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Impairments in social interaction are common symptoms of dementia and necessitate the use of validated neuropsychological instruments to measure social cognition. We aim to investigate the Hinting Task – Dutch version (HT-NL), which measures the ability to infer intentions behind indirect speech to assess Theory of Mind, in dementia.
Method:
Sixty-six patients with dementia, of whom 22 had behavioral variant frontotemporal dementia (bvFTD), 21 had primary progressive aphasia, and 23 had Alzheimer’s disease (AD), and 99 healthy control participants were included. We examined the HT-NL’s psychometric properties, including internal consistency, between-group differences using analyses of covariance with Bonferroni-adjusted post hoc comparisons, discriminative ability and concurrent validity using the area under the receiver operating characteristic curve (AUC), and construct validity using Spearman rank correlations with other cognitive tests.
Results:
Internal consistency was acceptable (Cronbach’s α = 0.74). All patient groups scored lower on the HT-NL than the control group. Patients with bvFTD scored lower than patients with AD dementia. The HT-NL showed excellent discriminative ability (AUC = 0.83), comparable to a test of emotion recognition (ΔAUC = 0.03, p = .67). The HT-NL correlated significantly with a test for emotion recognition (r = .45), and with measures of memory and language (r = [.31, .40]), but not with measures of information processing speed, executive functioning, or working memory (r = [.00, .17]). Preliminary normative data are provided.
Conclusions:
The HT-NL is a psychometrically sound and valid instrument and is useful for identifying Theory of Mind impairments in patients with dementia.
Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.
Methods
T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).
Results
PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).
Conclusions
PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.
We present the first radio–continuum detection of the circumstellar shell around the well-known WN8 type Wolf-Rayet star WR16 at 943.5 MHz using the Australian Square Kilometre Array Pathfinder (ASKAP) Evolutionary Map of the Universe (EMU) survey. At this frequency, the shell has a measured flux density of 72.2$\pm$7.2 mJy. Using previous Australia Telescope Compact Array (ATCA) measurements at 2.4, 4.8, and 8.64 GHz, as well as the Evolutionary Map of the Universe (EMU) observations of the star itself, we determine a spectral index of $\alpha\,=\,+0.74\pm0.02$, indicating thermal emission. We propose that the shell and star both exhibit thermal emission, supported by the its appearance in near-infrared and H$\alpha$ observations. The latest Gaia parallax is used to determine a distance of 2.28$\pm$0.09 kpc. This star is well known for its surrounding circular nebulosity, and using the distance and an angular diameter of $8.^{\prime}42$, we determine the shell size to be 5.57$\pm$0.22 pc. We use the Gaia proper motion (PM) of WR16 to determine peculiar velocities of the star as $V_{\alpha}(pec) =$ –45.3$\pm$5.4 km s$^{-1}$ and $V_{\delta}(pec) =$ 22.8$\pm$4.7 km s$^{-1}$, which indicates that the star is moving in a north-west direction, and translates to a peculiar tangential velocity to be 50.7$\pm$6.9 km s$^{-1}$. We also use these proper motion (PM) to determine the shell’s origin, estimate an age of $\sim 9500\pm 1300$ yr, and determine its average expansion velocity to be $280\pm40$ km s$^{-1}$. This average expansion velocity suggests that the previous transitional phase is a Luminous Blue Variable (LBV) phase, rather than a Red Super Giant (RSG) phase. We also use the measured flux at 943.5 MHz to determine a mass-loss rate of $1.753\times 10^{-5}\,{\rm M}_\odot\,$yr$^{-1}$, and use this to determine a lower-limit on ionising photons of $N_{UV} \gt 1.406\times 10^{47}\,\textit{s}^{-1}$.
Background: The complement component C5 inhibitor, ravulizumab, is approved in Canada for the treatment of adults with AQP4-Ab+ NMOSD. Updated efficacy and safety results from the ongoing CHAMPION-NMOSD (NCT04201262) trial are reported. Methods: Participants received IV-administered, weight-based dosing of ravulizumab, with loading on day 1 and maintenance doses on day 15 and every 8 weeks thereafter. Following a primary treatment period (PTP; up to 2.5 years), patients could enter a long-term extension (LTE). Outcome measures included safety, time to first adjudicated on-trial relapse (OTR), risk reduction, and disability scores. Results: 56/41 patients entered/completed the LTE as of June 14, 2024. Median follow-up was 170.3 weeks (186.6 patient-years). No patients experienced an OTR. 94.8% (55/58 patients) had stable or improved Hauser Ambulation Index scores. 89.7% (52/58 patients) had no clinically important worsening in Expanded Disability Status Scale scores. Treatment-emergent adverse events (98.4%) were predominantly mild and unrelated to ravulizumab. Serious adverse events occurred in 25.9% of patients. Two cases of meningococcal infection occurred during the PTP, and none in the LTE. One unrelated death (cardiovascular) occurred during the LTE. Conclusions: Ravulizumab demonstrated long-term clinical benefit in AQP4-Ab+ NMOSD relapse prevention while maintaining or improving disability measures, with no new safety concerns.
Background: Attitudes toward aging influence many health outcomes, yet their relationship with cognition and Alzheimer’s disease (AD) remains unknown. To better understand their impact on cognition and AD risk, we examined whether positive attitudes predict better cognition and diminished risk on AD biomarkers. Methods: A subsample of older adults with a family history of AD (n=54; women=39) from the McGill PREVENT-AD cohort participated in this study. Participants completed the Attitudes to Ageing Questionnaire (AAQ-24), providing three scores: psychosocial loss, psychological growth and physical change. Participants underwent cognitive testing (Rey Auditory Verbal Learning Test, RAVLT; Delis-Kaplan Executive Function System-Color Word Interference Test, D-KEFS-CWIT), and AD blood-based biomarker assessments (p-tau217, Aβ42/40). Regression models tested associations, adjusting for covariates (age, sex, education, depression, APOE4), and were Bonferroni corrected. Results: Positive attitudes were associated with better recall and recognition (RAVLT) and improved word reading, colour naming, switching, and inhibition (D-KEFS-CWIT) (p<0.00077), while negative attitudes showed the opposite pattern. Negative attitudes were correlated with lower Aβ42/40 ratios, while positive attitudes were linked to lower p-tau217 (p<0.0167). Conclusions: These findings demonstrate that positive attitudes predict better cognition and a lower risk profile for AD biomarkers, suggesting that life outlook may be an early disease feature or a risk factor.
High density should drive greater parasite exposure. However, evidence linking density with infection generally uses density proxies or measures of population size, rather than measures of individuals per space within a continuous population. We used a long-term study of wild sheep to link within-population spatiotemporal variation in host density with individual parasite counts. Although four parasites exhibited strong positive relationships with local density, these relationships were mostly restricted to juveniles and faded in adults. Furthermore, one ectoparasite showed strong negative relationships across all age classes. In contrast, population size – a measure of global density – had limited explanatory power, and its effects did not remove those of spatial density, but were distinct. These results indicate that local and global density can exhibit diverse and contrasting effects on infection within populations. Spatial measures of within-population local density may provide substantial additional insight to temporal metrics based on population size, and investigating them more widely could be revealing.
Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health’s National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial’s duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator’s institution. The Initial Consultation process focuses on the study’s scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.
Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine.
Aims
Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes.
Method
We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial (N = 742). Participants were 60 years old or older with TRD. Participants were either (a) randomised to antidepressant augmentation with aripiprazole (2.5–15 mg), bupropion (150–450 mg) or lithium (target serum drug level 0.6 mmol/L) or (b) switched to bupropion (150–450 mg) or nortriptyline (target serum drug level 80–120 ng/mL). Treatment duration was 10 weeks. The two main outcomes of this analysis were (a) symptom improvement, defined as change in Montgomery–Asberg Depression Rating Scale (MADRS) scores from baseline to week 10 and (b) remission, defined as MADRS score of 10 or less at week 10.
Results
Of the 742 participants, 480 were randomised to augmentation and 262 to switching. The number of adequate previous antidepressant trials was a significant moderator of depression symptom improvement (b = −1.6, t = −2.1, P = 0.033, 95% CI [−3.0, −0.1], where b is the coefficient of the relationship (i.e. effect size), and t is the t-statistic for that coefficient associated with the P-value). The effect was similar across all augmentation strategies. No other putative moderators were significant.
Conclusions
Augmenting was superior to switching antidepressants only in older patients with fewer than three previous antidepressant trials. This suggests that other intervention strategies should be considered following three or more trials.
Recent changes to US research funding are having far-reaching consequences that imperil the integrity of science and the provision of care to vulnerable populations. Resisting these changes, the BJPsych Portfolio reaffirms its commitment to publishing mental science and advancing psychiatric knowledge that improves the mental health of one and all.
The Australian SKA Pathfinder (ASKAP) offers powerful new capabilities for studying the polarised and magnetised Universe at radio wavelengths. In this paper, we introduce the Polarisation Sky Survey of the Universe’s Magnetism (POSSUM), a groundbreaking survey with three primary objectives: (1) to create a comprehensive Faraday rotation measure (RM) grid of up to one million compact extragalactic sources across the southern $\sim50$% of the sky (20,630 deg$^2$); (2) to map the intrinsic polarisation and RM properties of a wide range of discrete extragalactic and Galactic objects over the same area; and (3) to contribute interferometric data with excellent surface brightness sensitivity, which can be combined with single-dish data to study the diffuse Galactic interstellar medium. Observations for the full POSSUM survey commenced in May 2023 and are expected to conclude by mid-2028. POSSUM will achieve an RM grid density of around 30–50 RMs per square degree with a median measurement uncertainty of $\sim$1 rad m$^{-2}$. The survey operates primarily over a frequency range of 800–1088 MHz, with an angular resolution of 20” and a typical RMS sensitivity in Stokes Q or U of 18 $\mu$Jy beam$^{-1}$. Additionally, the survey will be supplemented by similar observations covering 1296–1440 MHz over 38% of the sky. POSSUM will enable the discovery and detailed investigation of magnetised phenomena in a wide range of cosmic environments, including the intergalactic medium and cosmic web, galaxy clusters and groups, active galactic nuclei and radio galaxies, the Magellanic System and other nearby galaxies, galaxy halos and the circumgalactic medium, and the magnetic structure of the Milky Way across a very wide range of scales, as well as the interplay between these components. This paper reviews the current science case developed by the POSSUM Collaboration and provides an overview of POSSUM’s observations, data processing, outputs, and its complementarity with other radio and multi-wavelength surveys, including future work with the SKA.
The quasi-geostrophic two-layer model is a widely used tool to study baroclinic instability in the ocean. One instability criterion for the inviscid two-layer model is that the potential vorticity (PV) gradient must change sign between the layers. This has a well-known implication if the model includes a linear bottom slope: for sufficiently steep retrograde slopes, instability is suppressed for a flow parallel to the isobaths. This changes in the presence of bottom friction as well as when the PV gradients in the layers are not aligned. We derive the generalised instability condition for the two-layer model with non-zero friction and arbitrary mean flow orientation. This condition involves neither the friction coefficient nor the bottom slope; even infinitesimally weak bottom friction destabilises the system regardless of the bottom slope. We then examine the instability characteristics as a function of varying slope orientation and magnitude. The system is stable across all wavenumbers only if friction is absent and if the planetary, topographic and stretching PV gradients are aligned. Strong bottom friction decreases the growth rates but also alters the dependence on bottom slope. In conclusion, the often mentioned stabilisation by steep bottom slopes in the two-layer model holds only in very specific circumstances, thus probably plays only a limited role in the ocean.
Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.
Methods
We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).
Results
Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.
Conclusions
Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.
Inflammation and infections such as malaria affect concentrations of many micronutrient biomarkers and hence estimates of nutritional status. We aimed to assess the relationship between malaria infection and micronutrient biomarker concentrations in pre-school children (PSC), school-age children (SAC) and women of reproductive age (WRA) in Malawi and examine the potential role of malarial immunity on the relationship between malaria and micronutrient biomarkers. Data from the 2015/2016 Malawi micronutrient survey were used. The associations between current or recent malaria infection, detected by rapid diagnostic test and concentration of serum ferritin, soluble transferrin receptor (sTfR), zinc, serum folate, red blood cell folate and vitamin B12 were estimated using multivariable linear regression. Factors related to malarial immunity including age, altitude and presence of hemoglobinopathies were examined as effect modifiers. Serum ferritin, sTfR and zinc were adjusted for inflammation using the BRINDA method. Malaria infection was associated with 68 % (95 % CI 51, 86), 28 % (18, 40) and 34 % (13, 45) greater inflammation-adjusted ferritin in PSC, SAC and WRA, respectively (P < 0·001 for each). In PSC, the positive association was stronger in younger children, high altitude and children who were not carriers of the sickle cell trait. In PSC and SAC, sTfR was elevated (+ 25 % (16, 29) and + 15 % (9, 22) respectively, P < 0·001). Serum folate and erythrocyte folate were elevated in WRA with malaria (+ 18 % (3, 35) and + 11 % (1, 23), P = 0·01 and P = 0·003 respectively). Malaria affects the interpretation of micronutrient biomarker concentrations, and examining factors related to malarial immunity may be informative.
Compulsive-like rigidity may be associated with hyposerotonergia and increased kynurenine (KYN) pathway activity. Conversion of tryptophan (TRP) to KYN, which may contribute to hyposerotonergia, is bolstered by inflammation and could be related to altered gut microbiota composition. Here, we studied these mechanisms in a naturalistic animal model of compulsive-like behavioural rigidity, that is, large nest building (LNB) in deer mice (Peromyscus sp.).
Methods:
Twenty-four (24) normal nest building (NNB) and 24 LNB mice (both sexes) were chronically administered either escitalopram (a selective serotonin reuptake inhibitor; 50 mg/kg/day) or a control solution, with nesting behaviour analysed before and after intervention. After endpoint euthanising, frontal cortices and striata were analysed for TRP and its metabolites, plasma for microbiota-derived lipopolysaccharide (LPS) and its binding protein (lipopolysaccharide binding protein), and stool samples for microbial DNA.
Results:
LNB, but not NNB, decreased after escitalopram exposure. At baseline, LNB was associated with reduced frontal cortical TRP concentrations and hyposerotonergia that was unrelated to altered KYN pathway activity. In LNB mice, escitalopram significantly increased frontal-cortical and striatal TRP without altering serotonin concentrations. Treated LNB, compared to untreated LNB and treated NNB mice, had significantly reduced plasma LPS as well as a microbiome showing a decreased inferred potential to synthesise short-chain fatty acids and degrade TRP.
Conclusions:
These findings support the role of altered serotonergic mechanisms, inflammatory processes, and gut microbiome involvement in compulsive-like behavioural rigidity. Our results also highlight the importance of gut-brain crosstalk mechanisms at the level of TRP metabolism in the spontaneous development of such behaviour.
Epidemiological evidence shows a concerning rise in youth mental health difficulties over the past three decades. Most evidence, however, comes from countries in Europe or North America, with far less known about changes in other global regions. This study aimed to compare adolescent mental health across two population-based cohorts in the UK, and two population-based cohorts in Pelotas, Brazil.
Methods
Four population-based cohorts with identical mental health measures were compared. In Brazil, these included the 1993 Pelotas Birth Cohort and the 2004 Pelotas Birth Cohort. In the UK, cohorts included the Avon Longitudinal Study of Parents and Children, and the Millennium Cohort Study. Mental health was measured in all cohorts using identical, parent-rated scores from the Strengths and Difficulties Questionnaire (SDQ). This was assessed in both countries over approximately the same time periods, when adolescents were aged 11 (2004 vs 2015 in Brazil, and 2003 vs 2012 in the UK), with follow-up analyses focused on outcomes in later adolescence.
Results
Mental health problems were higher in the UK for adolescents born in the early 2000s compared to those born in the early 1990s. In Pelotas, the opposite was found, whereby problems were lower for adolescents born in the early 2000s compared to those born in the early 1990s. Despite these promising reductions in mental health problems in Pelotas over time, SDQ scores remained higher in Pelotas compared to the UK.
Conclusions
Our study represents the first to compare two population-based cohorts in the UK, and two population-based cohorts in Pelotas, Brazil, to understand how mental health problems have changed over time across the two settings. Our findings provide the most up-to-date insight into population-level rates of youth mental health problems in Pelotas, and shed novel insight into how these have changed over the last two decades in comparison to the UK. In doing so, our study provides a tentative first step towards understanding youth mental health over time at a more global scale, and presents a valuable opportunity to examine putative contributors to differences across time.
Quantum field theory predicts a nonlinear response of the vacuum to strong electromagnetic fields of macroscopic extent. This fundamental tenet has remained experimentally challenging and is yet to be tested in the laboratory. A particularly distinct signature of the resulting optical activity of the quantum vacuum is vacuum birefringence. This offers an excellent opportunity for a precision test of nonlinear quantum electrodynamics in an uncharted parameter regime. Recently, the operation of the high-intensity Relativistic Laser at the X-ray Free Electron Laser provided by the Helmholtz International Beamline for Extreme Fields has been inaugurated at the High Energy Density scientific instrument of the European X-ray Free Electron Laser. We make the case that this worldwide unique combination of an X-ray free-electron laser and an ultra-intense near-infrared laser together with recent advances in high-precision X-ray polarimetry, refinements of prospective discovery scenarios and progress in their accurate theoretical modelling have set the stage for performing an actual discovery experiment of quantum vacuum nonlinearity.
In many species with encapsulated larval development, the larvae play an active role in hatching. However, the factors that control when the larvae hatch from each egg-capsule within an egg-mass are largely unknown. Advanced egg-masses of the gastropod Crepipatella peruviana were used to determine the hatching time of capsules from each egg-mass. After each female was detached, the egg-mass was also removed from the substrate and all capsules were then counted and measured. All capsules were examined to determine the time of hatching and the order in which capsules hatched from each egg-mass. Larvae were collected from each hatched egg-capsule and the number, size and weight of larvae from each capsule were determined. After 50–60% of the capsules from each egg-mass had hatched, the same characteristics of the remaining unhatched larvae from sister capsules were documented. Larvae were found to have hatched when they reached a size of 354 ± 22 μm (n = 245). Larvae from capsules within the same egg-mass hatched over a period of up to 12-days. The order of hatching in capsules from the same egg-mass was determined by larval content: capsules with fewer larvae and smaller capsules with heavier larvae hatched first. The hatching from one capsule in any given egg-mass did not induce the hatching of its sister capsules. Furthermore, hatching also occurred successfully in the mother absence, suggesting that this process is largely or completely controlled by the encapsulated larvae, although a possible maternal role in synchronizing hatching cannot be excluded.
Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
This paper gives a method for determining a sample size that will achieve a prespecified bound on confidence interval width for the interrater agreement measure, κ. The same results can be used when a prespecified power is desired for testing hypotheses about the value of kappa. An example from the literature is used to illustrate the methods proposed here.