Quantifying global soil carbon losses in response to warming.

The majority of the Earth's terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12-17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon-climate feedback that could accelerate climate change.

Mapping tree density at a global scale.

The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.

Imaging of tau deposits in adults with Niemann-Pick type C disease: a case-control study.

PURPOSE: Niemann-Pick type C (NPC) is a cholesterol storage disease characterized by disruption in the endosomal-lysosomal transport system that leads to the accumulation of cholesterol and glycolipids in lysosomes. Developmental cognitive delay and progressive motor and cognitive impairment are characteristic of the disease. Tau accumulation has been reported in some NPC patients. We investigated the presence of tau and Aß-amyloid deposits in a group of NPC patients and for comparison in age-matched healthy controls (HC). METHODS: Eight NPC patients and seven HC were included in the study. Participants underwent tau imaging with 18F-AV1451 and amyloid imaging with 11C-PiB. Both 18F-AV1451 and 11C-PiB standardized uptake value ratios were generated using the cerebellar cortex as the reference region. Associations between imaging results, and clinical and neurocognitive parameters were assessed through nonparametric analyses. RESULTS: All participants were Aß-negative. Four NPC patients presented with high tau burden in the brain. A 21-year-old female patient and a 40-year-old male patient showed high neocortical tau burden in a pattern different from that observed in patients with Alzheimer's disease, while the same 40-year-old male patient, a 40-year-old female patient and a 50-year-old female patient showed high regional tau burden in the mesial temporal cortex. Spearman's correlation analysis showed an association between tau burden in the mesial temporal lobe and age (p = 0.022), and age at symptom onset (p = 0.009), and between frontotemporal tau and duration of symptoms (p = 0.027). There were no correlations between global and regional tau and cognitive parameters. CONCLUSION: Four of eight NPC patients showed tau deposition in the brain. The results of our exploratory study suggest that while tau deposits do not affect cognitive performance, tau deposits are associated with measures of disease onset and progression. Further studies in a larger cohort of NPC patients are needed to confirm these initial findings.

An intravenous insulin protocol designed for pregnancy reduces neonatal hypoglycaemia following betamethasone administration in women with gestational diabetes.

AIMS: Marked hyperglycaemia is common following betamethasone administration in women with gestational diabetes (GDM), and may contribute to neonatal hypoglycaemia. Validated protocols to deliver glycaemic stability following betamethasone are lacking. We hypothesized that an intravenous insulin (IVI) protocol for pregnancy-specific glycaemic targets (Pregnancy-IVI) would achieve greater at-target glycaemic control than a generic adult intravenous insulin protocol (Adult-IVI), and may reduce neonatal hypoglycaemia. METHODS: A retrospective cohort study of the performance Adult-IVI and Pregnancy-IVI following betamethasone in GDM, sequentially implemented at a tertiary hospital, without change in indication for IVI. Cases were identified by electronic record search. Primary outcome was percentage of on-IVI time with at-target glycaemia [blood glucose level (BGL) 3.8-7 mmol/l]. Secondary outcomes were time with critical hyperglycaemia (BGL > 10 mmol/l), occurrence of maternal hypoglycaemia (BGL < 3.8 mmol/l), and incidence of neonatal hypoglycaemia (BGL ≤ 2.5 mmol/l) if betamethasone was administered within 48 h of birth. RESULTS: The cohorts comprised 151 women (Adult-IVI n = 86; Pregnancy-IVI n = 65). The primary outcome was 68% time-at-target [95% confidence interval (CI) 64-71%) for Pregnancy-IVI compared with 55% (95% CI 50-60%) for Adult-IVI (P = 0.0002). Critical maternal hyperglycaemia (0% vs. 2%, P = 0.02) and hypoglycaemia (2% vs. 12%, P = 0.02) were both lower with Pregnancy-IVI than Adult-IVI. Neonatal hypoglycaemia was less common after Pregnancy-IVI (29%) than after Adult-IVI (54%, P = 0.03). A multiple logistic regression model adjusting for potential confounders gave an odds ratio for neonatal hypoglycaemia with Pregnancy-IVI of 0.27 (95% CI 0.10-0.76, P = 0.01). CONCLUSIONS: An IVI protocol designed for pregnancy effectively controlled maternal hyperglycaemia following betamethasone administration in GDM. This is the first intervention to show a reduction in betamethasone-associated neonatal hypoglycaemia, linked with optimum maternal glycaemic control.

Young children, adolescent girls and women with type 1 diabetes are more overweight and obese than reference populations, and this is associated with increased cardiovascular risk factors.

AIM: Overweight and obesity are frequently reported in young persons with type 1 diabetes, however its relative magnitude in comparison to the general population is not well understood. This study compared the prevalence of overweight and obesity in young persons with type 1 diabetes to a reference population and explored possible associated factors, including gender, age, HbA1c , insulin regimen, age at diagnosis, diabetes duration, socio-economic status and cardiovascular disease risk factors. METHODS: A cross-sectional review was undertaken of data collected from youth (3-17 years) in 2016 and young adults (18-30 years) in 2015 with a diagnosis of type 1 diabetes for > 3 months attending diabetes centres in Newcastle, Australia. Rates of overweight and obesity were compared with matched population survey results. RESULTS: Data from 308 youth and 283 young adults were included. In girls, significantly higher prevalence of overweight and obesity were seen in the 5-8 (43% vs. 18%), 13-16 (41% vs. 27%), 18-24 (46% vs. 34%) and 25-30 (60% vs. 43%) years age groups; whereas in boys increased prevalence was observed in the 5-8 years age group only (41% vs. 18%). Rates of overweight and obesity increased with age across sexes. In youth, BMI standard deviation score was correlated with socio-economic status, insulin regimen, blood pressure and blood lipids (P < 0.05). In adults, BMI was positively associated with blood pressure, and longer diabetes duration (P < 0.02). CONCLUSIONS: Overweight and obesity are over-represented in young persons with type 1 diabetes, particularly girls. As overweight is associated with other cardiovascular disease markers early intervention is paramount.

Level of contact hypersensitivity response to diphencyprone and keratinocyte cancer.

BACKGROUND: Keratinocyte cancers (KC) are common and pose a significant financial burden globally. Ultraviolet radiation is a significant factor in their development, through mutagenesis promotion but also through local and systemic immunosuppression. Although systemic immunosuppression is well understood, cutaneous immunity has been more difficult to evaluate. OBJECTIVES: This study used a contact sensitizer, diphencyprone (DPCP), which elicits a contact hypersensitivity reaction in skin, to compare the degree of reactivity to DPCP in patients with a high KC burden versus those with a low KC burden. METHODS: A prospective study was performed in immunocompetent patients aged 70 ± 5 years of age, comparing patients with a high KC burden (>10 previous KC) with those with a low KC burden (<2 previous KC). All patients were sensitized with 2% DPCP and then patch tested two weeks later with eight different concentrations of DPCP with the threshold concentration and total degree of reaction recorded. RESULTS: Nine patients were recruited, 5 in the 'high cancer' group and 4 in the 'low cancer' group. All patients were Fitzpatrick skin type 1 or 2. All patients developed a reaction to DPCP. Patients in the low cancer group developed a reaction at a significantly lower threshold DPCP concentration than the high cancer group (P = 0.039). The cumulative intensity of reaction was higher in the low cancer group (P = 0.087). CONCLUSION: Patients with a high KC burden required a higher threshold concentration of DPCP to elicit a hypersensitivity reaction, supporting the concept of a lower skin immunity in these patients. DPCP reactivity threshold could be a useful tool in the evaluation of skin immunity and propensity to develop keratinocyte cancers.

Tau imaging with [18 F]THK-5351 in progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Visualization of pathogenic protein aggregates is crucial to elucidate pathomechanisms and to make an accurate diagnosis in many neurodegenerative conditions. Aggregates of the microtubule-binding protein, tau, are one of the most important pathogenic molecules in neurodegenerative disorders. Progressive supranuclear palsy (PSP) is characterized by the deposition of tau proteins in some specific area such as the basal ganglia and brainstem. We tried to detect tau lesions in the brains of living patients with PSP with a novel positron emission tomography (PET) tracer, [18 F]THK-5351, which we have recently developed. METHODS: Paraffin-embedded brain sections of the patients with PSP were used for autoradiography with [3 H]THK-5351 and immunohistochemistry. Nine healthy controls, 13 patients with Alzheimer's disease and three patients with PSP participated in this PET study with [18 F]THK-5351. To detect amyloid-ß deposition, PET imaging with Pittsburgh compound B was also performed. RESULTS: Autoradiography in the brain sections of patients with PSP demonstrated [3 H]THK-5351 binding to tau deposits with a high selectivity. Although patients with PSP exhibited no remarkable [18 F]THK-5351 retention in the temporal cortex, significantly higher tracer retention was observed in the globus pallidus and midbrain. In contrast, amyloid imaging with Pittsburgh compound B showed no remarkable accumulation in the cerebral cortex of PSP. CONCLUSIONS: We conclude that [18 F]THK-5351 PET can potentially be used to detect the regional brain distribution of tau lesions in PSP, thereby facilitating the differential diagnosis of neurodegenerative disorders associated with tau protein.

Prevalence of systemic anticancer therapy for patients within the last 30 days of life: experience in a private hospital oncology group.

BACKGROUND: In recent years, there has been a significant increase in the number of cancer treatments that have become available. However, it has remained difficult to choose the most appropriate time to cease active therapy in individual patients. AIMS: To determine the proportion of patients being treated with palliative intent who received systemic anticancer treatment in the last 30 days of life. METHODS: This is a retrospective cohort study conducted within the Melbourne Oncology Group at Cabrini Hospital. Patients managed with palliative intent who died between 1 January 2014 and 30 June 2014 were included. Outcomes measured were the percentage of patients who received systemic anticancer treatment in the last 30 days of life, palliative care referral status, Emergency Department presentations, hospital admissions and place of death. RESULTS: A total of 80 patients was included in the study. Of these patients, 21 (26%) received systemic anticancer treatment in the last 30 days of life. There was no statistically significant difference between patients who received treatment in the last month of life and those who did not in terms of the number of patients who were referred to palliative care, presented to an Emergency Department, were admitted to hospital or died in an acute ward. CONCLUSION: Although over a quarter of patients dying from advanced cancer received anticancer treatment in the last month of life, these patients did not present acutely to hospital more often and had the same extent of palliative care team involvement.

APOE and BDNF polymorphisms moderate amyloid ß-related cognitive decline in preclinical Alzheimer's disease.

Accumulation of ß-amyloid (Aß) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aß-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aß neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aß positron emission tomography neuroimaging was used to classify participants as Aß(-) or Aß(+). Relative to Aß(-)ɛ4(-), Aß(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aß(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aß(-)ɛ4(-) and Aß(-)ɛ4(+) groups. Among Aß(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aß-related cognitive decline. Aß(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aß(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aß(-) and Aß(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

Prognostic serum miRNA biomarkers associated with Alzheimer's disease shows concordance with neuropsychological and neuroimaging assessment.

There is no consensus for a blood-based test for the early diagnosis of Alzheimer's disease (AD). Expression profiling of small non-coding RNA's, microRNA (miRNA), has revealed diagnostic potential in human diseases. Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum. The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients, which may aid in diagnosis. Using next-generation deep sequencing, we profiled exosomal miRNA from serum (N=49) collected from the Australian Imaging, Biomarkers and Lifestyle Flagship Study (AIBL). Sequencing results were validated using quantitative reverse transcription PCR (qRT-PCR; N=60), with predictions performed using the Random Forest method. Additional risk factors collected during the 4.5-year AIBL Study including clinical, medical and cognitive assessments, and amyloid neuroimaging with positron emission tomography were assessed. An AD-specific 16-miRNA signature was selected and adding established risk factors including age, sex and apolipoprotein ɛ4 (APOE ɛ4) allele status to the panel of deregulated miRNA resulted in a sensitivity and specificity of 87% and 77%, respectively, for predicting AD. Furthermore, amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD. These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD.

Dietary patterns and cognitive decline in an Australian study of ageing.

The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) ɛ4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE ɛ4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.

Associations between gonadotropins, testosterone and ß amyloid in men at risk of Alzheimer's disease.

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of ß amyloid (Aß) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aß levels have focused primarily on plasma Aß(1-40) and not on the more pathogenic Aß(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aß levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aß(1-40) and Aß(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aß(1-40); beta=0.208, P=0.017; Aß(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

A blood-based predictor for neocortical Aß burden in Alzheimer's disease: results from the AIBL study.

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.

Survival outcomes in patients with multiple primary melanomas.

BACKGROUND: A substantial number of melanoma patients will develop multiple primary melanomas (MPM). Currently, little is known about the impact of MPM on survival. OBJECTIVE: We aimed to determine whether melanoma survival is worse for patients with MPM compared to those with a single invasive primary melanoma (SPM). MATERIALS AND METHODS: A cohort study was conducted. Patients were sourced from an Australian population, with follow-up information collected retrospectively from registry data. Melanoma-specific survival analysis was performed to find associated variables after adjustment for known prognostic factors, using four different models, each selecting a different index melanoma lesion. RESULTS: 1068 stage I and II melanoma patients were followed up for a median of 24.4 years. MPM was found in 17.8% of the cohort (190 patients), more likely among males and older age groups. Other clinicopathological parameters were similar between the MPM and SPM (878 patients) cohorts. After adjustment for age, sex and Breslow thickness, MPM was a hazard for death from melanoma, across all models, reaching significance when considering the last invasive lesion as the index melanoma (HR = 2.76, P = 0.017). CONCLUSION: Patients with multiple invasive lesions seem more at risk of death from melanoma, independent of known prognostic factors.

Physical activity and amyloid-ß plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing.

Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-ß (Aß) and Aß brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aß and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aß levels were measured in fasting blood samples. A subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aß1-42/1-40 ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aß from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ε4 carriers. Lower plasma Aß1-42/1-40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.

Factors affecting subjective memory complaints in the AIBL aging study: biomarkers, memory, affect, and age.

BACKGROUND: The prognostic value of subjective memory complaints (SMCs) in the diagnosis of dementia of the Alzheimer's type is unclear. While some studies have found an association between SMCs and cognitive decline, many have found a stronger association with depression, which raises questions about their diagnostic utility. METHODS: We examined the cross-sectional association between SMC severity (as measured using the MAC-Q, a brief SMC questionnaire) and affect, memory, and Alzheimer's disease (AD) biomarkers (ß-amyloid deposition and the apolipoprotein E ε4 (APOEε4) allele) in healthy elderly controls (HC; M = 78.74 years, SD = 6.7) and individuals with mild cognitive impairment (MCI; M = 72.74 years, SD = 8.8). We analyzed a subset of individuals drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Aging. RESULTS: SMCs were more severe in MCI patients than in HCs. SMC severity was related to affective variables and the interaction between age and group membership (HC/MCI). Within the HC group, SMC severity was related to affective variables only, while severity correlated only with age in the MCI group. SMCs were not related to cognitive variables or AD biomarkers. CONCLUSION: SMCs were related to solely by poorer mood (greater depressive and anxious symptomatology) in the cognitively healthy elderly however mean levels were subclinical. This finding argues for the assessment of affective symptomatology in conjunction with cognitive assessment in elderly memory complainers. Future AIBL research will focus on assessing other AD biomarkers, such as brain atrophy and Aß plasma markers, in relation to complaint severity. Once our 36-month follow-up data are collected, we propose to assess whether SMCs can predict future cognitive decline.

Identification of risk factors associated with acute kidney injury in patients admitted to acute medical units.

In 2009, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report identified significant deficiencies in the management of acute kidney injury (AKI) in hospitals in the UK. Many errors arose from failure to recognise patients with AKI and those at risk of developing AKI. Currently, there is no universally accepted risk factor assessment for identifying such patients on admission to acute medical units (AMUs). A multicentre prospective observational study was performed in the AMUs of 10 hospitals in England and Scotland to define the risk factors associated with AKI and to assess quality of care. Data were collected on consecutive acute medical admissions over two separate 24-h periods. Acute kidney injury was present in 55/316 (17.7%) patients, with sepsis, hypovolaemia, chronic kidney disease (CKD) and diabetes mellitus identified as the major risk factors. Deficiencies in patient care were identified, reinforcing the continuing need to improve the management of AKI.

Cross-Sectional and Longitudinal Comparison of Tau Imaging with 18F-MK6240 and 18F-Flortaucipir in Populations Matched for Age, MMSE and Brain Beta-Amyloid Burden.

OBJECTIVES: Longitudinal tau quantification may provide a useful marker of drug efficacy in clinical trials. Different tau PET tracers may have different sensitivity to longitudinal changes, but without a head-to-head dataset or a carefully designed case-matching procedure, comparing results in different cohorts can be biased. In this study, we compared the tau PET tracers, 18F-MK6240 and 18F-flortaucipir (FTP), both cross-sectionally and longitudinally by case-matching subjects in the AIBL and ADNI longitudinal cohort studies. METHODS: A subset of 113 participants from AIBL and 113 from ADNI imaged using 18F-MK6240 and 18F-FTP respectively, with baseline and follow-up, were matched based on baseline clinical diagnosis, MMSE, age and amyloid (Aß) PET centiloid value. Subjects were grouped as 64 Aß- cognitively unimpaired (CU), 22 Aß+ CU, 14 Aß+ mild cognitive impairment (MCI) and 13 Aß+ Alzheimer's disease (AD). Tracer retention was measured in the mesial, temporoparietal, rest of the cortex, and a meta-temporal region composed of entorhinal, inferior/middle temporal, fusiform, parahippocampus and amygdala. T-tests were employed to assess group separation at baseline using SUVR Z-scores and longitudinally using SUVR%/Yr. RESULTS: Both tracers detected statistically significant differences at baseline in most regions between all clinical groups. Only 18F-MK6240 showed statistically significant higher rate of SUVR increase in Aß+ CU compared to Aß- CU in the mesial, meta-temporal and temporoparietal regions. CONCLUSION: 18F-MK6240 appears to be a more sensitive tracer for change in tau level at the preclinical stage of AD.

Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer's Continuum.

BACKGROUND: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß and tau in predicting cognitive decline are unknown. OBJECTIVES: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aß (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). PARTICIPANTS: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. MEASUREMENTS: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aß-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. RESULTS: In CI, p217+tau was a significant predictor of change in MMSE (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU. CONCLUSIONS: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.