Alzheimer’s disease (AD) is increasingly prevalent worldwide, and disease‐modifying treatments may soon be at hand; hence, now, more than ever, there is a need to develop techniques that allow ...earlier and more secure diagnosis. Current biomarker‐based guidelines for AD diagnosis, which have replaced the historical symptom‐based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. While these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population‐based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost‐effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration AT(N) criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid‐based biomarkers, with a particular emphasis on those with potential to be translated into blood‐based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N) and phosphorylated tau (p‐tau; T) show particular potential for translation into clinical practice. However, p‐tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non‐AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre‐analytical protocols.
Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We ...identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
An oral loading dose was combined with intravenous infusion of 6% alcohol at rates adjusted on-line to close the gap between measurements of breath alcohol concentration (BrAC) and a target of 50 ...mg%. The goal was to minimize the deviation from a prescribed course of BrAC over time. In a pilot study of 10 young men, subjects underwent three experimental sessions: twice at 50 mg% and once in a 0 mg% control condition. The pilot study assessed the performance of the BrAC clamp, its potential utility in studies of acute tolerance to alcohol, and the retest reliability of directly measuring the alcohol elimination rate (AER) calculated from the steady-state infusion rate. Reduced variance was demonstrated in 4 of 5 experimental parameters, compared with results of an earlier approach using a split-dose oral administration procedure. Subjects' perceptions about alcohol effects were measured in one BrAC clamping session, using Schuckit's Subjective High Assessment Scale: 3 of 15 Schuckit's items demonstrated statistically significant indices of acute tolerance to alcohol. Within-subject AERs calculated in the steady-state had a coefficient of variation of 6.5%. Details of the BrAC clamping procedure are provided. The pilot study demonstrated the ability to prescribe experimental parameters of the brain's exposure to alcohol while preserving experimental flexibility in studies of acute tolerance to alcohol and AER.
The FORCAsT (FORest Canopy Atmosphere Transfer) model version 1.0 is updated to FORCAsT 2.0 by implementing five major changes, including (1) a change to the operator splitting, separating chemistry ...from emission and dry deposition, which reduces the run time of the gas-phase chemistry by 70 % and produces a more realistic in-canopy profile for isoprene; (2) a modification of the eddy diffusivity parameterization to produce greater and more realistic vertical mixing in the boundary layer, which ameliorates the unrealistic simulated end-of-day peaks in isoprene under well-mixed conditions and improves daytime air temperature; (3) updates to dry deposition velocities with available measurements; (4) implementation of the Reduced Caltech Isoprene Mechanism (RCIM) to reflect the current knowledge of isoprene oxidation; and (5) extension of the aerosol module to include isoprene-derived secondary organic aerosol (iSOA) formation. Along with the operator splitting, modified vertical mixing, and dry deposition, RCIM improves the estimation of first-generation isoprene oxidation products (methyl vinyl ketone and methacrolein) and some second-generation products (such as isoprene epoxydiols). Inclusion of isoprene in the aerosol module in FORCAsT 2.0 leads to a 7 % mass yield of iSOA. The most important iSOA precursors are IEPOX and tetrafunctionals, which together account for >86 % of total iSOA. The iSOA formed from organic nitrates is more important in the canopy, accounting for 11 % of the total iSOA. The tetrafunctionals compose up to 23 % of the total iSOA formation, highlighting the importance of the fate (i.e., dry deposition and gas-phase chemistry) of later-generation isoprene oxidation products in estimating iSOA formation.
The aquatic Coleoptera of Irish offshore islands are poorly known. Published records of aquatic beetles from offshore islands have mainly been incidental to lists of other invertebrate groups ...(Lansbury 1965, Carter 1969, Moore 1981, Reynolds 1985) and consequently the number of aquatic beetle species recorded is low. The present survey was undertaken with the aim of compiling a list of the aquatic beetles on the island of Inishbofin. To this end, a range of habitats was visited and thoroughly searched for aquatic beetles using a variety of collecting techniques.
Two leading theories within the field of suicide prevention are the interpersonal psychological theory of suicidal behaviour (IPT) and the integrated motivational-volitional (IMV) model. The IPT ...posits that suicidal thoughts emerge from high levels of perceived burdensomeness and thwarted belongingness. The IMV model is a multivariate framework that conceptualizes defeat and entrapment as key drivers of suicide ideation. We applied network analysis to cross-sectional data collected as part of the Scottish Wellbeing Study, in which a nationally representative sample of 3508 young adults (18–34 years) completed a battery of psychological measures. Network analysis can help us to understand how the different theoretical components interact and how they relate to suicide ideation. Within a network that included only the core factors from both models, internal entrapment and perceived burdensomeness were most strongly related to suicide ideation. The core constructs defeat, external entrapment and thwarted belonginess were mainly related to other factors than suicide ideation. Within the network of all available psychological factors, 12 of the 20 factors were uniquely related to suicide ideation, with perceived burdensomeness, internal entrapment, depressive symptoms and history of suicide ideation explaining the most variance. None of the factors was isolated, and we identified four larger clusters: mental wellbeing, interpersonal needs, personality, and suicide-related factors. Overall, the results suggest that relationships between suicide ideation and psychological risk factors are complex, with some factors contributing direct risk, and others having indirect impact.
•12 of the 20 psychological factors were uniquely related to suicide ideation.•Perceived burdensomness and internal entrapment made equal contribution to suicide ideation.•Defeat, external entrapment and thwarted belonginess were mainly related to other factors than suicide ideation.•Networks highlight complexity between psychological factors and suicide ideation.
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