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Residential InReach presents an alternative to hospital admission for aged care residents swabbed for coronavirus disease 2019 (COVID-19), although relative outcomes remain unknown.To compare rates and predictors of 28-day mortality for aged care residents seen by InReach with COVID-19, or 'suspected COVID-19' (sCOVID), including hospital versus InReach-based care.Prospective observational study of consecutive patients referred to a Victorian InReach service meeting COVID-19 testing criteria between April and October 2020 (prevaccine availability). COVID-19 was determined by positive polymerase chain reaction testing on nasopharyngeal swab. sCOVID-19 was defined as meeting symptomatic Victorian Government testing criteria but persistently swab negative.There were no significant differences in age, sex, Clinical Frailty Score (CFS) or Charlson Comorbidity Index (CCI) between 152 patients with COVID-19 and 118 patients with sCOVID. Similar results were found for 28-day mortality between patients with COVID-19 (35/152, 23%) and sCOVID (32/118, 27%) (P = 0.4). For the combined cohort, 28-day mortality was associated with initial oxygen saturation (P 0.001), delirium (P 0.001), hospital transfer for acuity (P = 0.02; but not public health/facility reasons), CFS (P = 0.04), prior ischaemic heart disease (P = 0.01) and dementia (P = 0.02). For patients with COVID-19, 28-day mortality was associated with initial oxygen saturation (P = 0.02), delirium (P 0.001) and hospital transfer for acuity (P = 0.01), but not public health/facility reasons.Unvaccinated aged care residents meeting COVID-19 testing criteria seen by InReach during a pandemic experience high mortality rates, including with negative swab result. Residents remaining within-facility (with InReach) experienced similar adjusted mortality odds to residents transferred to hospital for public health/facility-based reasons, and lower than those transferred for clinical acuity.

Objectives Advance Care Planning (ACP) is a process by which people communicate their healthcare preferences and values, planning for a time when they are unable to voice them. Within Residential Aged Care Facilities (RACF) both the completion and the clarity of ACP documents is variable and, internationally, medical treatment orders have been used to address these issues. In this study, Goals of Patient Care (GOPC) medical treatment orders were introduced alongside usual ACP in three RACF to improve healthcare decision-making for residents. This study explored the experiences of RACF healthcare-providers with ACP and GOPC medical treatment orders. Methods The study was of Explanatory Descriptive design. Within three RACF where the GOPC medical treatment orders had been introduced, focus groups and interviews with healthcare-providers were performed. The transcribed interviews were analysed thematically. Results Healthcare-providers reported support for ACP and GOPC but also discussed many problematic issues. Analysis of the data identified four main themes: Enablers, Barriers, Resident autonomy and Advance documentation (ACP and GOPC). Conclusion Healthcare-providers identified ACP and GOPC as positive tools for assisting with medical decision-making for residents. Although barriers exist in completion and activation of plans, healthcare-providers described them as progressing resident-centred care. Willingness to follow ACP instructions was reported to be reduced by lack of trust by clinicians. Families were also reported to change their views from those documented in family-completed ACP, attributed to poor understanding of their purpose. Participants reported that GOPC led to clearer documentation of residents' medical treatment-plans than relying on ACP documents alone. This article is protected by copyright. All rights reserved.

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Background Older people living in residential aged care facilities are at high risk of acquiring infections such as influenza, gastroenteritis, and more recently COVID-19. These infections are a major cause of morbidity and mortality among this cohort. Quality infection prevention and control practice in residential aged care is therefore imperative. Although appointment of a dedicated infection prevention and control (IPC) lead in every Australian residential aged care facility is now mandated, all people working in this setting have a role to play in IPC. The COVID-19 pandemic revealed inadequacies in IPC in this sector and highlighted the need for interventions to improve implementation of best practice. Methods Using mixed methods, this four-phase implementation study will use theory-informed approaches to: (1) assess residential aged care facilities’ readiness for IPC practice change, (2) explore current practice using scenario-based assessments, (3) investigate barriers to best practice IPC, and (4) determine and evaluate feasible and locally tailored solutions to overcome the identified barriers. IPC leads will be upskilled and supported to operationalise the selected solutions. Staff working in residential aged care facilities, residents and their families will be recruited for participation in surveys and semi-structured interviews. Data will be analysed and triangulated at each phase, with findings informing the subsequent phases. Stakeholder groups at each facility and the IMMERSE project’s Reference Group will contribute to the interpretation of findings at each phase of the project. Discussion This multi-site study will comprehensively explore infection prevention and control practices in residential aged care. It will inform and support locally appropriate evidence-based strategies for enhancing infection prevention and control practice.

Background Clinicians in acute hospitals make important discharge decisions that require them to estimate patients’ life expectancies. This is a particularly challenging task when it comes to older palliative care patients, even for experienced clinicians. Aim To identify factors that predict palliative care patients’ survival to discharge from hospital to residential aged care and examine the accuracy of survival predictions of two prognostic tools (Palliative Prognostic Score and Palliative Prognostic Index). Methods Retrospective file audit of palliative care inpatients referred for residential aged care placement over a 2-year period in an acute hospital in Melbourne, Australia. Files were excluded when patients had died or been discharged home before being reviewed by the hospital's assessment team. Findings Overall, 44% of the 71 palliative care patients referred for residential aged care placement died before being discharged from hospital. Significant predictors of survival to discharge were nonmalignant diagnoses, higher performance status, and favourable prognoses according to the Palliative Prognostic Index. The least favourable survival category of the modified Palliative Prognostic Score predicted inpatient death with low sensitivity but high specificity. Discussion Many palliative care patients are commencing upon the taxing residential aged care placement pathway with questionable benefits to them, their families, and the healthcare system. The low rate of patients surviving to discharge may reflect gaps in the recognition of dying, amongst other system-specific challenges. Conclusion Prognostic tools can feasibly be completed with routinely collected hospital data and their use is indicated to support clinical decision-making and inform transfer decisions in acute settings. Such decisions can rely on the high specificity of the least favourable survival category of the modified Palliative Prognostic Score, which yields fewer false-negatives that would unnecessarily stretch patients’ length of stay. Equally, a favourable prognosis according to the Palliative Prognostic Index can reassure assessment teams, patients and families that a transfer is likely to be appropriate. For those patients who fall between these two categories, decisions can be supplemented by other factors shown to predict survival to discharge, including malignancy, reduced oral intake, anorexia, and a poor Karnofsky Performance Index. The need for subacute palliative care options with timely transfer processes warrants further investigation.

Objective In parts of Australia, Residential In-Reach (RIR) services have been implemented to treat residential aged care (RAC) residents for acute conditions in their place of residence to avoid preventable hospital presentation. Our service was initiated in 2009 and restructured in 2014. We compared acute healthcare resource utilization (RIR activity and emergency hospital presentations) by RAC residents under 2 RIR models of care. Design Acute RAC RIR service model of care was changed from existing nurse/emergency physician-led service to nurse/geriatrician-led service and incorporate inpatient liaison nurse consultant into the team. Setting RAC episodes and hospital presentations from a single tertiary referral hospital and its associated RAC RIR service. Methods Retrospective audit comparing RIR activity, hospital presentations, and associated costs from 2 12-month periods, prior to and postimplementation. Data were expressed as a proportion of the total number of RAC beds in the hospital RIR catchment. Results After implementation of the new model of care, RIR episodes of care increased from 589 to 985 (15.3 vs 24.7 episodes/100 RAC beds, P

Predicting older patients' life expectancy is an important yet challenging task. Hospital aged care assessment teams advise treating teams on older patients' type and place of care, directly affecting quality of care. Yet, little is known about their experiences with prognostication.Twenty semi-structured interviews were conducted with seven geriatricians/ registrars, ten nurses and three allied health staff from aged care assessment teams across two hospitals in Melbourne, Australia. Data were analysed thematically.To generate prognoses, clinicians used analytical thinking, intuition, assessments from others, and pattern matching. Prognostic tools were an underutilised resource. Barriers to recognition of dying included: diffusion of responsibility regarding whose role it is to identify patients at end-of-life; lack of feedback about whether a prognosis was correct; system pressures to pursue active treatment and vacate beds; avoidance of end-of-life discussions; lack of confidence, knowledge and training in prognostication and pandemic-related challenges.

BACKGROUND: Residential respite is an important support for many community-dwelling older Australians and their caregivers. Respite clients are often very frail with high or specific care needs. Little is known about the comparative outcomes of hospital admission between permanent residential aged care facility (RACF) residents and residential respite residents. AIM: To determine the number of residential respite clients admitted to an acute tertiary hospital, and compare characteristics and in-hospital outcomes with those of permanent residential care residents. METHODS: Retrospective study of residential respite patients admitted to an Australian tertiary hospital between November 2014 and September 2017. Comparison groups: all RACF patients admitted during same period (general RACF group), and control group matched (2:1) for aged, gender and diagnosis. MAIN OUTCOME MEASURES: in-hospital mortality, hospital length of stay (LOS), in-hospital complications (including fall, delirium, pressure injury, Medical Emergency Team (MET) call). Comparisons adjusted for age, gender, presenting symptom and matching variable. RESULTS: A total of 166 admissions from residential respite and 332 matched RACF controls identified from 4575 admissions for permanent RACF residents. Mortality was significantly higher in respite group versus general RACF group (15.1 vs 8.2%, P < 0.001) but not matched control group (15.1 vs 16.3%, P = 0.795). LOS was significantly higher in respite patients than either control group. Respite patients had significantly higher prevalence of in-hospital fall (10.8 vs 1.5%, P < 0.0001) and delirium (35.5 vs 17.7%, P < 0.001) than matched RACF controls. No significant differences were seen in in MET-call and pressure injury rates. CONCLUSION: Although residential respite recipients represent a minority of total residential aged care admissions, they are at high risk of poor outcomes. Prospective identification and timely intervention may improve quality of care for this vulnerable cohort.

The COVID-19 pandemic has significantly impacted those in residential aged care facilities (RACF). This research was undertaken to explore and better understand the effects of the pandemic on the experience of next-of-kin and carers who encountered the death of a loved one who resided within a RACF during the pandemic.To explore end-of-life experiences for residents who die in RACF and their next-of-kin/carers during the COVID-19 pandemic, to identify areas of concern and areas for improvement.Prospective single-centre mixed methods research was undertaken involving telephone interview with next-of-kin or carers of residents who died within 30 days of being referred to Austin Health Residential InReach Service during the 'second wave' of COVID-19 in Melbourne, Australia, in 2020. Qualitative and quantitative data were collected. Qualitative description and aspects of grounded theory were used for analysing qualitative data. Thematic analysis of the interview transcripts used open and axial coding to identify initial themes and then to group these under major themes.Forty-one telephone interviews were analysed. Major themes identified included: COVID-19 pandemic, communication and technology, death and dying experience, bereavement and grief, and social supports and external systems.Findings identify the many COVID-19 pandemic-related challenges faced by participants and their dying loved one in RACF. Access to palliative care and bereavement support is crucial for dying residents and for grieving that has been made more difficult by the pandemic.

Background The highly encouraging findings from the Finnish Geriatric Intervention Study (known as FINGER) led to the global initiative for dementia risk reduction known as world-wide FINGERS (WW FINGERS). As part of the collaboration, our Australian AU-ARROW trial will follow the general protocol of the FINGER trial, and will also be aligned with the U.S. arm of the study, US-POINTER, though will have minor cultural and dietary modifications to determine the validity of the intervention in an Australian setting. Method AU-ARROW is a randomised, single-blind 2-year clinical trial that will recruit 600 participants aged 60-79 satisfying specific inclusion/exclusion criteria, including normal cognition and one or more cardiovascular risk factors that place them at greater risk of cognitive decline. Participants will be distributed across two sites (a) Macquarie University Health Clinics, Sydney, NSW and (b) Sarich Neuroscience Research Institute, Edith Cowan University, Perth, WA, and will be randomised equally into either the innovative multi-modal intervention group or the study control group, who will receive general lifestyle advice and annual health check-ups, without treatment. Multi-modal intervention consists of aerobic exercise, resistance training and stretching; dietary advice with monitoring to encourage adherence to the MIND diet; cognitive training sessions via the Brain HQ computerised online training system; and medical monitoring and regular health education sessions. Heart rate trackers, diet and exercise log books, and the monitoring of Brain HQ sessions will all help with adherence. Primary outcome measure is improvement in global cognitive score, measured using neurocognitive tests identical to those in the US-POINTER protocol. Additional neurocognitive tests, physical function improvements, detailed diet monitoring and sleep monitoring will provide added data. The unique extra value of AU-ARROW trial consists of the testing for Alzheimer’s disease (AD) blood biomarkers in all participants; as well as the AD Aβ amyloid-specific ligand-PET imaging, brain MRI and retinal biomarker tests that half of the participants will undergo. These tests will provide comprehensive data which have the ultimate purpose of increasing knowledge of the preclinical stages of AD, and help not only to develop preclinical AD diagnostic tests but also efficacy of AU-ARROW’s intervention.

Background Cortical iron accumulation has been reported as a pathological feature of Alzheimer's disease (AD). The cause of cortical iron elevation in AD is unknown but may be contributed by hemosiderin deposits in cerebral microbleeds that frequently occur in this disease. Objective To investigate the impact of cerebral microbleeds (which are more frequent in AD) on the magnetic susceptibility of the surrounding brain tissue. Methods 32 MRI scans from the Australian Imaging, Biomarker and Lifestyle (AIBL) study were found to have cerebral microbleeds by manual assessment of susceptibility weighted images. Quantitative susceptibility mapping (QSM; an MRI technique that is sensitive to iron) was used to estimate iron content in the tissue surrounding the microbleed in four concentric radii. Furthermore, the mirror regions on the contralateral hemisphere were also demarcated. A simulation analysis was conducted to investigate the effect of QSM imaging on cerebral microbleeds with varying sizes. Results 77 microbleeds were identified from the available scans. The immediate proximal region to the cerebral microbleeds had enhanced tissue susceptibility (∼0.02 PPM), but importantly, this did not extend beyond one voxel radius. This finding with in vivo data was also replicated in a simulation study. However, the presence of microbleeds could lead to over-estimation of tissue QSM in unsupervised quantification, therefore processing methods to avoid this artefact without the need for their manual identification are proposed. Conclusion The local changes in susceptibility due to microbleeds outside the focal lesion are restricted to 1 voxel and may be explained by partial voluming artefacts caused by limited imaging resolution. The susceptibly change induced by the microbleed is a relatively small proportion of tissue and could not account for regional iron changes observed in AD cortex.

Objective To investigate decision-making around hospital transfer and/or referral of residents to a Residential InReach (RiR) service in north-eastern metropolitan Melbourne, Australia, from the perspectives of residential aged care facility (RACF) staff, general practitioners (GPs) and RiR registered nurses (RNs). Methods Thirty-one staff from eight RACFs, five GPs and four RiR RNs participated in individual or group interviews. Results Residential aged care facility staff and GPs valued and relied upon RiR to manage unwell residents. Thematic analysis identified RiR utilisation was driven by the following: (i) complexity of decision-making processes in RACFs; (ii) variability in facility-based medical and nursing care; and (iii) impact of RiR service outcomes on patients and referrers. Conclusion Availability of timely and appropriate medical and nursing care in RACFs was reported to influence transfers to the hospital and/or referrals to RiR. RiR was used to complement or substitute usual care available to residents. Further research and improvements in RACF and RiR resources are required.

ObjectivesThe onset of many illnesses is confounded with age and sex. Increasing age is a risk factor for the development of many illnesses, and sexual dimorphism influences brain anatomy, function, and cognition. Here, we examine frequency-specific connectivity in resting-state networks in a large sample (n = 406) of healthy aged adults.MethodWe quantify frequency-specific connectivity in three resting-state networks known to be implicated in age-related decline: the default mode, dorsal attention, and salience networks, using multiband functional magnetic resonance imaging. Frequency-specific connectivity was quantified in four bands: low (0.015–0.027 Hz), moderately low (0.027–0.073 Hz), moderately high (0.073–0.198 Hz), and high (0.198–0.5 Hz) frequency bands, using mean intensity and spatial extent. Differences in connectivity between the sexes in each of the three networks were examined.ResultsEach network showed the largest intensity and spatial extent at low frequencies and smallest extent at high frequencies. Males showed greater connectivity than females in the salience network. Females showed greater connectivity than males in the default mode network.DiscussionResults in this healthy aged cohort are compatible with those obtained in young samples, suggesting that frequency-specific connectivity, and differences between the sexes, are maintained into older age. Our results indicate that sex should be considered as an influencing factor in studies of resting-state connectivity.

Background and Objective Cerebral microbleeds (CMB) are important biomarkers of cerebrovascular diseases and cognitive dysfunctions. Susceptibility weighted imaging (SWI) is a common MRI sequence where CMB appear as small hypointense blobs. The prevalence of CMB in the population and in each scan is low, resulting in tedious and time-consuming visual assessment. Automated detection methods would be of value but are challenged by the CMB low prevalence, the presence of mimics such as blood vessels, and the difficulty to obtain sufficient ground truth for training and testing. In this paper, synthetic CMB (sCMB) generation using an analytical model is proposed for training and testing machine learning methods. The main aim is creating perfect synthetic ground truth as similar as reals, in high number, with a high diversity of shape, volume, intensity, and location to improve training of supervised methods. Method sCMB were modelled with a random Gaussian shape and added to healthy brain locations. We compared training on our synthetic data to standard augmentation techniques. We performed a validation experiment using sCMB and report result for whole brain detection using a 10-fold cross validation design with an ensemble of 10 neural networks. Results Performance was close to state of the art (~9 false positives per scan), when random forest was trained on synthetic only and tested on real lesion. Other experiments showed that top detection performance could be achieved when training on synthetic CMB only. Our dataset is made available, including a version with 37,000 synthetic lesions, that could be used for benchmarking and training. Conclusion Our proposed synthetic microbleeds model is a powerful data augmentation approach for CMB classification with and should be considered for training automated lesion detection system from MRI SWI.

ObjectiveTo assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity.MethodsWe pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs).ResultsThirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11–3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48–3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity.ConclusionCAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.

OBJECTIVE To assess relationships between resilience, frailty and outcomes in geriatric rehabilitation inpatients. METHODS Eighty-nine inpatients had Brief Resilience Scale (BRS) and frailty index (FI-CGA) completed. Pearson's or Spearman's correlation was used to determine correlation between BRS, FI-CGA and covariates. Multivariate logistic regression was used to determine associations between resilience, frailty and covariates with functional independence measure gain, length of stay (LOS) > 21 days, mortality and discharge care requirements. RESULTS There was a negative correlation between BRS and premorbid FI-CGA (r = -0.31, P = 0.03) and admission FI-CGA (r = -0.26, P = 0.01) and between BRS and Mini-Mental State Examination score (rho = -0.26, P = 0.02). BRS was not associated with observed outcomes. Premorbid FI-CGA was associated with inpatient mortality, and greater increase in FI-CGA during acute stay was associated with greater LOS. All patients who died were frail (FI-CGA > 0.25). CONCLUSION Resilience and frailty were inversely related. Frailty was an independent predictor of rehabilitation LOS and mortality.

Brain atrophy can occur several decades prior to onset of cognitive impairments. However, few longitudinal studies have examined the relationship between brain volume changes and cognition over a long follow-up period in healthy elderly women. In the present study we investigate the relationship between whole brain and hippocampal atrophy rates and longitudinal changes in cognition, including verbal episodic memory and executive function, in older women. We also examine whether baseline brain volume predicts subsequent changes in cognitive performance over a 10-year period. A total of 60 individuals from the population-based Women's Healthy Ageing Project with a mean age at baseline of 59 years underwent 3T MRI. Of these, 40 women completed follow-up cognitive assessments, 23 of whom had follow-up MRI scans. Linear regression analysis was used to examine the relationship between brain atrophy and changes in verbal episodic memory and executive function over a 10-year period. The results show that baseline measurements of frontal and temporal grey matter volumes predict changes in verbal episodic memory performance, whereas hippocampal volume at baseline is associated with changes in executive function performance over a 10-year period of follow-ups. In addition, higher whole brain and hippocampal atrophy rates are correlated with a decline in verbal episodic memory. These findings indicate that in addition to atrophy rate, smaller regional grey matter volumes even 10 years prior is associated with increased rates of cognitive decline. This study suggests useful neuroimaging biomarkers for the prediction of cognitive decline in healthy elderly women.

BACKGROUND: Quantifying the contribution of cerebrovascular disease to the clinical and pathological profile of Alzheimer's disease is challenging. OBJECTIVE: We aimed to determine the influence of cerebrovascular disease, amyloid-β (Aβ), and their comorbidity on cognitive decline, hippocampal atrophy, and Aβ deposition, by evaluating data from the Australian Imaging, Biomarker and Lifestyle Study of Ageing. METHODS: Two-hundred and eighteen participants underwent Aβ PET, MRI, and cognitive assessment at 18-month intervals for up to 90 months. Aβ status was determined on baseline PET. Participants were also classified as V+ on baseline MRI if they had≥1 large cortical infarcts, subcortical infarcts, or cortical cerebral microinfarcts; or white matter hyperintensity volume greater than the 90th percentile of healthy controls. Linear mixed models were conducted comparing slopes of change in cognition, hippocampal volume, and Aβ load between the four resultant groups. RESULTS: Mean age at baseline was 74 years (range 59-96). One-hundred and fifteen participants were cognitively normal, 54 had mild cognitive impairment, and 49 had Alzheimer's disease. Compared to the Aβ-/V- group, the Aβ+/V- and Aβ+/V+ groups showed significantly faster cognitive decline and hippocampal atrophy over 90 months. V+ status was associated with greater cognitive decline (Cohen's d = 0.85, p

This case report presents in-vivo findings on the spatial and temporal relationship between focal Ab-amyloid deposition, cerebral micro-haemorrhages and superficial siderosis. A 65-year-old woman underwent 11C-PiB PET scans that revealed an atypical focal and asymmetrical pattern of Ab-amyloid deposition and MRI scans that revealed cerebral micro-haemorrhages and superficial siderosis. Almost all micro-haemorrhages were associated with focal Ab-amyloid deposition. Follow-up 11C-PiB PET and MRI scans showed progression of the disease. We speculate that Abamyloid deposition affects the structural integrity of arterioles, thereby predisposing them to micro haemorrhages. In support of this hypothesis, progression of MRI lesions was observed only in areas associated with Ab-amyloid deposition.

Machine learning applied to medical imaging for lesions detection, such as cerebral microbleeds (CMB) from Magnetic Resonance Imaging (MRI), is challenged by the relatively small datasets available for which only subjective and tedious visual reading is available, and by the low prevalence of lesions (a few in ~10% of a typical elderly cohort) resulting in unbalanced classes. Moreover, the lack of actual ground truth might limit the performance of any machine learning method to that of human performance. Yet, the automatic identification of those lesions is relevant to quantify cerebrovascular burden associated with dementia, such as identifying co-morbidity for Alzheimer’s disease. In this paper, we investigated a novel approach consisting of simulating synthetic CMB on SWI MRI scans from healthy individuals to create a large and well characterized training dataset, as a data augmentation strategy. Firstly, we characterized actual CMBs from MRI SWI scans and designed a method to create realistic synthetic CMBs whose location, shape, appearance, and size are similar to actual CMBs. We then tested a supervised neural network classifier using various combinations of actual CMB and synthetic CMBs for training. Augmenting data with synthetic CMBs resulted in a large improvement over training on only actual CMBs only when tested on unseen lesions, and provided better results than other standard data augmentation approaches. Our results suggest that data augmentation using synthetic lesions can address the lack of ground truth and low prevalence limitations for medical imaging analysis allowing the deployment of data hungry supervised learning techniques such as deep learning.

Alzheimer disease is the cause of up to one-third of cases of primary progressive aphasia or corticobasal syndrome. The primary objective of this study was to determine the accuracy of 18F-FDG PET metabolic imaging for the detection of Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome. Methods: A cohort of patients (n = 94), including those with an expert clinical diagnosis of logopenic (n = 19), nonfluent (n = 16), or semantic (n = 13) variants of primary progressive aphasia, corticobasal syndrome (n = 14), or Alzheimer disease (n = 24), underwent 18F-FDG metabolic and 11C-labeled Pittsburgh compound B (11C-PiB) amyloid PET brain imaging. 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays were classified as revealing Alzheimer disease or “other” by interpreters who were unaware of the clinical assessments and 11C-PiB PET results. 11C-PiB PET imaging was considered to be the diagnostic reference standard, with a threshold standardized uptake value ratio of 1.5 being indicative of Alzheimer disease pathology. To address possible bias from subgroup selection for the Alzheimer disease binary classifier, we calculated both conventional and balanced accuracies. Results: Diagnoses of Alzheimer disease based on 18F-FDG PET resulted in 84% accuracy (both conventional and balanced). In comparison, diagnoses based on clinical assessments resulted in 65% conventional accuracy and 67% balanced accuracy. Conclusion: Brain 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays accurately detected Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome as focal-onset dementias. In such diagnostically challenging cohorts, 18F-FDG PET imaging can provide more accurate diagnoses, enabling more appropriate therapy.

Alzheimer’s Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose individuals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify individuals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer’s participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk individuals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ε4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ε4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of individuals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial.

Introduction Systematic reviews demonstrate that advance care planning (ACP) has many positive effects for residents of aged care facilities, including decreased hospitalisation. The proposed Residential Aged Care Facility (RACF) ‘Goals of Patient Care’ (GOPC) form incorporates a resident9s prior advance care plan into medical treatment orders. Where none exists, it captures residents9 preferences. This documentation helps guide healthcare decisions made at times of acute clinical deterioration. Methods and analysis This is a mixed methods study. An unblinded cluster randomised controlled trial is proposed in three pairs of RACFs. In the intervention arm, GOPC forms will be completed by a doctor incorporating advance care plans or wishes. In the control arm, residents will have usual care which may include an advance care plan. The primary hypothesis is that the GOPC form is superior to standard ACP alone and will lead to decreased hospitalisation due to clearer documentation of residents9 medical treatment plans. The primary outcome will be an analysis of the effect of the GOPC medical treatment orders on emergency department attendances and hospital admissions at 6 months. Secondary outcome measurements will include change in hospitalisation rates at 3 and 12 months, length of stay and external mortality rates among others. Qualitative interviews, 12 months post GOPC implementation, will be used for process evaluation of the GOPC and to evaluate staff perceptions of the form9s usefulness for improving communication and medical decision-making at a time of deterioration. Dissemination The results will be disseminated in peer review journals and research conferences. This robust randomised controlled trial will provide high-quality data about the influence of medical treatment orders that incorporate ACP or preferences adding to the current gap in knowledge and evidence in this area. Trial registration number ACTRN12615000298516, Results.

Despite delirium being described in the Greek literature as far back as 400 bc, current levels of knowledge and practice, in comparison to other medical conditions, lag considerably behind. However, over the past 20 years, there has been signicant progress in the way that we understand, conceptualize and manage delirium (Maclullich et al., 2013).

Disease-modifying treatments for Alzheimer’s disease (AD) may require implementation during early stages of β-amyloid accumulation, well before patients have objective cognitive decline. In this study we aimed to assess the clinical value of subjective cognitive impairment (SCI) by examining the cross-sectional relationship between β-amyloid load and SCI. Cerebral β-amyloid and SCI was assessed in a cohort of 112 cognitively normal subjects. Subjective cognition was evaluated using specific questions on memory and cognition and the MAC-Q. Participants had cerebral β-amyloid load measured with 18F–Florbetaben Positron Emission Tomography (PET). No associations were found between measures of subjective memory impairment and cerebral β-amyloid. However, by self-reported confusion was predictive of a higher global β-amyloid burden (p = 0.002), after controlling for confounders. Regional analysis revealed significant associations of confusion with β-amyloid in the prefrontal region (p = 0.004), posterior cingulate and precuneus cortices (p = 0.004) and the lateral temporal lobes (p = 0.001) after controlling for confounders. An in vivo biomarker for AD pathology was associated with SCI by self-reported confusion on cross-sectional analysis. Whilst there has been a large body of research on SMC, our results indicate more research is needed to explore symptoms of confusion.

Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer's disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer's disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike 11C-Pittsburgh compound B, 18F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, 18F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimer's disease.

Objective:We sought to determine the incidence and associations of lobar microbleeds (LMBs) in a longitudinal cohort with C-11-Pittsburgh compound B (PiB) PET imaging.Methods:One hundred seventy-four participants from the observational Australian Imaging, Biomarkers and Lifestyle Study of Ageing (97 with normal cognition [NC], 37 with mild cognitive impairment [MCI], and 40 with Alzheimer disease [AD] dementia) were assessed at 3 time points over 3 years with 3-tesla susceptibility-weighted MRI and C-11-PiB PET. MRIs were inspected for microbleeds, siderosis, infarction, and white matter hyperintensity severity, blind to clinical and PiB findings. Neocortical PiB standardized uptake value ratio, normalized to cerebellar cortex, was dichotomized as positive or negative (PiB+/-, standardized uptake value ratio >1.5). Annualized LMB incidence was calculated, and logistic regression was used to determine the association of incident LMBs with PiB, APOE epsilon 4+ status, and cerebrovascular disease.Results:LMBs were present in 18.6% of NC, 24.3% of MCI, and 40% of AD participants (p < 0.05 vs NC). LMB incidence was 0.2 0.6 per year in NC participants, 0.2 +/- 0.5 in MCI, and 0.7 +/- 1.4 in AD (p < 0.03 vs NC) and was 6-fold higher in PiB+ than PiB-NC. Incident LMBs were associated with age, APOE epsilon 4+, PiB+, and baseline LMBs. Incidence of multiple LMBs was also associated with lacunar infarction and white matter hyperintensity severity.Conclusions:Older age, baseline LMBs, higher -amyloid burden, and concomitant cerebrovascular disease may all confer higher risk of incident LMBs. This should be considered when designing protocols for amyloid-modifying clinical trials.

Diagnosis of tauopathies such as Alzheimer's disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate (18)F-THK523 as a potential tau imaging tracer.Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as (18)F-THK523 and (11)C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for (18)F-THK523 and (11)C-PIB were estimated for all participants. Correlational analyses were performed between global and regional (18)F-THK523, (11)C-PIB, cognition and brain volumetrics.(18)F-THK523 presented with fast reversible kinetics. Significantly higher (18)F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical (18)F-THK523 retention did not correlate with Aβ distribution as assessed by (11)C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike (11)C-PIB, hippocampal (18)F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy.(18)F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical (18)F-THK523 retention in AD patients as well as the association of hippocampal (18)F-THK523 retention with cognitive parameters and hippocampal volume suggests (18)F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high (18)F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.

Aims: Test the robustness of a linear regression transformation of semiquantitative values from different Aβ tracers into a single continuous scale. Study Design: Retrospective analysis. Place and Duration of Study: PET imaging data acquired in Melbourne and Perth, Australia, between August 2006 and May 2014. Methodology: Aβ imaging in 633 participants was performed with four different radiotracers: flutemetamol (n=267), florbetapir (n=195), florbetaben (n=126) and NAV4694 (n=45). SUVR were generated with the methods recommended for each tracer, and classified as high (Aβ+) or low (Aβ-) based on their respective thresholds. Linear regression transformation based on reported head-to-head comparisons of each tracer with PiB was applied to each tracer result. Each tracer native classification was compared with the classification derived from the transformed data into PiB-like SUVR units (or BeCKeT: Before the Centiloid Kernel Transformation) using 1.50 as a cut-off. Results: Misclassification after transformation to PiB-like SUVR compared to native classification was extremely low with only 3/267 (1.1%) of flutemetamol, 1/195 (0.5%) of florbetapir, 1/45 (2.2%) of NAV4694, and 1/126 (0.8%) of florbetaben cases assigned into the wrong category. When misclassification occurred (

Rationale Cerebral microbleeds seen on brain magnetic resonance imaging are markers of small vessel disease, linked to cognitive dysfunction and increased ischemic and hemorrhagic stroke risk. Observational studies suggest that aspirin use may induce cerebral microbleeds, and associated overt intracranial hemorrhage, but this has not been definitively resolved. Aims ASPREE-NEURO will determine the effect of aspirin on cerebral microbleed development over three years in healthy adults aged 70 years and over, participating in the larger ‘ASPirin in Reducing Events in the Elderly (ASPREE)’ primary prevention study of aspirin. Sample size Five hundred and fifty-nine participants provide 75% power (two-sided p value of 0.05) to determine an average difference of 0.5 cerebral microbleed per person after three years. Methods and design A multi-center, randomized placebo-controlled trial of 100 mg daily aspirin in participants who have brain magnetic resonance imaging at study entry, one and three years after randomization and who undergo cognitive testing at the same time points. Study outcomes The primary outcome is the number of new cerebral microbleeds on magnetic resonance imaging after three years. Secondary outcomes are the number of new cerebral microbleeds after one year, change in volume of white matter hyperintensity, cognitive function, and stroke. Discussion ASPREE-NEURO will resolve whether aspirin affects the presence and number of cerebral microbleeds, their relationship with cognitive performance, and indicate whether consideration of cerebral microbleeds alters the risk-benefit profile of aspirin in primary prevention for older people. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001313729.

The origins of the term control and restraint, abbreviated to C&r, lie in the prison service. its assimilation into the vernacular of mental health care happened via the training of health service staff by prison service instructors, first in Falkirk in scotland, and then via the english special hospitals in the 1980s (Turnbull et al 1990). The term originally referred to a programme of physical intervention training designed by the english prison service in response to inquiries into serious and sometimes fatal injuries sustained by prisoners during physical confrontations. The health service training programmes were initially rigidly controlled by the prison service, but were later allowed to proliferate throughout the nhs independent of any central regulation. Consequently, although the phrase C&r came into common use in the health service, at almost no point did it describe any coherent national training programme. instead, it served to conceal the widespread local ad hoc adaptation of physical breakaway and restraint procedures. These adapted training programmes, which had not been subjected to any quality assurance arrangements (Duxbury and Paterson 2005). The underlying perception of physical interventions implicit to C&r was of a skill that needed to be taught to staff, rather than an intervention done to service users. such skills in physical interventions were sometimes taught without any attempt to teach violence prevention in services that had inadequate insight into their culture, leading to serious abuses. one consequence of the lack of central control in the nhs was that a large-scale, uncontrolled experiment into the effects of training staff in physical interventions was allowed to happen. This has now lasted two decades and unfortunately the dependant variables have been staff and service user safety. While much has been written on the risks to service users during restraint, there have also been numerous instances of serious injuries to staff during C&r training, owing to poor technique design and unsafe teaching methods. ConTrol anD resTrainT: Changing Thinking, PraCTiCe anD PoliCy

Locusts lay their eggs by digging into a substrate using rhythmic opening and closing movements of ovipositor valves at the end of the abdomen. The digging rhythm is inhibited by chemosensory stimulation of chemoreceptors on the valves. Nitric oxide (NO) modulated the effects of chemosensory stimulation on the rhythm. Stimulation with either sucrose or sodium chloride (NaCl) stopped the digging rhythm, whereas simultaneous bath application of the NO inhibitor, N-nitro-L-arginine methyl ester (L-NAME), increased the duration for which the digging rhythm stopped. Increasing NO levels caused a significant reduction in the cessation of the rhythm in response to the same 2 chemicals. Bath applying cyclic guanosine monophosphate (cGMP), the soluble guanylate inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and the generic protein kinase inhibitor H-7 had no effect on the duration for which the rhythm stopped in response to NaCl stimulation. Conversely, bath application of cGMP and ODQ resulted in a significant decrease and increase, respectively, in the duration for which the digging rhythm stopped when stimulated with sucrose. Moreover, bath application of the selective protein kinase G (PKG) inhibitor KT-5823 also resulted in a significant increase in the duration of cessation of the rhythm when stimulated with sucrose. Results suggest that NO modulates the behavioral responses to NaCl via a cGMP/PKG-independent pathway while modulating the responses to sucrose via a NO-cGMP/PKG-dependent pathway.