considered for inclusion. Selected studies will be assessed for methodological quality by two independent reviewers, using standardized critical appraisal instruments. Where possible, qualitative research findings will be pooled. Where textual pooling is not possible, the findings will be presented in narrative form.
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Pessoal de Saúde , Farmacêuticos , Idoso , Austrália , Humanos , Equipe de Assistência ao Paciente , Pesquisa Qualitativa , Literatura de Revisão como AssuntoRESUMO
BACKGROUND: The high burden of infectious disease and associated antimicrobial use likely contribute to the emergence of antimicrobial resistance in remote Australian Aboriginal communities. We aimed to develop and apply context-specific tools to audit antimicrobial use in the remote primary healthcare setting. METHODS: We adapted the General Practice version of the National Antimicrobial Prescribing Survey (GP NAPS) tool to audit antimicrobial use over 2-3 weeks in 15 remote primary healthcare clinics across the Kimberley region of Western Australia (03/2018-06/2018), Top End of the Northern Territory (08/2017-09/2017) and far north Queensland (05/2018-06/2018). At each clinic we reviewed consecutive clinic presentations until 30 presentations where antimicrobials had been used were included in the audit. Data recorded included the antimicrobials used, indications and treating health professional. We assessed the appropriateness of antimicrobial use and functionality of the tool. RESULTS: We audited the use of 668 antimicrobials. Skin and soft tissue infections were the dominant treatment indications (WA: 35%; NT: 29%; QLD: 40%). Compared with other settings in Australia, narrow spectrum antimicrobials like benzathine benzylpenicillin were commonly given and the appropriateness of use was high (WA: 91%; NT: 82%; QLD: 65%). While the audit was informative, non-integration with practice software made the process manually intensive. CONCLUSIONS: Patterns of antimicrobial use in remote primary care are different from other settings in Australia. The adapted GP NAPS tool functioned well in this pilot study and has the potential for integration into clinical care. Regular stewardship audits would be facilitated by improved data extraction systems.
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[This corrects the article DOI: 10.1371/journal.pone.0231798.].
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OBJECTIVE: To describe antibiotic prescription rates for Australian Aboriginal children aged <2 years living in three remote Northern Territory communities. DESIGN: A retrospective cohort study using electronic health records. SETTING: Three primary health care centres located in the Katherine East region. PARTICIPANTS: Consent was obtained from 149 mothers to extract data from 196 child records. There were 124 children born between January 2010 and July 2014 who resided in one of the three chosen communities and had electronic health records for their first two years of life. MAIN OUTCOME MEASURES: Antibiotic prescription rates, factors associated with antibiotic prescription and factors associated with appropriate antibiotic prescription. RESULTS: There were 5,675 Primary Health Care (PHC) encounters for 124 children (median 41, IQR 25.5, 64). Of the 5,675 PHC encounters, 1,542 (27%) recorded at least one infection (total 1,777) and 1,330 (23%) had at least one antibiotic prescription recorded (total 1,468). Children had a median five (IQR 2, 9) prescriptions in both their first and second year of life, with a prescription rate of 5.99/person year (95% CI 5.35, 6.63). Acute otitis media was the most common infection (683 records, 38%) and Amoxycillin was the most commonly prescribed antibiotic (797 prescriptions, 54%). Of the 1,468 recorded prescriptions, 398 (27%) had no infection recorded and 116 (8%) with an infection recorded were not aligned with local treatment guidelines. CONCLUSION: Prescription rates for Australian Aboriginal children in these communities are significantly higher than that reported nationally for non-Aboriginal Australians. Prescriptions predominantly aligned with treatment guidelines in this setting where there is a high burden of infectious disease.
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Antibacterianos/uso terapêutico , Austrália , Peso ao Nascer , Criança , Feminino , Humanos , Incidência , Recém-Nascido , Infecções/tratamento farmacológico , Havaiano Nativo ou Outro Ilhéu do Pacífico , Northern Territory , Razão de Chances , Gravidez , Prescrições , Atenção Primária à SaúdeRESUMO
BACKGROUND: Treatment with anticoagulants, including direct oral anticoagulants (DOACs), should be considered for patients diagnosed with atrial fibrillation (AF) deemed at risk of ischaemic stroke. There are limited real world data related to the characteristics of patients with non-valvular AF who were not taking anticoagulants at the time of first ischaemic stroke and their subsequent DOAC treatment for the secondary prevention of stroke. Furthermore, little is known about patient adherence and experiences of DOAC treatment, especially for patients with non-valvular AF receiving DOAC therapy for the secondary prevention of stroke. METHODS: This is a UK mixed methodology, non-interventional study, involving retrospective and prospective medical record reviews and a prospective patient survey, in progress in six UK National Health Service secondary/tertiary care centres. The study comprises two groups of patients. Group 1 will include 300 eligible consenting patients with a first ischaemic stroke associated with non-valvular AF untreated with anticoagulants in the 12 months prior to stroke. Group 2 will include a subgroup of 150 patients from Group 1 initiated on one of the DOACs targeting activated Factor X (n = 50 on apixaban, n = 50 on edoxaban and n = 50 on rivaroxaban). The primary endpoint of the study is the CHA2DS2-VASc Risk Score prior to initiation of anticoagulation for patients included in Group 1. Secondary endpoints to be evaluated in Group 1 include patient demographics, clinical characteristics, relevant medical history, anticoagulant therapy initiated for secondary prevention of stroke, and relevant concomitant medication. Secondary endpoints to be evaluated in Group 2 include the time between stroke and DOAC initiation; prescribing of DOACs, other anticoagulants and concomitant medication; clinical assessments and hospital resource use; patient reported outcome measures, including the Morisky Medication Adherence Scale questionnaire and the Treatment Satisfaction Questionnaire for Medication. DISCUSSION: This mixed methodology study will provide new real world insights into the characteristics and management pathways and patient-reported experiences of this important group of patients. It is anticipated that the results of this study will provide the medical community and patients with important information to inform clinical decision-making and help facilitate meaningful improvements in the care of patients with non-valvular AF.
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Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Isquemia Encefálica/etiologia , Acidente Vascular Cerebral/etiologia , Administração Oral , Humanos , Estudos Prospectivos , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Rivaroxabana/administração & dosagem , Tiazóis/administração & dosagem , Reino UnidoRESUMO
St George's Hospital hyperacute neurology service (HANS) is a comprehensive, consultant-delivered service set in a teaching hospital regional neuroscience centre. The service addresses deficiencies in acute neurological care previously highlighted by the Royal College of Physicians and the Association of British Neurologists. HANS adopts a disease-agnostic approach to acute neurology, prioritising the emergency department (ED) management of both stroke and stroke mimics alike alongside proactive daily support to the acute medical unit and acute medical take. Rapid access clinics provide a means to assess ambulatory patients, providing an outlet to reduce the burden of referral from primary care to acute medicine. This paper reports the results from the first year of the service. Admission was avoided in 25% of the cases reviewed in the ED. Compared to historic data, there was a significant improvement in the length of stay for non-stroke disorders while the occupancy of stroke beds by non-stroke cases reduced by 50%. The configuration of this service is replicable in other neuroscience centres and provides a framework to reduce the barriers facing patients who present with acute neurological symptoms.
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Centros Médicos Acadêmicos/organização & administração , Neurologia/organização & administração , Neurociências/organização & administração , Ambulatório Hospitalar/organização & administração , Adulto , Idoso , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/terapia , Neurologistas/organização & administração , Ambulatório Hospitalar/estatística & dados numéricos , Admissão do Paciente/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Reino UnidoRESUMO
Mutations in the gene encoding DJ-1 are associated with autosomal recessive forms of Parkinson's disease (PD). DJ-1 plays a role in protection from oxidative stress, but how it functions as an "upstream" oxidative stress sensor and whether this relates to PD is still unclear. Intriguingly, DJ-1 may act as an RNA binding protein associating with specific mRNA transcripts in the human brain. Moreover, we previously reported that the yeast DJ-1 homolog Hsp31 localizes to stress granules (SGs) after glucose starvation, suggesting a role for DJ-1 in RNA dynamics. Here, we report that DJ-1 interacts with several SG components in mammalian cells and localizes to SGs, as well as P-bodies, upon induction of either osmotic or oxidative stress. By purifying the mRNA associated with DJ-1 in mammalian cells, we detected several transcripts and found that subpopulations of these localize to SGs after stress, suggesting that DJ-1 may target specific mRNAs to mRNP granules. Notably, we find that DJ-1 associates with SGs arising from N-methyl-D-aspartate (NMDA) excitotoxicity in primary neurons and parkinsonism-inducing toxins in dopaminergic cell cultures. Thus, our results indicate that DJ-1 is associated with cytoplasmic RNA granules arising during stress and neurodegeneration, providing a possible link between DJ-1 and RNA dynamics which may be relevant for PD pathogenesis.
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Grânulos Citoplasmáticos/metabolismo , Degeneração Neural/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteína Desglicase DJ-1/metabolismo , Ribonucleoproteínas/metabolismo , Estresse Fisiológico , Animais , Grânulos Citoplasmáticos/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , N-Metilaspartato/toxicidade , Degeneração Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pressão Osmótica , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Ratos , Estresse Fisiológico/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: Cerebral small-vessel disease is a major cause of cognitive impairment. Perivascular spaces (PvS) occur in small-vessel disease, but their relationship to cognitive impairment remains uncertain. One reason may be difficulty in distinguishing between lacunes and PvS. We determined the relationship between baseline PvS score and PvS volume with change in cognition over a 5-year follow-up. We compared this to the relationship between baseline lacune count and total lacune volume with cognition. In addition, we examined change in PvS volume over time. METHODS: Data from the prospective SCANS study (St Georges Cognition and Neuroimaging in Stroke) of patients with symptomatic lacunar stroke and confluent leukoaraiosis were used (n=121). Multimodal magnetic resonance imaging was performed annually for 3 years and neuropsychological testing annually for 5 years. Lacunes were manually identified and distinguished from PvS. PvS were rated using a validated visual rating scale, and PvS volumes calculated using T1-weighted images. Linear mixed-effect models were used to determine the impact of PvS and lacunes on cognition. RESULTS: Baseline PvS scores or volumes showed no association with cognitive indices. No change was detectable in PvS volumes over the 3 years. In contrast, baseline lacunes associated with all cognitive indices and predicted cognitive decline over the 5-year follow-up. CONCLUSIONS: Although a feature of small-vessel disease, PvS are not a predictor of cognitive decline, in contrast to lacunes. This study highlights the importance of carefully differentiating between lacunes and PvS in studies investigating vascular cognitive impairment.