A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric ...abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer’s disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation P301S/G335D; line 66 (L66) and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296–390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.
Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR (CF transmembrane conductance regulator) ...genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance.
Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity.
Whole-genome sequencing data on 4,248 unique pwCF with pancreatic insufficiency and lung function measures were combined with imputed genotypes from an additional 3,592 patients with pancreatic insufficiency from the United States, Canada, and France. This report describes association of approximately 15.9 million SNPs using the quantitative Kulich normal residual mortality-adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using premodulator lung function data.
Testing included common and rare SNPs, transcriptome-wide association, gene-level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize that these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous genome-wide association study findings. These whole-genome sequencing data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or rare variants were found. Multilocus effects at chr5p13 (
) and chr11p13 (
) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects.
This premodulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and postmodulator genetic studies and the development of novel therapeutics for CF lung disease.
It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve ...understanding of disease mechanisms.
Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 ) relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 ) involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies.
These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.
Abstract
Purpose
to support older people with several healthcare needs in sustaining adequate functioning and independence, more proactive approaches are needed. This purpose of this study is to ...summarise the (cost-) effectiveness of proactive, multidisciplinary, integrated care programmes for older people in Dutch primary care.
Methods design
individual patient data (IPD) meta-analysis of eight clinically controlled trials.
Setting
primary care sector.
Interventions
combination of (i) identification of older people with complex problems by means of screening, followed by (ii) a multidisciplinary integrated care programme for those identified.
Main outcome
activities of daily living, i.e. a change on modified Katz-15 scale between baseline and 1-year follow-up.
Secondary outcomes
quality of life (visual analogue scale 0–10), psychological (mental well-being scale Short Form Health Survey (SF)-36) and social well-being (single item, SF-36), quality-adjusted life years (Euroqol-5dimensions-3level (EQ-5D-3L)), healthcare utilisation and cost-effectiveness.
Analysis
intention-to-treat analysis, two-stage IPD and subgroup analysis based on patient and intervention characteristics.
Results
included were 8,678 participants: median age of 80.5 (interquartile range 75.3; 85.7) years; 5,496 (63.3%) women. On the modified Katz-15 scale, the pooled difference in change between the intervention and control group was −0.01 (95% confidence interval −0.10 to 0.08). No significant differences were found in the other patient outcomes or subgroup analyses. Compared to usual care, the probability of the intervention group to be cost-effective was less than 5%.
Conclusion
compared to usual care at 1-year follow-up, strategies for identification of frail older people in primary care combined with a proactive integrated care intervention are probably not (cost-) effective.
ABSTRACT
We present the first large sample of scintillation arcs in millisecond pulsars (MSPs), analysing 12 sources observed with the Large European Array for Pulsars (LEAP), and the Effelsberg ...100-m telescope. We estimate the delays from multipath propagation, measuring significant correlated changes in scattering time-scales over a 10 yr time span. Many sources show compact concentrations of power in the secondary spectrum, which in PSRs J0613−0200 and J1600−3053 can be tracked between observations, and are consistent with compact scattering at fixed angular positions. Other sources such as PSRs J1643−1224 and J0621+1002 show diffuse, asymmetric arcs which are likely related to phase-gradients across the scattering screen. PSR B1937+21 shows at least three distinct screens which dominate at different times and evidence of varying screen axes or multiscreen interactions. We model annual and orbital arc curvature variations in PSR J0613−0200, providing a measurement of the longitude of ascending node, resolving the sense of the orbital inclination, where our best-fit model is of a screen with variable axis of anisotropy over time, corresponding to changes in the scattering of the source. Unmodelled variations of the screen’s axis of anisotropy are likely to be a limiting factor in determining orbital parameters with scintillation, requiring careful consideration of variable screen properties, or independent very long baseline interferometry (VLBI) measurements. Long-term scintillation studies such as this serve as a complementary tool to pulsar timing, to measure a source of correlated noise for pulsar timing arrays, solve pulsar orbits, and to understand the astrophysical origin of scattering screens.
ABSTRACT
We report on the detection of quasi-periodic micro-structure in three millisecond pulsars (MSPs), PSRs J1022+1001, J2145−0750, and J1744−1134, using high time resolution data acquired with ...the Large European Array for Pulsars at a radio frequency of 1.4 GHz. The occurrence rate of quasi-periodic micro-structure is consistent among pulses with different peak flux densities. Using an auto-correlation analysis, we measure the periodicity and width of the micro-structure in these three pulsars. The detected micro-structure from PSRs J1022+1001 and J1744−1134 is often highly linearly polarized. In PSR J1022+1001, the linear polarization position angles of micro-structure pulses are in general flat with a small degree of variation. Using these results, we further examine the frequency and rotational period dependency of micro-structure properties established in previous work, along with the angular beaming and temporal modulation models that explain the appearance of micro-structure. We also discuss a possible link of micro-structure to the properties of some of the recently discovered fast radio bursts which exhibit a very similar emission morphology.
To investigate practical fitness to drive mobility scooters, comparing visually impaired participants with healthy controls.
Between-subjects design.
Forty-six visually impaired (13 with very low ...visual acuity, 10 with low visual acuity, 11 with peripheral field defects, 12 with multiple visual impairment) and 35 normal-sighted controls.
Participants completed a practical mobility scooter test-drive, which was recorded on video. Two independent occupational therapists specialized in orientation and mobility evaluated the videos systematically.
Approximately 90% of the visually impaired participants passed the driving test. On average, participants with visual impairments performed worse than normal-sighted controls, but were judged sufficiently safe. In particular, difficulties were observed in participants with peripheral visual field defects and those with a combination of low visual acuity and visual field defects.
People with visual impairment are, in practice, fit to drive mobility scooters; thus visual impairment on its own should not be viewed as a determinant of safety to drive mobility scooters. However, special attention should be paid to individuals with visual field defects with or without a combined low visual acuity. The use of an individual practical fitness-to-drive test is advised.
ABSTRACT
Observations of radio relics at very high frequency (>10 GHz) can help to understand how particles age and are (re-)accelerated in galaxy cluster outskirts and how magnetic fields are ...amplified in these environments. In this work, we present new single-dish 18.6 GHz Sardinia Radio Telescope and 14.25 GHz Effelsberg observations of the well-known northern radio relic of CIZA J2242.8+5301. We detected the relic which shows a length of ∼1.8 Mpc and a flux density equal to $S_{14.25\, \mathrm{ GHz}}=(9.5\pm 3.9)\, \mathrm{ mJy}$ and $S_{18.6\, \mathrm{ GHz}}=(7.67\pm 0.90)\, \mathrm{ mJy}$ at 14.25 and 18.6 GHz, respectively. The resulting best-fitting model of the relic spectrum from 145 MHz to 18.6 GHz is a power-law spectrum with spectral index α = 1.12 ± 0.03: no evidence of steepening has been found in the new data presented in this work. For the first time, polarization properties have been derived at 18.6 GHz, revealing an averaged polarization fraction of $\sim\! 40{{\ \rm per\ cent}}$ and a magnetic field aligned with the ’filaments’ or ’sheets’ of the relic.
The Santorini caldera has been the focus of several large explosive eruptions in the past, the last of which occurred in the early 1950s. The volcano was dormant until early 2011 when increasing ...number of earthquakes accompanied significant intra-caldera uplift. This seismic activity was recorded by 8 temporary as well as 19 permanent seismic stations that were installed on Santorini and nearby islands after the onset of the unrest. Using data from January 2011 until June 2012 we calculated accurate relative locations for 490 events utilizing both catalog and waveform cross-correlation differential travel times of P- and S-phases. The distribution of relocated events exhibits a large cluster between Thera and Nea Kameni islands along the caldera rim, suggesting the activation of a preexisting ring fault. All hypocenters are located between 5 and 11km resulting in a sharp cutoff of seismicity above and below these depths. We also used P and S travel times in order to calculate average Vp/Vs ratios and estimated shear wave splitting parameters (fast direction φ, delay time δt) for events within the shear wave window. The Vp/Vs ratios at several stations exhibit a majority of values consistently below the regional one (~1.77). Their temporal variations can be explained as periods of gas influx and depletion in the upper crust beneath the caldera. A comparison of δt for a number of earthquake doublets shows a progressive decrease of delay times towards the end of the unrest probably as a result of cracks closing owing to stress relaxation. The seismological observations presented here are compatible with petrological models that suggest the existence of a deep (11–14km) dacitic magma reservoir and a shallower (<5km) rhyolitic magma chamber.
•During 2011 Santorini caldera exhibited signs of unrest.•In total 490 earthquakes were accurately relocated delineating a ring-fault.•Variations of Vp/Vs ratios signify periods of gas influx/depletion within cracks.•Decreasing delay splitting times during the unrest indicate closing of cracks.•Hypocenters support the view of one deep and one shallower magma reservoir.
We are conducting a Jansky Very Large Array (VLA) Ka-band (8 mm and 1 cm) and C-band (4 cm and 6.4 cm) survey of all known protostars in the Perseus Molecular Cloud, providing resolution down to ...~0".06 and ~0".35 in the Ka band and C band, respectively. Here we present first results from this survey that enable us to examine the source NGC 1333 IRAS2A in unprecedented detail and resolve it into a protobinary system separated by 0".621 + or - 0".006 (~143 AU) at 8 mm, 1 cm, and 4 cm. These two sources (IRAS2A VLA1 and VLA2) are likely driving the two orthogonal outflows known to originate from IRAS2A. The brighter source IRAS2A VLA1 is extended perpendicular to its outflow in the VLA data, with a deconvolved size of 07055 (~13 AU), possibly tracing a protostellar disk. The recently reported candidate companions (IRAS2A MM2 and MM3) are not detected in either our VLA data, Combined Array for Research in Millimeter-wave Astronomy (CARMA) 1.3 mm data, or Submillimeter Array (SMA) 850 mu m data. SMA CO (J = 3 arrow right 2), CARMA CO (J = 2 arrow right 1), and lower-resolution CARMA CO (J = 1 arrow right 0) observations are used to examine the outflow origins and the nature of the candidate companions to IRAS2A VLA1. The CO (J = 3 arrow right 2) and (J = 2 arrow right 1) data show that IRAS2A MM2 is coincident with a bright CO emission spot in the east-west outflow, and IRAS2A MM3 is within the north-south outflow. In contrast, IRAS2A VLA2 lies at the east-west outflow symmetry point. We propose that IRAS2A VLA2 is the driving source of the east-west outflow and a true companion to IRAS2A VLA1, whereas IRAS2A MM2 and MM3 may not be protostellar.
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