Density-Conditional Forecasts in Dynamic Multivariate Models

When generating conditional forecasts in dynamic models it is common to impose the conditions as restrictions on future structural shocks. However, these conditional forecasts often ignore that there may be uncertainty about the future development of the restricted variables. Our paper therefore proposes a generalization such that the conditions can be given as the full distribution of the restricted variables. We demonstrate, in two empirical applications, that ignoring the uncertainty about the conditions implies that the distributions of the unrestricted variables are too narrow

Distinct ¹⁸F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease

Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease

Candidate Genes for Expansion and Transformation of Hematopoietic Stem Cells by NUP98-HOX Fusion Genes

BACKGROUND: Hox genes are implicated in hematopoietic stem cell (HSC) regulation as well as in leukemia development through translocation with the nucleoporin gene NUP98. Interestingly, an engineered NUP98-HOXA10 (NA10) fusion can induce a several hundred-fold expansion of HSCs in vitro and NA10 and the AML-associated fusion gene NUP98-HOXD13 (ND13) have a virtually indistinguishable ability to transform myeloid progenitor cells in vitro and to induce leukemia in collaboration with MEIS1 in vivo. METHODOLOGY/PRINCIPAL FINDINGS: These findings provided a potentially powerful approach to identify key pathways mediating Hox-induced expansion and transformation of HSCs by identifying gene expression changes commonly induced by ND13 and NA10 but not by a NUP98-Hox fusion with a non-DNA binding homedomain mutation (N51S). The gene expression repertoire of purified murine bone marrow Sca-1+Lin- cells transduced with retroviral vectors encoding for these genes was established using the Affymetrix GeneChip MOE430A. Approximately seventy genes were differentially expressed in ND13 and NA10 cells that were significantly changed by both compared to the ND13(N51S) mutant. Intriguingly, several of these potential Hox target genes have been implicated in HSC expansion and self-renewal, including the tyrosine kinase receptor Flt3, the prion protein, Prnp, hepatic leukemia factor, Hlf and Jagged-2, Jag2. Consistent with these results, FLT3, HLF and JAG2 expression correlated with HOX A cluster gene expression in human leukemia samples. CONCLUSIONS: In conclusion this study has identified several novel Hox downstream target genes and provides important new leads to key regulators of the expansion and transformation of hematopoietic stem cells by Hox

Self – perceived and clinically diagnosed dental and periodontal health status among young adults and their implications for epidemiological surveys

BACKGROUND: Clinical (normative) and subjective (self-assessment) evaluation of caries and periodontal diseases have been reported to demonstrate a significant disparity. The dental public health team is obligated to recognize and understand this gap. The objectives of the study were to investigate the practical values of using questionnaires (self–perceived assessment) as compared to clinical examinations (normative assessment) and to evaluate the implications of the results in understanding the public's perception of oral health. METHODS: The investigation was performed on 4920, 21 year-old Israeli adults upon release from compulsory military service between 1996 and 1998. Participants were asked to fill in a questionnaire inquiring how they would rate their personal dental and periodontal health levels. Clinical examinations, employing the DMFT and CPITN indices, were performed to determine normative oral health status. Perceived and normative assessments were compared for sensitivity, specificity, positive and negative predictive values and overall proportions using the clinical examinations as a gold standard. RESULTS: The sensitivity (disease perception) for dental status was found to be 0.34, while the specificity (health perception) was found to be 0.83. The positive predictive value for perceived dental status was found to be 0.68, whereas the negative predictive value was found to be 0.54. The sensitivity for perceived periodontal status was found to be 0.28, while the specificity was found to be 0.83. The positive predictive value for perceived periodontal status was found to be 0.05, whereas the negative predictive value was found to be 0.97. Regarding the overall proportions, a large discrepancy was found between self–assessment and professional assessment for both dental and periodontal health status. CONCLUSIONS: Self-assessment questionnaires were of low value in evaluating oral health status both in the individual and public levels, though perception levels of health were higher than that of disease. Findings reflects a low level of awareness of the public that may influence care-seeking behavior and highlight the importance of oral health promotion and the crucial need for public health action

Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related β-Amyloid Status

Importance: Accurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. // Objective: To examine the accuracy of plasma β-amyloid (Aβ) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral Aβ. // Design, Setting, and Participants: Two prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study. // Main Outcome and Measures: The cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio was used as the reference standard for brain Aβ status. Plasma Aβ42, Aβ40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of Aβ status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1. // Results: The mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma Aβ42 and Aβ40 predicted Aβ status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to Aβ42, Aβ40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma Aβ42 and Aβ40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma Aβ42, Aβ40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. // Conclusions and Relevance: Plasma Aβ42 and Aβ40 measured using Elecsys immunoassays predict Aβ status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of Aβ positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures

Chemical and structural changes of pretreated empty fruit bunch (EFB) in ionic liquid-cellulase compatible system for fermentability to bioethanol

The pretreatment of empty fruit bunch (EFB) was conducted using an integrated system of IL and cellulases (IL-E), with simultaneous fermentation in one vessel. The cellulase mixture (PKC-Cel) was derived from Trichoderma reesei by solid-state fermentation. Choline acetate [Cho]OAc was utilized for the pretreatment due to its biocompatibility and biodegradability. The treated EFB and its hydrolysate were characterized by the Fourier transform infrared spectroscopy, scanning electron microscopy, and chemical analysis. The results showed that there were significant structural changes in EFB after the treatment in IL-E system. The sugar yield after enzymatic hydrolysis by the PKC-Cel was increased from 0.058 g/g of EFB in the crude sample (untreated) to 0.283 and 0.62 ± 06 g/g in IL-E system after 24 and 48 h of treatment, respectively. The EFB hydrolysate showed the eligibility for ethanol production without any supplements where ethanol yield was 0.275 g ethanol/g EFB in the presence of the IL, while lower yield obtained without IL-pretreatment. Moreover, it was demonstrated that furfural and phenolic compounds were not at the level of suppressing the fermentation process

Low tumour cell proliferation at the invasive margin is associated with a poor prognosis in Dukes' stage B colorectal cancers

The conflicting results about the prognostic impact of tumour cell proliferation in colorectal cancer might be explained by the heterogeneity observed within these tumours. We have investigated whether a systematic spatial heterogeneity exists between different compartments, and whether the presence of such a systematic heterogeneity has any impact on survival. Fifty-six Dukes' stage B colorectal cancers were carefully morphometrically quantified with respect to the immunohistochemical expression of the proliferative marker Ki-67 at both the luminal border and the invasive margin. The proliferative activity was significantly higher at the luminal border compared with the invasive margin (P < 0.001), although the two compartments were also significantly correlated with each other. Tumours with low proliferation at the invasive margin had a significantly poorer prognosis both in univariate (P = 0.014) and in multivariate survival analyses (P = 0.042). We conclude that Dukes' B colorectal cancers exhibit a systematic spatial heterogeneity with respect to proliferation, and tumours with low proliferation at the invasive margin had a poor prognosis. The present data independently confirm recent results from the authors, and provide new insights into the understanding of tumour cell proliferation in colorectal cancer. © 1999 Cancer Research Campaig

Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol

BACKGROUND: To compare the efficacy and safety of budesonide/formoterol (Symbicort(®)) with formoterol (Oxis(®)) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β(2)-agonist therapy. METHODS: In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV(1 )40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 μg), were randomized to receive either budesonide/formoterol (320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 μg]) or formoterol (9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 μg]). The primary efficacy variable was the average FEV(1 )from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV(1 )at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. RESULTS: FEV(1 )increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. CONCLUSION: Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting β(2)-agonist

Insulin-like growth factors and cancer: no role in screening. Evidence from the BUPA study and meta-analysis of prospective epidemiological studies

Insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), and insulin-like growth factor binding protein-3 (IGFBP-3) were measured in frozen serum samples from 1051 men with cancer and 3142 controls in a nested case–control study from the British United Provident Association (BUPA) study cohort and associations with 14 cancers were examined, including prostate, colorectal, and lung. A meta-analysis of studies on these three cancer sites was also conducted. In the meta-analysis the odds ratio between the highest quartile IGF-1 group and the lowest quartile group was 1.31 (95% confidence interval (CI): 1.03–1.67) for prostate, 1.37 (1.05–1.78) for colorectal and 1.02 (0.80–1.31) for lung cancer, and for IGF-2 it was 0.72 (0.36–1.44) for prostate and 1.95 (1.26–3.00) for colorectal cancer. Results from the BUPA study were consistent with the estimates from the other studies. There were no statistically significant associations with IGFBP-3 and any of the cancer sites considered. Our results suggest that IGF-1, IGF-2, and IGFBP-3 measurements have no value in cancer screening, although IGF-1 and IGF-2 may be of aetiological significance in relation to colorectal and prostate cancer