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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.
Threat sensitivity, an individual difference construct reflecting variation in responsiveness to threats of various types, predicts physiological reactivity to aversive stimuli and shares heritable variance with anxiety disorders in adults. However, no research has been conducted yet with youth to examine the heritability of threat sensitivity or evaluate the role of genetic versus environmental influences in its relations with mental health problems. The current study addressed this gap by evaluating the psychometric properties of a measure of this construct, the 20-item Trait Fear scale (TF-20), and examining its phenotypic and genotypic correlations with different forms of psychopathology in a sample of 346 twin pairs (121 monozygotic), aged 9–14 years. Analyses revealed high internal consistency and test-retest reliability for the TF-20. Evidence was also found for its convergent and discriminant validity in terms of phenotypic and genotypic correlations with measures of fear-related psychopathology. By contrast, the TF-20’s associations with depressive conditions were largely attributable to environmental influences. Extending prior work with adults, current study findings provide support for threat sensitivity as a genetically-influenced liability for phobic fear disorders in youth.
Anhedonia characterizes major depressive episodes in bipolar depression and is associated with more severe illness/poor prognosis. These post hoc analyses assess effect of cariprazine 1.5 and 3 mg/d on anhedonia symptoms in patients with bipolar I depression.
Methods
Data were pooled from 3 randomized, double-blind, placebo-controlled bipolar I depression trials in cariprazine. Cariprazine 1.5 and 3 mg/d versus placebo were evaluated in patient subgroups stratified by median baseline MADRS anhedonia score (higher anhedonia=score ≥19; lower anhedonia=score <19). Outcomes included mean change from baseline to week 6 in MADRS total and anhedonia factor score (sum of apparent sadness, reported sadness, concentration, lassitude, and inability to feel items). The proportion of patients with week 6 anhedonia factor response (≥50% improvement from baseline) was also determined. Changes from baseline were analyzed using a mixed-effect model for repeated measures.
Results
There were 760 patients in the higher anhedonia subgroup (placebo=249, cariprazine: 1.5 mg/d=261; 3 mg/d=250) and 623 patients in the lower anhedonia subgroup (placebo=211, cariprazine: 1.5 mg/d=200; 3 mg/d=212). Mean baseline MADRS total score was higher in the higher anhedonia subgroup (total=33.6) than in the lower anhedonia subgroup (total=27.6). Change from baseline to week 6 in MADRS total score was greater for both cariprazine doses versus placebo in the higher anhedonia subgroup (least squares mean difference [LSMD] and 95% confidence interval [CI]: 1.5 mg/d=-3.01 [-4.84, -1.19], P=.0012; 3 mg/d: -3.26 [-5.12, -1.40], P=.0006); in the lower anhedonia subgroup, cariprazine 1.5 mg/d was statistically significant versus placebo (-2.61 [-4.28, -0.93], P=.0024). In the higher anhedonia subgroup at week 6, change from baseline in anhedonia factor score was significant versus placebo for both cariprazine doses (1.5 mg/d=-1.97 [-3.13, -0.81], P=.0009; 3 mg/d=-2.07 [-3.26, -0.89], P=.0006); in the lower subgroup, the difference was significant versus placebo for cariprazine 1.5 mg/d (-1.70 [-2.77, -0.62], P=.0021). After adjusting for changes in other depressive symptoms, LSMDs versus placebo in the anhedonia factor score remained significant for cariprazine 1.5 mg/d (-1.21 [-2.05, -0.36], P=.0052) and 3 mg/d (-1.00 [-1.86, -0.14], P=.0233) in the higher anhedonia subgroup, and for 1.5 mg/d (-1.06 [-1.92, -0.19], P=.0164) in the lower subgroup. In the higher anhedonia subgroup, rates of anhedonia factor response were greater versus placebo (31.7%) for cariprazine 1.5 mg/d (44.8%, P=.0028) and 3 mg/d (45.6%, P=.0019); in the lower subgroup, response rates were 39.3% for placebo, 48.0% for 1.5 mg/d, and 46.7% for 3 mg/d. Adverse events in ≥5% cariprazine and twice placebo were nausea, akathisia, restlessness, and EPS.
Importance
Those with bipolar depression and anhedonia cariprazine demonstrated a potent antidepressant and antianhedonic effect in higher/lower anhedonia subgroups.
Funding
AbbVie
This data was previously presented at the European College of Neuropsychopharmacology (ECNP) Congress; Barcelona, Spain; October 7 – 10, 2023.
Anhedonia, a multidimensional domain including the reduced ability to experience pleasure, is a core diagnostic symptom of major depressive disorder (MDD) and a common residual symptom. In patients with MDD, anhedonia has been associated with poor treatment outcomes, suicide and reduced functioning and quality of life. This post-hoc analysis of data from a phase 3 trial (NCT03738215) evaluated the efficacy of adjunctive cariprazine (CAR) treatment on anhedonia symptoms in patients with MDD.
Methods
Patients with MDD and inadequate response to ongoing antidepressant therapy (ADT) were randomized to CAR 1.5 mg/d + ADT, CAR 3 mg/d + ADT, or placebo + ADT for 6 weeks of double-blind treatment. Post hoc analyses evaluated the change from baseline to Week 6 in Montgomery–Åsberg Depression Rating Scale (MADRS) total score, MADRS anhedonia subscale score (items: 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]), and MADRS anhedonia item 8 in the overall modified intent-to-treat (mITT) population and in subgroups of patients with baseline MADRS anhedonia item 8 score of ≥4 or baseline anhedonia subscale score of ≥18. Least square (LS) mean change from baseline to Week 6 was analyzed using a mixed-effects model for repeated measures.
Results
There were 751 patients in the mITT population (CAR + ADT: 1.5 mg/d=250, 3 mg/d=252; placebo + ADT=249). At baseline, 508 (67.6%) patients had MADRS anhedonia item 8 scores ≥4, and 584 (77.8%) had MADRS anhedonia subscale scores ≥18. In the overall mITT population, LS mean change from baseline to Week 6 in anhedonia subscale score was significantly greater for CAR 1.5 mg/d + ADT (-8.4) and CAR 3 mg/d + ADT (-7.9) than for placebo + ADT (-6.8; both P<.05). The LS mean change from baseline in MADRS individual item 8 was also significantly greater for CAR 1.5 mg/d + ADT (-1.7) vs placebo + ADT (-1.3; P=.0085). In both subgroups of patients with baseline anhedonia, CAR 1.5 mg/d + ADT was associated with significantly greater reduction in MADRS total score, MADRS anhedonia subscale score, and MADRS item 8 score compared with placebo + ADT (all P<.05). In the CAR 3 mg/d + ADT group, significantly greater reductions vs placebo + ADT were observed for MADRS total score and MADRS anhedonia subscale score in the subgroup of patients with baseline anhedonia subscale scores ≥18 (both P<.05).
Importance
Adjunctive treatment with CAR was associated with a reduction in symptoms of anhedonia relative to adjunctive placebo in patients with MDD and inadequate response to ADT alone. In subgroups of patients with moderate-to-severe anhedonia at baseline, CAR + ADT demonstrated greater improvements than placebo + ADT in overall depressive symptoms and symptoms of anhedonia. These results suggest that adjunctive CAR treatment may be effective for improving symptoms of anhedonia in patients with MDD who have symptoms of anhedonia.
Patients with progressive neurologic illness still lack access to quality palliative care services. Barriers to the comprehensive provision of neuropalliative care include gaps in palliative care education. To address this barrier, a novel international model of neuropalliative care education e-learning program was launched in 2022.
Methods
This is a qualitative study on the self-reported learning outcomes and educational gains of participants of a neuropalliative care e-learning course.
Results
Thematic analysis shows changes in the participants’ perceptions of neuropalliative care and several specific educational gains. After attending the course, participants recognized neuropalliative care as a multiprofessional and interdisciplinary effort requiring more than medical knowledge and disease-specific treatment skills. They gained understanding of the complexity of prognosis in neurological diseases, as well as ethical concepts as the basis to approach difficult decisions. Valuing the needs of patients and caregivers, as well as honest and open communication were recognized as key components of the caring process. In particular, providing emotional support and building relationships to enhance the spiritual component of care were avidly discussed as essential nonmedical treatment options.
Significance of results
E-learning courses are helping to close the gaps in healthcare professionals’ knowledge and skills about neuropalliative care.
Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk.
Methods
Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11–36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones.
Results
Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20).
Conclusions
Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.
The UK National Health Service (NHS) has committed £250 million toward the deployment of artificial intelligence (AI). One compelling use case involves patient-recorded cardiac waveforms, interpreted in real-time by AI to predict the presence of common, clinically actionable cardiovascular diseases. Waveforms are recorded by a handheld device applied by the patient at home in a self-administered “smart” stethoscope examination. The deployment of such a novel home-based screening program, combining hardware, AI, and a cloud-based administrative platform, raises ethical challenges, including considerations of equity, agency, data rights, and, ultimately, responsibility for safe, effective, and trustworthy implementation. The meaningful use of these devices without direct clinician involvement transfers the responsibility for conducting a diagnostic test with potentially life-threatening consequences onto the patient. The use of patients’ own smartphones and internet connections should also meet the data security standards expected of NHS activity. Additional complexity arises from rapidly evolving questions around data “ownership,” according to European law a term applicable only to the patient from whom the data originate, when “controllership” of patient data falls to commercial entities. Clarifying the appropriate consent mechanism requires the reconciliation of commercial, patient, and health system rights and obligations. Oriented to this real-world clinical setting, this chapter evaluates the ethical considerations of extending home-based, self-administered AI diagnostics in the NHS. It discusses the complex field of stakeholders, including patients, academia, and industry, all ultimately beholden to governmental entities. It proposes a multi-agency approach to balance permissive regulation and deployment (to align with the speed of innovation) against ethical and statutory obligations to safeguard public health. It further argues that a strong centralized approach to carefully evaluating and integrating home-based AI diagnostics is necessary to balance the considerations outlined above. The chapter concludes with specific, transferable policy recommendations applicable to NHS stewardship of this novel diagnostic pathway.
Tissue inhibitor of metalloproteinases 2 (TIMP2) is produced peripherally, crosses the blood-brain barrier, and improves synaptic plasticity and hippocampal-dependent cognition in aged mice; however, the role of TIMP2 in human cognitive aging is unclear. We examined associations of circulating TIMP2 levels in blood with a known plasticity-inducing behavior, physical activity, and cognitive functioning among older adults along the Alzheimer’s disease continuum.
Participants and Methods:
Participants included 84 community-dwelling older adults (meanage = 78.8; 57% female; 82% cognitively normal; 14% MCI; 4% mild dementia; 35% PET Aß+) enrolled in the UC San Francisco Memory and Aging Center. All participants completed 30 days of observational FitbitTM monitoring to quantify physical activity (average daily steps), as well as a comprehensive in-person visit including blood draw (proteins assayed on SOMAscan platform), [18F]AV-45 positron emission tomography (PET) to quantify brain beta-amyloid (centiloids), and neuropsychological assessment. Composite cognitive z-scores were calculated for memory (California Verbal Learning Test-II [CVLT-II] and Benson Figure Recall), semantic processing (animal fluency and Boston Naming Test), and executive functioning (digits backwards span, Stroop inhibition, modified trail making test, lexical fluency, and design fluency). Multiple linear regression examined TIMP2 as a function of physical activity, covarying for age and PET centiloids. Additional regression models separately examined cognitive z-scores as a function of TIMP2, covarying for age, sex, education, PET centiloids, and body mass index (BMI).
Results:
TIMP2 was not significantly correlated with age, sex, education, or PET centiloids (ps > 0.05); however, TIMP2 was negatively correlated with BMI (r = -0.23, p = 0.036). Greater average daily steps related to higher levels of TIMP2 (b = 0.30, 95%CI = 0.04-0.55, p = 0.022). TIMP2 also related to better semantic processing (b = 0.28, 95%CI = 0.04-0.51, p = 0.021) and executive functioning (b = 0.26, 95%CI = 0.03-0.49, p = 0.028). TIMP2 did not significantly relate to memory (p > 0.05).
Conclusions:
Greater physical activity was associated with higher concentrations of blood factor TIMP2, which in turn related to better cognitive functioning independent of Alzheimer’s disease pathology burden. These results support previous mouse models by broadly replicating relationships between TIMP2 and cognition in humans, while also uniquely demonstrating an association between TIMP2 and physical activity, a modifiable protective factor in both typical and diseased cognitive aging. Our domain-specific results, however, suggest that benefits of TIMP2 in humans may involve a broader neuroanatomical network than the hippocampal-specific effects previously shown in mice. Although exact mechanisms of TIMP2 need further examination, TIMP2 is known to be enriched in human umbilical cord plasma, has been shown to be involved in cell-growth promoting activities, and may relate to increased neural plasticity in older age. Further examination of TIMP2 and other novel blood-based proteins as potential therapeutic targets for improved cognitive aging, including in the presence of Alzheimer’s disease, is warranted.
Females outperform males on verbal memory tests across the lifespan. Females also exhibit greater Alzheimer’s disease (AD) pathology at preclinical stages and faster atrophy and memory decline during disease progression. Synaptic factors influence the accumulation of AD proteins and may underpin cognitive resilience against AD, though their role in sex-related cognitive and brain aging is unknown. We tested interactive effects of sex and genetic variation in SNAP-25, which encodes a presynaptic protein that is dysregulated in AD, on cognition and AD-related biomarkers in cognitively unimpaired older adults.
Participants and Methods:
Participants included a discovery cohort of 311 cognitively unimpaired older adults (age mean [range]=70 [44-100]; 56% female; education mean=17.3 years; 24% APOE-e4+), and an independent, demographically-comparable replication cohort of 82 cognitively unimpaired older adults. All participants completed neurological examination, informant interview (CDR=0), neuropsychological testing, and blood draw. Participants were genotyped for the SNAP-25 rs105132 (T→C) single-nucleotide polymorphism via Sequenom (discovery cohort) or Omni 2.5M (replication cohort). In vitro models show the C-allele is associated with increased SNAP-25 expression compared to T/T genotype. A subset of the discovery cohort completed structural MRI (n=237) and florbetapir Aβ-PET (n=97). Regression analyses across cohorts examined the interaction of sex and SNAP-25 genotype (T/T homozygotes [53% prevalence] vs. C-carriers [47% prevalence]) on cognitive z-scores (verbal memory, visual memory, executive function, language), adjusting for age, education, APOE-e4, and APOE-e4 x sex. Discovery cohort models also examined sex-dependent effects of SNAP-25 on temporal lobe volumes and Aβ-PET positivity.
Results:
SNAP-25 T/T vs. C-carriers did not differ on demographics or APOE-e4 status across cohorts or within sexes. Sex interacted with SNAP-25 to predict verbal memory (p=.024) and language (p=.008) in the discovery cohort, with similar verbal memory differences observed in the replication cohort. In sex-stratified analyses, C-carriers exhibited better verbal memory than T/T carriers among females (d range: 0.41 to 0.64, p range: .008 to .046), but not males (d range: 0.03 to 0.12, p range: .499 to .924). In SNAP-25-stratified analyses, female verbal memory advantages were larger among C-carriers (d range: 0.74 to 0.89, p range: <.001 to .034) than T/T (d range: 0.13 to 0.36, p range: .022 to .682). Sex also interacted with SNAP-25 to predict Aβ-PET positivity (p=.046) such that female C-carriers exhibited the lowest prevalence of Aβ-PET positivity (13%) compared to other groups (23% to 35%). C-carriers exhibited larger temporal lobe volumes across sex, yet this effect only reached statistical significance among females (females: d=0.41, p=.018; males: d=0.26, p=.179). In post-hoc analyses, larger temporal lobe volumes were selectively associated with better verbal memory in female C-carriers (β=0.36, p=.026; other groups: |βs|<0.10, ps>.538).
Conclusions:
Among clinically normal older adults, we demonstrate female-specific advantages of carrying the SNAP-25 rs105132 C-allele across cognitive, neural, and molecular markers of AD. The rs105132 C-allele putatively reflects higher endogenous levels of SNAP-25. Our findings suggest a female-specific pathway of cognitive and neural resistance, whereby higher genetically-driven expression of SNAP-25 may reduce likelihood of amyloid plaque formation and support verbal memory, possibly through fortification of temporal lobe structure.
The intensity of an antibiotic stewardship intervention to achieve clinical impact is not known. We conducted a multisite dissemination project of an intervention to reduce treatment of asymptomatic bacteriuria (ASB) and studied: (1) the association between implementation metrics and clinical outcomes and (2) the cost of implementation.
Design/Setting/Participants:
A central site facilitated a multimodality intervention to decrease unnecessary urine cultures and antibiotic treatment in patients with ASB at 4 Veterans Affairs medical centers.
Methods:
The intervention consisted of a decision support aid algorithm and interactive teaching cases that provided in the moment audit and feedback on how to manage ASB. Implementation outcomes included minutes spent in intervention delivery, number of healthcare professionals reached, and number of sessions delivered. Clinical outcomes included days of antibiotic therapy (DOT), length of antibiotic therapy (LOT), and number of urine cultures ordered per 1000 bed days. Personnel reported weekly time logs.
Results:
Minutes spent in intervention delivery were inversely correlated with two clinical outcomes, DOT (R −0.3, P = .04) and LOT (R −0.3, P = .02). Number of healthcare professionals reached and number of sessions delivered were not correlated with clinical outcomes of DOT (R –0.003, P = .98, R = −0.059, P = .69) or LOT (R +0.073, P = .62, R −0.102, P = .49). Physician champions spent an average of 3.8% of effort on the intervention. The implementation cost was USD 22,299/year per site on average.
Conclusions:
The amount of time local teams spent in delivery of an antibiotic stewardship intervention was correlated with the desired decrease in antibiotic use. Implementing this successful antibiotic stewardship intervention required minimal time.
Patients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.
Methods
Post hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).
Results
Of the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).
Conclusions
In this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.
Maser polarization changes during a pulsation in the CSE of an AGB star are related in a complicated way to the magnetic field structure. 43 GHz SiO maser transitions are useful for polarization study because of their relatively simple Zeeman splitting structure and their location. This work uses 3D maser simulation to investigate the effect of the magnetic field on maser polarization with different directions. The results show that linear polarization depends on the magnetic direction while circular polarization is less significant. The EVPA changes through π/2 at an angle of around 50 degrees, approximately the Van Vleck angle. The EVPA rotation result from 3D maser simulation is consistent with results from 1D simulations, and may explain the 90 degree change of the EVPA within a single cloud in the observational cases of TX Cam and R Cas.
The “right to repair” movement highlights opportunities to reduce health care costs and promote public health resilience through increased competition in the way in which medical devices are serviced and updated over their lifespan. We review legislative and legal facets of third-party repair of medical devices, and conclude with specific recommendations to help this market function more efficiently to the benefit of patients and health care systems.
The purpose of this study was to examine possible pathways by which genetic risk associated with externalizing is transmitted in families. We used molecular data to disentangle the genetic and environmental pathways contributing to adolescent externalizing behavior in a sample of 1,111 adolescents (50% female; 719 European and 392 African ancestry) and their parents from the Collaborative Study on the Genetics of Alcoholism. We found evidence for genetic nurture such that parental externalizing polygenic scores were associated with adolescent externalizing behavior, over and above the effect of adolescents’ own externalizing polygenic scores. Mediation analysis indicated that parental externalizing psychopathology partly explained the effect of parental genotype on children’s externalizing behavior. We also found evidence for evocative gene-environment correlation, whereby adolescent externalizing polygenic scores were associated with lower parent–child communication, less parent–child closeness, and lower parental knowledge, controlling for parental genotype. These effects were observed among participants of European ancestry but not African ancestry, likely due to the limited predictive power of polygenic scores across ancestral background. These results demonstrate that in addition to genetic transmission, genes influence offspring behavior through the influence of parental genotypes on their children’s environmental experiences, and the role of children’s genotypes in shaping parent–child relationships.
MeerTime is a five-year Large Survey Project to time pulsars with MeerKAT, the 64-dish South African precursor to the Square Kilometre Array. The science goals for the programme include timing millisecond pulsar (MSPs) to high precision (${<} 1 \unicode{x03BC} \mathrm{s}$) to study the Galactic MSP population and to contribute to global efforts to detect nanohertz gravitational waves with the International Pulsar Timing Array (IPTA). In order to plan for the remainder of the programme and to use the allocated time most efficiently, we have conducted an initial census with the MeerKAT ‘L-band’ receiver of 189 MSPs visible to MeerKAT and here present their dispersion measures, polarisation profiles, polarisation fractions, rotation measures, flux density measurements, spectral indices, and timing potential. As all of these observations are taken with the same instrument (which uses coherent dedispersion, interferometric polarisation calibration techniques, and a uniform flux scale), they present an excellent resource for population studies. We used wideband pulse portraits as timing standards for each MSP and demonstrated that the MeerTime Pulsar Timing Array (MPTA) can already contribute significantly to the IPTA as it currently achieves better than $1\,\unicode{x03BC}\mathrm{s}$ timing accuracy on 89 MSPs (observed with fortnightly cadence). By the conclusion of the initial five-year MeerTime programme in 2024 July, the MPTA will be extremely significant in global efforts to detect the gravitational wave background with a contribution to the detection statistic comparable to other long-standing timing programmes.
Brain research in Europe is a rapidly evolving field, and increasingly at the forefront of science. Although considerable amounts of knowledge and innovative approaches have been generated, the translation into new health interventions is hindered by excessive fragmentation. Effective and efficient collaboration and cooperation among the various initiatives are often identified as a key success factor to achieve brain research full impact. EBRA fully responds to these needs by bringing together the various stakeholders and major brain research initiatives, at European level and beyond. EBRA creates the conditions for real and effective cross fertilisation, dialogue, building consensus and exploiting research potential. On the operational level, EBRA facilitates the emergence of research projects in specific areas in active clusters. A cluster is understood as a research community that can be directed towards basic research, clinical research and/or methodological approaches under a common topic and disease area within brain research. EBRA support clusters to: 1. Consolidate or expand further the research community expand their community, 2. Engage with policy makers and other relevant stakeholders, 3. Build consensus on various issues (research priorities, research roadmap, data sharing, etc.), 4. Promote links with existing research infrastructures, 5. Increase the visibility of the research community through communication and dissemination activities, 6. Coordinate the development of position/consensus papers, white papers, guidelines, meeting reports and/or other cluster outcomes. EBRA currently has 6 existing clusters: EPICLUSTER, Prevention of Severe Mental Disorders (PSMD)-cluster, TRISOMY21-cluster, BRAINFOOD-cluster., PREMOS-cluster and ECIB-cluster.
Brain research in Europe is a rapidly evolving field, and increasingly at the forefront of science. Although considerable amounts of knowledge and innovative approaches have been generated, the translation into new health interventions is hindered by excessive fragmentation. Effective and efficient collaboration and cooperation among the various initiatives are often identified as a key success factor to achieve brain research full impact. EBRA fully responds to these needs by bringing together the various stakeholders and major brain research initiatives, at European level and beyond. EBRA creates the conditions for real and effective cross fertilisation, dialogue, building consensus and exploiting research potential. At the strategic level, EBRA acts by fostering alignment and better coordination of research strategies across European and global brain initiatives. Therefore, an overview of the scale and scope of brain research activities funded in the EU framework programme and the funding initiatives of JPND, NEURON and HBP has been created. The results of the mapping exercise then underpinned the development of a Shared European Brain Research Agenda (SEBRA). The SEBRA focuses on research opportunities and research gaps to be addressed in the field, and priorities for action in the short- and long-term. It integrates pre-existing documents as well as expert (i.e., researchers, neurologists/psychiatrists, patient representatives) input that has been collected through surveys and in a dedicated expert workshop. The SEBRA will be used to provide recommendations on future areas for excellent, innovative, and translational research comprising those for maximized cooperation, reduced overlap, and fragmentation.
Potential loss of energetic ions including alphas and radio-frequency tail ions due to classical orbit effects and magnetohydrodynamic instabilities (MHD) are central physics issues in the design and experimental physics programme of the SPARC tokamak. The expected loss of fusion alpha power due to ripple-induced transport is computed for the SPARC tokamak design by the ASCOT and SPIRAL orbit-simulation codes, to assess the expected surface heating of plasma-facing components. We find good agreement between the ASCOT and SPIRAL simulation results not only in integrated quantities (fraction of alpha power loss) but also in the spatial, temporal and pitch-angle dependence of the losses. If the toroidal field (TF) coils are well-aligned, the SPARC edge ripple is small (0.15–0.30 %), the computed ripple-induced alpha power loss is small (${\sim } 0.25\,\%$) and the corresponding peak surface power density is acceptable ($244\ \textrm{kW}\ \textrm {m}^{-2}$). However, the ripple and ripple-induced losses increase strongly if the TF coils are assumed to suffer increasing magnitudes of misalignment. Surface heat loads may become problematic if the TF coil misalignment approaches the centimetre level. Ripple-induced losses of the energetic ion tail driven by ion cyclotron range of frequency (ICRF) heating are not expected to generate significant wall or limiter heating in the nominal SPARC plasma scenario. Because the expected classical fast-ion losses are small, SPARC will be able to observe and study fast-ion redistribution due to MHD including sawteeth and Alfvén eigenmodes (AEs). SPARC's parameter space for AE physics even at moderate $Q$ is shown to reasonably overlap that of the demonstration power plant ARC (Sorbom et al., Fusion Engng Des., vol. 100, 2015, p. 378), and thus measurements of AE mode amplitude, spectrum and associated fast-ion transport in SPARC would provide relevant guidance about AE behaviour expected in ARC.
The SPARC tokamak is a critical next step towards commercial fusion energy. SPARC is designed as a high-field ($B_0 = 12.2$ T), compact ($R_0 = 1.85$ m, $a = 0.57$ m), superconducting, D-T tokamak with the goal of producing fusion gain $Q>2$ from a magnetically confined fusion plasma for the first time. Currently under design, SPARC will continue the high-field path of the Alcator series of tokamaks, utilizing new magnets based on rare earth barium copper oxide high-temperature superconductors to achieve high performance in a compact device. The goal of $Q>2$ is achievable with conservative physics assumptions ($H_{98,y2} = 0.7$) and, with the nominal assumption of $H_{98,y2} = 1$, SPARC is projected to attain $Q \approx 11$ and $P_{\textrm {fusion}} \approx 140$ MW. SPARC will therefore constitute a unique platform for burning plasma physics research with high density ($\langle n_{e} \rangle \approx 3 \times 10^{20}\ \textrm {m}^{-3}$), high temperature ($\langle T_e \rangle \approx 7$ keV) and high power density ($P_{\textrm {fusion}}/V_{\textrm {plasma}} \approx 7\ \textrm {MW}\,\textrm {m}^{-3}$) relevant to fusion power plants. SPARC's place in the path to commercial fusion energy, its parameters and the current status of SPARC design work are presented. This work also describes the basis for global performance projections and summarizes some of the physics analysis that is presented in greater detail in the companion articles of this collection.
A subcommittee of the Hawaii Governor's Joint Task Force on Rat Lungworm Disease developed preliminary guidelines for the diagnosis and treatment of neuroangiostrongyliasis (NAS) in 2018 (Guidelines, 2018). This paper reviews the main points of those guidelines and provides updates in areas where our understanding of the disease has increased. The diagnosis of NAS is described, including confirmation of infection by real-time polymerase chain reaction (RTi-PCR) to detect parasite DNA in the central nervous system (CNS). The treatment literature is reviewed with recommendations for the use of corticosteroids and the anthelminthic drug albendazole. Long-term sequelae of NAS are discussed and recommendations for future research are proposed.