Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer's disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is ...unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 95% CI 0.85-0.98) and presymptomatic (EYO ≥ -7 years) (AUC 0.86 95% CI 0.72-0.94) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.
Abstract
We use very long baseline interferometry to measure the proper motions of three black hole X-ray binaries (BHXBs). Using these results together with data from the literature and Gaia DR2 to ...collate the best available constraints on proper motion, parallax, distance, and systemic radial velocity of 16 BHXBs, we determined their three-dimensional Galactocentric orbits. We extended this analysis to estimate the probability distribution for the potential kick velocity (PKV) a BHXB system could have received on formation. Constraining the kicks imparted to BHXBs provides insight into the birth mechanism of black holes (BHs). Kicks also have a significant effect on BH–BH merger rates, merger sites, and binary evolution, and can be responsible for spin–orbit misalignment in BH binary systems. 75 per cent of our systems have potential kicks $\gt 70\, \rm {km\,s^{-1}}$. This suggests that strong kicks and hence spin–orbit misalignment might be common among BHXBs, in agreement with the observed quasi-periodic X-ray variability in their power density spectra. We used a Bayesian hierarchical methodology to analyse the PKV distribution of the BHXB population, and suggest that a unimodal Gaussian model with a mean of 107 $\pm \,\,16\, \rm {km\,s^{-1}}$ is a statistically favourable fit. Such relatively high PKVs would also reduce the number of BHs likely to be retained in globular clusters. We found no significant correlation between the BH mass and PKV, suggesting a lack of correlation between BH mass and the BH birth mechanism. Our python code allows the estimation of the PKV for any system with sufficient observational constraints.
Summary Background The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and ...genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD). Methods We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. Findings Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years SD 7·2 vs 50·4 years SD 5·2, respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1's first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 47% with PSEN1 mutations and 12 33% with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP ), which affected around a quarter of the patients in each group (20 24% and nine 25%, respectively). A number of patients with PSEN1 mutations had pyramidal (21 25%), extrapyramidal (12 14%), or cerebellar (three 4%) signs. Interpretation ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. Funding Medical Research Council and National Institute for Health Research.
The Nr4a family of nuclear hormone receptors is composed of three members-Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown ...to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.
In this review article, we compiled peer-reviewed literature describing PFAS exposure and reproductive effects in animals and humans. The aim was to compare environmental occurrence and effects of ...the most prominent long-chain PFAS compounds and their short-chain replacements. Long-chain PFAS compounds are known to persist in the environment due to their chemical stability, and also known to bioaccumulate; hence, these compounds are being replaced globally. Indeed, PFOA and PFOS are considered long-chain "forever pollutants," and thus the potential reproductive risk may continue for decades. Much less is known about their short-chain replacements despite the fact that they becoming more widespread in the environment. Short-chain PFAS are generally less bioaccumulative than long-chain, but they are more mobile and persistent in aquatic ecosystems. The three most prominent of these are commonly referred to as GenX, ADONA and F53B. The short-chain PFAS have similar physical and chemical properties as their predecessors; however, because they are relatively new, much less is known about the potential to disrupt reproduction. Indeed, high-quality epidemiological studies are needed to determine associations between short-chain PFAS exposure and effects on reproductive health. However, epidemiological evidence is mounting that long-chain PFAS exposure is associated with reproductive effects (i.e., decrease in fertility, reduced fetal growth and birth weight, pregnancy-induced hypertension and preeclampsia, thyroid hormone disruption during pregnancy, and preterm birth). Evidence from animal models and human cell lines indicates that short-chain PFAS similarly affect reproductive endpoints; however, epidemiological studies are scarce and inconsistent. Although short-chain PFAS have been quantified in drinking water and sediment worldwide, most of these studies did not focus on quantitation of GenX, ADONA, and F53B. There are also many other short-chain PFAS byproducts of manufacturing that have yet to be identified and studied. When sum total concentration of long- and short-chain PFAS are considered, the concentration rises by an order or magnitude or greater, as will the risk of exposure and subsequent reproductive effects.
Emerging lower cost titanium metal powder produced via an electrolytic method has been fully consolidated using spark plasma sintering (SPS) generating microstructures comparable to those observed in ...Ti–6Al–4V PM product. This is the first time powder from an alternative titanium extraction method has been processed via SPS and it is benchmarked with commercial alloys (CP–Ti, Ti–6Al–4V, and Ti–5Al–5V–5Mo–3Cr). The effect of powder feedstock size, morphology, and alloy chemistry on the consolidated density and microstructure is presented. Through a design of experiments (DoE) type approach the effect of SPS processing conditions on these alloy powders, including maximum sintering temperature, pressure, heating rate, and dwell time were investigated. The SPS process is found to be largely insensitive to feedstock size and morphology, although very large or highly porous powder particles are more difficult to fully consolidate. The maximum sintering temperature and pressure have the largest contribution to achieving full consolidation, with higher pressures and temperatures increasing the final density. Increasing heating rate increases the final grain size, despite less time being spent at the higher temperature and it is thought this is due to bypassing the traditional first phase of sintering. This paper shows that SPS is a viable step for a low-cost manufacturing route, for example to produce preform billets to be finished with a one-step forging operation, especially when combined with the possibility of lower cost powder. In the long-term, SPS will allow a significant reduction in the processing cost, contributing to an increased usage of titanium powder feedstock for a range of applications. This is reinforced by the successful large scale production of a 5 kg SPS Ti-6-4 billet, demonstrating the potential industrial scalability of the process, particularly for the aerospace industry.
To investigate how serum neurofilament light (NfL) concentration changes through the course of disease in familial Alzheimer's disease (FAD) and to assess when NfL concentration first increases.
NfL ...was measured using an ultrasensitive immunoassay in 117 serum samples from 61 individuals from families with PSEN1 or APP mutations in a longitudinal study (mean ± SD = 1.9 ± 1.1 visits/patient; inter-visit interval = 1.8 ± 1.1 years). The relationship between NfL concentration and estimated years to/from symptom onset (EYO) was modelled using linear regression, including all time points and robust standard errors to allow for repeated measurements, adjusting for age at visit and sex. Also, for the 27 participants who became symptomatic (during or before the study), NfL concentration was also modelled against known actual years to/from onset (AYO).
There were 15 non-carriers and 46 mutation carriers (21 symptomatic; 25 presymptomatic). NfL concentration was increased (p = 0.045) in mutation carriers compared with non-carriers 15 years prior to expected symptom onset, increasing progressively thereafter. There was a significant inter- and intra-individual variability in the longitudinal pattern of change. Modelling NfL for the 27 mutation carriers with known AYO also showed a progressive increase over time.
There is evidence that serum NfL is increased more than a decade before the onset of clinical symptoms in FAD and rises thereafter. While there is variability in change over time, both within and between individuals, and more work is needed to understand the sources of this variability, serum NfL remains a promising, accessible biomarker of early neurodegeneration in presymptomatic Alzheimer's disease.
Tests sensitive to presymptomatic changes in Alzheimer's disease could be valuable for clinical trials. Accelerated long-term forgetting—during which memory impairment becomes apparent over longer ...periods than usually assessed, despite normal performance on standard cognitive testing—has been identified in other temporal lobe disorders. We assessed whether accelerated long-term forgetting is a feature of presymptomatic autosomal dominant (familial) Alzheimer's disease, and whether there is an association between accelerated long-term forgetting and early subjective memory changes.
This was a cross-sectional study at the Dementia Research Centre, University College London (London, UK). Participants were recruited from a cohort of autosomal dominant Alzheimer's disease families already involved in research at University College London, and had to have a parent known to be affected by an autosomal dominant Alzheimer's disease mutation, and not report any current symptoms of cognitive decline. Accelerated long-term forgetting of three tasks (list, story, and figure recall) was assessed by comparing 7-day recall with initial learning and 30-min recall. 7-day recognition was also assessed. Subjective memory was assessed using the Everyday Memory Questionnaire. The primary outcome measure for each task was the proportion of material retained at 30 min that was recalled 7 days later (ie, 7-day recall divided by 30-min recall). We used linear regression to compare accelerated long-term forgetting scores between mutation carriers and non-carriers (adjusting for age, IQ, and test set) and, for mutation carriers, to assess whether there was an association between accelerated long-term forgetting and estimated years to symptom onset (EYO). Spearman's correlation was used to examine the association between accelerated long-term forgetting and subjective memory scores.
Between Feb 17, 2015 and March 30, 2016, we recruited 35 people. 21 participants were mutation carriers (mean EYO 7·2 years, SD 4·5). Across the three tasks, we detected no differences between carriers and non-carriers for initial learning or 30-min recall. The proportion of material recalled at 7 days was lower in carriers than non-carriers for list (estimated difference in mean for list recall −30·94 percentage points, 95% CI −45·16 to −16·73; p=0·0002), story (–20·10, −33·28 to −6·91; p=0·0048), and figure (–15·41, −26·88 to −3·93; p=0·012) recall. Accelerated long-term forgetting was greater in carriers nearer to their estimated age at onset (p≤0·01 for all three tests). Mutation carriers' 7-day recognition memory was also lower across all tasks (list mean difference −5·80, 95% CI −9·96 to −2·47; p<0·01, story –6·84, −10·94 to −3·37; p<0·01, and figure –17·61, −27·68 to −7·72; p<0·01 recognition). Subjective memory scores were poorer in asymptomatic carriers compared with non-carriers (adjusted difference in means 7·88, 95% CI 1·36 to 14·41; p=0·016), and we found a correlation between accelerated long-term forgetting and subjective memory in mutation carriers.
Accelerated long-term forgetting is an early presymptomatic feature of autosomal dominant Alzheimer's disease, which appears to pre-date other amnestic deficits and might underpin subjective memory complaints in Alzheimer's disease. Accelerated long-term forgetting testing might be useful in presymptomatic Alzheimer's disease trials.
MRC, NIHR, Alzheimer's Research UK, Dementias Platform UK, Dunhill Medical Trust, ERUK, Great Western Research, Health Foundation, Patrick Berthoud Trust.
The healthcare landscape is in a state of constant evolution, presenting both challenges and opportunities. Recent trends, including the departure or retirement of medical professionals, the rise in ...travel and per diem positions, and the expansive growth of healthcare networks, have resulted in a palpable divide within the field. This divide often manifests as a shift from prioritizing patient care and staff well-being toward financial security and operational efficiency and productivity. Amid these ongoing changes, vascular centers possess the potential for a positive distinction that extends beyond their specialization to encompass their approaches to patient care and team dynamics. This article presents a 3-phase strategy for vascular clinicians and centers to consider as they seek to attract and retain top-tier staff, provide exceptional patient care, and attain sustainable growth and financial success.
This paper provides new insight into how the hydraulic transients that occur within drinking water distribution networks can mobilise material adhered to the pipe wall and hence cause unacceptable ...water quality and customer dissatisfaction. Results are reported from extensive, representative, physical experiments covering a wide range of repeatable rapidly accelerating and decelerating hydraulic conditions. Novel time synchronous analysis shows that mobilisation always occurs in the first dynamic surge of the transient; however, differences in the physical processes that govern mobilisation were observed between the two groups of transient type studied. A function to estimate the mobilising force is proposed and applied to the physical experiments performed. The research provides important insights for identifying and understanding the mechanisms and forces induced during transients, vital for ensuring the supply of safe drinking water in operational distribution systems.
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