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Lewy body dementias (LBD) are the second most common dementia. Several genes have been associated with LBD, but little is known about their contributions to LBD pathophysiology. Each gene may transcribe multiple RNA, and LBD brains have extensive RNA splicing dysregulation. Hence, we completed the first transcriptome-wide transcript-level differential expression analysis of post-mortem LBD brains for gaining more insights into LBD molecular pathology that are essential for facilitating discovery of novel therapeutic targets and biomarkers for LBD. We completed transcript-level quantification of next-generation RNA-sequencing data from post-mortem anterior cingulate (ACC) and dorsolateral prefrontal cortices (DLPFC) of people with pathology-verified LBD (LBD = 14; Controls = 7) using Salmon. We identified differentially expressed transcripts (DET) using edgeR and investigated their functional implications using DAVID. We performed transcriptome-wide alternative splicing analysis using DRIMseq. We identified 74 DET in ACC and 96 DET in DLPFC after Benjamini-Hochberg false discovery rate (FDR) correction (5%). There were 135 and 98 FDR-corrected alternatively spliced genes in ACC and DLPFC of LBD brains, respectively. Identified DET may contribute to LBD pathology by altering DNA repair, apoptosis, neuroplasticity, protein phosphorylation, and regulation of RNA transcription. We confirm widespread alternative splicing and absence of chronic neuroinflammation in LBD brains. Transcript-level differential expression analysis can reveal specific DET that cannot be detected by gene-level expression analyses. Therapeutic and diagnostic biomarker potential of identified DET, especially those from TMEM18, MICB, MPO, and GABRB3, warrant further investigation. Future LBD blood-based biomarker studies should prioritise measuring the identified DET in small extracellular vesicles.
Highly portable and accessible MRI technology will allow researchers to conduct field-based MRI research in community settings. Previous guidance for researchers working with fixed MRI does not address the novel ethical, legal, and societal issues (ELSI) of portable MRI (pMRI). Our interdisciplinary Working Group (WG) previously identified 15 core ELSI challenges associated with pMRI research and recommended solutions. In this article, we distill those detailed recommendations into a Portable MRI Research ELSI Checklist that offers practical operational guidance for researchers contemplating using this technology.
To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.
Design:
Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.
Setting:
Community settings and care homes in 26 UK centers.
Participants:
People with probable or possible Alzheimer’s disease and agitation.
Measurements:
Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.
Results:
One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.
Conclusions:
On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.
Among bilinguals, language-related variables such as first and second language proficiency and balance may be related to important cognitive and academic outcomes, but approaches to characterizing these variables are inconsistent, particularly among at-risk samples of children. The current study employed comprehensive language assessment of English and Spanish language skills and contrasted various approaches to the characterization of language among at-risk ELs in middle school (N = 161). Specifically, we contrasted variable-centered and person-centered approaches, and convergence between objective and self-report measures. Findings support a two-factor structure of English and Spanish language skills in this population, three profiles of students (balanced, moderately unbalanced-higher Spanish, and very unbalanced-higher English), convergence between variable-centered and person-centered approaches, and mixed support for subjective indices of usage. Results provide a foundation from which to examine the roles of L1 and L2 proficiency as well as balance in important cognitive and academic outcomes in this at-risk and understudied population.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Most of the African countries are undergoing a complex nutrition and epidemiologic transition associated with a rapid increase in the prevalence of diverse non-communicable diseases. Despite this alarming situation, the still limited and fragmented resources available in Africa impede the implementation of effective action plans to tackle the current and projected diet–disease burden. In order to address these common needs and challenges, the African Union is increasingly supporting continental approaches and strategies as reflected in the launching of the Agenda 2063 and the African regional nutrition strategy 2015–2025, among others. To assure the successful implementation of pan-African nutritional and health initiatives, cost-effective approaches considering similarities/disparities in economy, regional integration, development and nutritional aspects between countries are needed. In the absence of pre-existing models, we reviewed regional economic integration and nutritional indicators (n 13) available in international organisations databases or governmental agencies websites, for fifty-two African countries. These indicators were used to map the countries according to common languages (e.g. Arabic, English, French, Portuguese), development status (e.g. human development index), malnutrition status (e.g. obesity) and diet (e.g. staples predominantly based on either cereals or tubers). The review of the indicators showed that there exist similarities between African countries that can be exploited to benefit the continent with cross-national experiences in order to avoid duplication of efforts in the implementation of future pan-African health studies. In addition, including present and future nutrition surveillance programmes in Africa into national statistical systems might be cost-effective and sustainable in the longer term.
The use of artificial neural networks (ANNs) as a classifier of digital spectra is investigated. Using both simulated and real data, it is shown that neural networks can be trained to discriminate between the spectra of different classes of active galactic nucleus (AGN) with realistic sample sizes and signal-to-noise ratios. By working in the Fourier domain, neural nets can classify objects without knowledge of their redshifts.
Quasi-simultaneous optical/near-IR photometry is presented for a sample of 37 luminous optically selected QSOs drawn from the Large Bright QSO Survey. Most of the QSOs have decreased in brightness since discovery; this is expected in flux-limited samples. The continuum shape of most of the QSOs can be represented by a power law of the form F(v) ∝ v−0·3, but a few have softer (redder) continuum slopes.
Francis & Hewett (1993) identified two 10 Mpc-scale regions of the high-redshift universe that were seemingly very overdense in neutral hydrogen. Subsequent observations showed that at least one of these gas-rich regions enveloped a cluster of galaxies at redshift 2 ·38. We present improved observations of the three background QSOs with sightlines passing within a few Mpc of this cluster of galaxies. All three QSOs show strong neutral hydrogen absorption at the cluster redshift, suggesting that this cluster (and perhaps all high-redshift clusters) may be surrounded by a ~5 Mpc-scale region containing ~10 12 Mʘ of neutral gas. We show that if most high-redshift clusters are surrounded by such regions, the gas must be in the form of many small (<1 kpc), dense (> 0·03 cm ˗3 ) clouds, each of mass <10 6 Mʘ . These clouds are themselves probably gathered into >20 kpc-sized clumps, which may be galaxy halos or protogalaxies. If this gas exists, it will be partially photoionised by the UV background. We predict the diffuse Lyα flux from this photoionisation, and place observational limits on its intensity.
We present quasi-simultaneous multi-colour optical/near-IR photometry for 157 radio selected quasars, forming an unbiassed sub-sample of the Parkes Flat-Spectrum Sample. Data are also presented for 12 optically selected QSOs, drawn from the Large Bright QSO Survey. The spectral energy distributions of the radio- and optically-selected sources are quite different. The optically selected QSOs are all very similar: they have blue spectral energy distributions curving downwards at shorter wavelengths. Roughly 90% of the radio-selected quasars have roughly power-law spectral energy distributions, with slopes ranging from Fv∝v0 to Fv∝v−2. The remaining 10% have spectral energy distributions showing sharp peaks: these are radio galaxies and highly reddened quasars. Four radio sources were not detected down to magnitude limits of H ∼ 19·6. These are probably high redshift (z > 3) galaxies or quasars. We show that the colours of our red quasars lie close to the stellar locus in the optical: they will be hard to identify in surveys such as the Sloan Digital Sky Survey. If near-IR photometry is added, however, the red power-law sources can be clearly separated from the stellar locus: IR surveys such as 2MASS should be capable of finding these sources on the basis of their excess flux in the K-band.
We study the contents of an apparent void in the distribution of Lyα emitting galaxies at redshift 2.38. We show that this void is not empty, but contains a damped Lyα absorption-line system, seen in absorption against background QSO 2138-4427. Imaging does not reveal any galaxy associated with this absorption-line system, but it contains metals (Fe/H ∼ −1.3), and its large velocity range (∼180 km s−1) implies a significant mass.
Microlensing observations may give us the first nano-arcsecond scale information about the structure of quasars. I review what is currently known about quasars on these scales, highlighting the principal uncertainties. I cover both the continuum emission and the broad line region. I conclude that little is firmly known about the structure of quasars.
The use of role-playing exercises in the teaching of university astronomy and physics can enliven lectures, deepen student understanding and dramatically increase the level of classroom interaction. A series of case studies is presented, illustrating the nature of this technique, its advantages and some of its pitfalls. Several ready-to-run exercises are included.
We measure the spectral properties of a representative sub-sample of 187 quasars, drawn from the Parkes Half-Jansky, Flat-radio-spectrum Sample (PHFS). Quasars with a wide range of rest-frame optical/UV continuum slopes are included in the analysis: their colours range over 2 < B–K < 7. We present composite spectra of red and blue sub-samples of the PHFS quasars, and tabulate their emission line properties.
The median Hβ and [O III] emission line equivalent widths of the red quasar sub-sample are a factor of ten weaker than those of the blue quasar sub-sample. No significant differences are seen between the equivalent width distributions of the C IV, C III] and Mg II lines. Both the colours and the emission line equivalent widths of the red quasars can be explained by the addition of a featureless red synchrotron continuum component to an otherwise normal blue quasar spectrum. The red synchrotron component must have a spectrum at least as red as a power-law of the form Fυ α υ−2.8. The relative strengths of the blue and red components span two orders of magnitude at rest-frame 500 nm. The blue component is weaker relative to the red component in low optical luminosity sources. This suggests that the fraction of accretion energy going into optical emission from the jet is greater in lowluminosity quasars. This correlation between colour and luminosity may be of use in cosmological distance scale work.
This synchrotron model does not, however, fit ˜10% of the quasars, which have both red colours and high equivalent width emission lines.We hypothesise that these red, strong-lined quasars have intrinsically weak Big Blue Bumps.
There is no discontinuity in spectral properties between the BL Lac objects in our sample and the other quasars. BL Lac objects appear to be the red, low equivalent width tail of a continuous distribution. The synchrotron emission component only dominates the spectrum at longer wavelengths, so existing BL Lac surveys will be biased against high redshift objects. This will affect measurements of BL Lac evolution.
The blue PHFS quasars have significantly higher equivalent width C IV, Hβ and [O III] emission than a matched sample of optically selected QSOs.
The Two Micron All-Sky Survey (2MASS) has provided a uniform photometric catalog to search for previously unknown red active galactic nuclei (AGN) and Quasi-Stellar Objects (QSOs).We have extended the search to the southern equatorial sky by obtaining spectra for 1182 AGN candidates using the six degree field (6dF) multifibre spectrograph on the UK Schmidt Telescope. These were scheduled as auxiliary targets for the 6dF Galaxy Redshift Survey. The candidates were selected using a single color cut of J – Ks > 2 to Ks ≲ 15.5 and a galactic latitude of lbl > 30°. 432 spectra were of sufficient quality to enable a reliable classification. 116 sources (∼27%) were securely classified as type I AGN, 20 as probable type I AGN, and 57 as probable type II AGN. Most of them span the redshift range 0.05 < z < 0.5 and only 8 (∼6%) were previously identified as AGN or QSOs. Our selection leads to a significantly higher AGN identification rate amongst local galaxies (>20%) than in any previous (mostly blue-selected) galaxy survey. A small fraction of the type I AGN could have their optical colors reddened by optically thin dust with AV < 2 mag relative to optically selected QSOs. A handful show evidence of excess far-infrared (IR) emission. The equivalent width (EW) and color distributions of the type I and II AGN are consistent with AGN unified models. In particular, the EW of the [Oiii] emission line weakly correlates with optical–near-IR color in each class of AGN, suggesting anisotropic obscuration of the AGN continuum. Overall, the optical properties of the 2MASS red AGN are not dramatically different from those of optically-selected QSOs. Our near-IR selection appears to detect the most near-IR luminous QSOs in the local universe to z≃0.6 and provides incentive to extend the search to deeper near-IR surveys.