Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease.

BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer's disease dementia (AD)) as an 'Inception cohort' who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an 'Enrichment cohort' (as of 10 April 2019). OBJECTIVE: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. METHODS: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. RESULTS: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aß-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. CONCLUSION: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

Widespread carbon-bearing materials on near-Earth asteroid (101955) Bennu.

Asteroid (101955) Bennu is a dark asteroid on an Earth-crossing orbit that is thought to have assembled from the fragments of an ancient collision. We use spatially resolved visible and near-infrared spectra of Bennu to investigate its surface properties and composition. In addition to a hydrated phyllosilicate band, we detect a ubiquitous 3.4-micrometer absorption feature, which we attribute to a mix of organic and carbonate materials. The shape and depth of this absorption feature vary across Bennu's surface, spanning the range seen among similar main-belt asteroids. The distribution of the absorption feature does not correlate with temperature, reflectance, spectral slope, or hydrated minerals, although some of those characteristics correlate with each other. The deepest 3.4-micrometer absorptions occur on individual boulders. The variations may be due to differences in abundance, recent exposure, or space weathering.

Trajectory Optimization for Missions to Small Bodies with a Focus on Scientific Merit.

Trajectory design for missions to small bodies is tightly coupled both with the selection of targets for a mission and with the choice of spacecraft power, propulsion, and other hardware. Traditional methods of trajectory optimization have focused on finding the optimal trajectory for an a priori selection of destinations and spacecraft parameters. Recent research has expanded the field of trajectory optimization to multidisciplinary systems optimization that includes spacecraft parameters. The logical next step is to extend the optimization process to include target selection based not only on engineering figures of merit but also scientific value. This paper presents a new technique to solve the multidisciplinary mission optimization problem for small-bodies missions, including classical trajectory design, the choice of spacecraft power and propulsion systems, and also the scientific value of the targets. This technique, when combined with modern parallel computers, enables a holistic view of the small body mission design process that previously required iteration among several different design processes.

Modeling orbital gamma-ray spectroscopy experiments at carbonaceous asteroids.

To evaluate the feasibility of measuring differences in bulk composition among carbonaceous meteorite parent bodies from an asteroid or comet orbiter, we present the results of a performance simulation of an orbital gamma-ray spectroscopy (GRS) experiment in a Dawn-like orbit around spherical model asteroids with a range of carbonaceous compositions. The orbital altitude was held equal to the asteroid radius for 4.5 months. Both the asteroid gamma-ray spectrum and the spacecraft background flux were calculated using the MCNPX Monte-Carlo code. GRS is sensitive to depths below the optical surface (to ≈20-50 cm depth depending on material density). This technique can therefore measure underlying compositions beneath a sulfur-depleted (e.g., Nittler et al. 2001) or desiccated surface layer. We find that 3σ uncertainties of under 1 wt% are achievable for H, C, O, Si, S, Fe, and Cl for five carbonaceous meteorite compositions using the heritage Mars Odyssey GRS design in a spacecraft-deck-mounted configuration at the Odyssey end-of-mission energy resolution, FWHM = 5.7 keV at 1332 keV. The calculated compositional uncertainties are smaller than the compositional differences between carbonaceous chondrite subclasses.

Five-year efficacy and safety of tenofovir-based salvage therapy for patients with chronic hepatitis B who previously failed LAM/ADV therapy.

BACKGROUND: Multidrug-resistant HBV continues to be an important clinical problem. The TDF-109 study demonstrated that TDF±LAM is an effective salvage therapy through 96 weeks for LAM-resistant patients who previously failed ADV add-on or switch therapy. We evaluated the 5-year efficacy and safety outcomes in patients receiving long-term TDF±LAM in the TDF-109 study. METHODS: A total of 59 patients completed the first phase of the TDF-109 study and 54/59 were rolled over into a long-term prospective open-label study of TDF±LAM 300 mg daily. RESULTS: Results are reported at the end of year 5 of treatment. At year 5, 75% (45/59) had achieved viral suppression by intent-to-treat analysis. Per-protocol assessment revealed 83% (45/54) were HBV DNA undetectable. Nine patients remained HBV DNA detectable, however 8/9 had very low HBV DNA levels (<264IU/mL) and did not meet virological criteria for virological breakthrough (VBT). One patient experienced VBT, but this was in the setting of documented non-compliance. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. Four patients discontinued TDF, one patient was lost to follow-up and one died from hepatocellular carcinoma. CONCLUSIONS: Long-term TDF treatment appears to be safe and effective in patients with prior failure of LAM and a suboptimal response to ADV therapy. These findings confirm that TDF has a high genetic barrier to resistance is active against multidrug-resistant HBV, and should be the preferred oral anti-HBV agent in CHB patients who fail treatment with LAM and ADV.

Fourier Transform Mass Spectrometry: The Transformation of Modern Environmental Analyses.

Unknown compounds in environmental samples are difficult to identify using standard mass spectrometric methods. Fourier transform mass spectrometry (FTMS) has revolutionized how environmental analyses are performed. With its unsurpassed mass accuracy, high resolution and sensitivity, researchers now have a tool for difficult and complex environmental analyses. Two features of FTMS are responsible for changing the face of how complex analyses are accomplished. First is the ability to quickly and with high mass accuracy determine the presence of unknown chemical residues in samples. For years, the field has been limited by mass spectrometric methods that were based on knowing what compounds of interest were. Secondly, by utilizing the high resolution capabilities coupled with the low detection limits of FTMS, analysts also could dilute the sample sufficiently to minimize the ionization changes from varied matrices.

Circulating CD147 predicts mortality in advanced hepatocellular carcinoma.

BACKGROUND AND AIM: The glycoprotein CD147 has a role in tumor progression, is readily detectable in the circulation, and is abundantly expressed in hepatocellular carcinoma (HCC). Advanced HCC patients are a heterogeneous group with some individuals having dismal survival. The aim of this study was to examine circulating soluble CD147 levels as a prognostic marker in HCC patients. METHODS: CD147 was measured in 277 patients (110 HCC, 115 chronic liver disease, and 52 non-liver disease). Clinical data included etiology, tumor progression, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment response. Patients with HCC were stratified into two groups based upon the 75th percentile of CD147 levels (24 ng/mL). RESULTS: CD147 in HCC correlated inversely with poor survival (P = 0.031). Increased CD147 predicted poor survival in BCLC stages C and D (P = 0.045), and CD147 levels >24 ng/mL predicted a significantly diminished 90-day and 180-day survival time (hazard ratio [HR] = 6.1; 95% confidence interval [CI]: 2.1-63.2; P = 0.0045 and HR = 2.8; 95% CI: 1.2-12.6; P = 0.028, respectively). In BCLC stage C, CD147 predicted prognosis; levels >24 ng/mL were associated with a median survival of 1.5 months compared with 6.5 months with CD147 levels ≤24 ng/mL (P = 0.03). CD147 also identified patients with a poor prognosis independent from treatment frequency, modality, and tumor size. CONCLUSIONS: Circulating CD147 is an independent marker of survival in advanced HCC. CD147 requires further evaluation as a potential new prognostic measure in HCC to identify patients with advanced disease who have a poor prognosis.

Macrophage activation marker soluble CD163 may predict disease progression in hepatocellular carcinoma.

BACKGROUND: Tumor associated macrophages are present in hepatocellular carcinoma (HCC) and associated with a poor prognosis. The aim of the present study was to investigate the levels and dynamics of soluble (s)CD163, a specific macrophage activation marker, in patients with HCC. METHODS: In a cohort from Australia, we studied 109 HCC patients, 116 patients with chronic liver disease (CLD), and 52 healthy controls. We examined associations between baseline sCD163 and parameters of HCC severity as well as overall and progression-free survival. In a cohort of 42 Danish HCC patients, we measured sCD163 at baseline and 1, 4 and 12 weeks after ablative treatment. RESULTS: In the Australian cohort, median sCD163 was similarly increased in HCC (5.6[interquartile range 3.5-8.0] mg/L) and CLD (6.1[3.6-9.6] mg/L) patients as compared to controls (2.0[1.5-2.7] mg/L, p < 0.001). sCD163 correlated with Child-Pugh and MELD scores in both HCC and CLD patients. Patients with high sCD163 levels had shorter progression-free survival (p < 0.001), but not overall survival (p = 0.15). In the Danish cohort, patients with HCC progression at 12 weeks had an increase in sCD163. There was no association between sCD163 and HCC size, number, vascular invasion or metastasis in any of the cohorts. CONCLUSIONS: We confirmed increased sCD163 levels in CLD and HCC patients associated with Child-Pugh and MELD scores and portal hypertension, but not with HCC size and number, or metastasis. As a novel finding, baseline sCD163 appeared to predict a rapid HCC progression, as sCD163 increased during follow-up in HCC patients who showed progression.

Lymphoma Remission by Interferon-Free HCV Eradication Without Chemotherapy.

Epidemiologic studies have suggested an association between hepatitis C virus (HCV) infection and antigendriven lymphoproliferative disorders, in particular marginal zone lymphomas. Antiviral therapy has been shown to exert an anti-lymphoma effect in these indolent B-cell lymphoproliferations, with survival gains observed. However, these protocols have traditionally incorporated interferon. We describe a patient with chronic hepatitis C, immune thrombocytopenia, and splenic marginal zone lymphoma who, after eradication of HCV with sofosbuvir and ribavirin, exhibited complete remission of both hematologic conditions. With the numerous new potent drugs currently available, the future looks positive with highly efficacious interferon-free regimens for HCV therapy.

Vitamin B12 and its binding proteins in hepatocellular carcinoma and chronic liver diseases.

BACKGROUND: The vitamin B12 (B12)-binding protein haptocorrin (HC) has proven to be a potentially useful biomarker in patients with fibrolamellar hepatocellular carcinoma (HCC). Little is known concerning the level of HC and other B12-related proteins in patients with HCC as compared to patients with other chronic liver diseases (CLDs) and healthy controls. We hypothesized that HC could be a biomarker of HCC. AIMS: To investigate levels of HC and B12-related proteins in HCC compared to CLDs and healthy controls. METHODS: We investigated two patient populations: A cross-sectional cohort of HCC patients (n = 130), CLD patients (n = 102) and healthy controls (n = 46) and a cohort of 38 HCC patients studied at baseline and 1, 4, and 12 weeks following ablative treatment. Patients were evaluated by standard biochemistry, Child-Pugh-score and Barcelona Clinic Liver Cancer (BCLC) classification. We analyzed total B12 by routine methods and HC, transcobalamin (TC), B12 saturated TC (holoTC), and the soluble cell surface receptor for holoTC (sCD320) by in-house enzyme-linked immunosorbent assay. RESULTS: HC showed higher median (range) levels for both HCC (590 [290-5860]) and CLD patients (620 [310-4010]) compared to controls (460 [250-2020]) (p < 0.01). Total B12, TC, holoTC, and sCD320 showed elevated levels in both HCC and CLD compared to controls. Only holoTC changed following treatment, without a concurrent change in TC. CONCLUSION: B12 and B12-related proteins (total B12, HC, TC, holoTC, and sCD320) show elevations in both HCC and CLD patients compared to controls, suggesting a relation to CLD in general rather than to primary liver cancer. Thus, HC is not useful as a biomarker for HCC.

Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma.

BACKGROUND & AIMS: The hepatitis B virus (HBV) genome encodes specific sequence elements which promote splicing of viral DNA. It has been previously suggested that spliced HBV (spHBV) variants promote viral replication and protein production, leading to hepatocellular carcinoma (HCC). In this study, we have analysed changes in spHBV over time; providing the first longitudinal analysis of spHBV in relation to the development of HCC. METHODS: Serial serum samples were collected from 165 patients with chronic HBV monoinfection, including 58 patients who later developed HCC. Real-time PCR was used to amplify and quantify wt and sp DNA loads. RESULTS: spHBV was detected in over 80% of patients with chronic HBV infection. Median serum spHBV levels were significantly higher in HCC patients than HCC-free control patients (p<0.001). Univariate analysis revealed a strong correlation between time to HCC diagnosis and spHBV DNA levels (τ=0.203; p=0.016). Asian HBV genotype (p=0.025) and increased viral load (p<0.001) were also significantly associated with increased spHBV DNA levels. Multiple regression analysis revealed time to diagnosis of HCC, Asian HBV genotypes, and viral load to be associated with increased spHBV DNA (model p<0.001; R(2)=0.189). CONCLUSIONS: HBV splicing is a common event during chronic infection and increases prior to diagnosis of HCC. Measurement of HBV splicing may prove a valuable adjunct to be used in the identification of chronically infected patients who are at increased risk of developing HCC.