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Stress and depression have a reciprocal relationship, but the neural underpinnings of this reciprocity are unclear. We investigated neuroimaging phenotypes that facilitate the reciprocity between stress and depressive symptoms.
In total, 22 195 participants (52.0% females) from the population-based UK Biobank study completed two visits (initial visit: 2006–2010, age = 55.0 ± 7.5 [40–70] years; second visit: 2014–2019; age = 62.7 ± 7.5 [44–80] years). Structural equation modeling was used to examine the longitudinal relationship between self-report stressful life events (SLEs) and depressive symptoms. Cross-sectional data were used to examine the overlap between neuroimaging correlates of SLEs and depressive symptoms on the second visit among 138 multimodal imaging phenotypes.
Longitudinal data were consistent with significant bidirectional causal relationship between SLEs and depressive symptoms. In cross-sectional analyses, SLEs were significantly associated with lower bilateral nucleus accumbal volume and lower fractional anisotropy of the forceps major. Depressive symptoms were significantly associated with extensive white matter hyperintensities, thinner cortex, lower subcortical volume, and white matter microstructural deficits, mainly in corticostriatal-limbic structures. Lower bilateral nucleus accumbal volume were the only imaging phenotypes with overlapping effects of depressive symptoms and SLEs (B = −0.032 to −0.023, p = 0.006–0.034). Depressive symptoms and SLEs significantly partially mediated the effects of each other on left and right nucleus accumbens volume (proportion of effects mediated = 12.7–14.3%, p < 0.001−p = 0.008). For the left nucleus accumbens, post-hoc seed-based analysis showed lower resting-state functional connectivity with the left orbitofrontal cortex (cluster size = 83 voxels, p = 5.4 × 10−5) in participants with high v. no SLEs.
The nucleus accumbens may play a key role in the reciprocity between stress and depressive symptoms.
We argue that i-frame interventions can and do increase support for systemic reforms, and s-frame interventions should be pursued in parallel to address key societal issues. Without accompanying i-frame interventions, s-frame interventions can fail. We offer an operant conditioning framework to generate positive spillover effects. Behavioral scientists should develop i-frame interventions that enhance, rather than compete with, s-frame interventions.
The University of Kansas Cancer Center (KU Cancer Center) initiated an engagement program to leverage the lived experience of individuals and families with cancer. KU Cancer Center faculty, staff, and patient partners built an infrastructure to achieve a patient-designed, patient-led, and research-informed engagement program called Patient and Investigator Voices Organizing Together (PIVOT). This special communication offers an engagement roadmap that can be replicated, scaled, and adopted at other cancer centers and academic health systems. PIVOT demonstrates that collaboration among academic leaders, investigators, and people with a lived experience yields a patient-centered, vibrant environment that enriches the research enterprise.
Despite replicated cross-sectional evidence of aberrant levels of peripheral inflammatory markers in individuals with major depressive disorder (MDD), there is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies.
To assess associations between plasma levels of pro-inflammatory markers and treatment response to escitalopram and adjunctive aripiprazole in adults with MDD.
In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10– 20 mg daily for 8 weeks. Responders continued on escitalopram while non-responders received adjunctive aripiprazole 2–10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers – C-reactive protein, Interleukin (IL)-1β, IL-6, IL-17, Interferon gamma (IFN)-Γ, Tumour Necrosis Factor (TNF)-α, and Chemokine C–C motif ligand-2 (CCL-2) - measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyses to assess associations between inflammatory markers and treatment response.
Pre-treatment levels of IFN-Γ and CCL-2 were significantly higher in escitalopram non-responders compared to responders. Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.
Pre-treatment levels of IFN-Γ and CCL-2 were predictive of response to escitalopram. Increasing levels of these pro-inflammatory markers may predict non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
We present the third data release from the Parkes Pulsar Timing Array (PPTA) project. The release contains observations of 32 pulsars obtained using the 64-m Parkes “Murriyang” radio telescope. The data span is up to 18 years with a typical cadence of 3 weeks. This data release is formed by combining an updated version of our second data release with ∼ 3 years of more recent data primarily obtained using an ultra-wide-bandwidth receiver system that operates between 704 and 4032 MHz. We provide calibrated pulse profiles, flux-density dynamic spectra, pulse times of arrival, and initial pulsar timing models. We describe methods for processing such wide-bandwidth observations, and compare this data release with our previous release.
The deformable wing structure can change its aerodynamic shape according to the change of flight mission and flight environment, so as to obtain better lift-drag, stability and control characteristics, which is considered as one of the future research directions of aviation technology. Considering the current technology maturity and reliability, a gradient corrugated fin is designed to realise the bending deformation of the wing. The structure of the skin is optimised to keep the skin smooth during deformation. In addition, a progressive push and pull rod is proposed to drive the wing deformation, and the fluid-structure interaction simulation is carried out for the wing deformation. At the same time, the changes of wing aerodynamic characteristics under different angles of leading and trailing edges and different push rod action schemes are analysed. Finally, a dry wind tunnel simulation test of the designed progressive flexible variable bending wing is carried out. The results of fluid-structure interaction simulation and dry wind tunnel test show that the progressive flexible variable bending wing proposed in this paper has a simple and reliable structure and remarkable deformation effect. It has advantages in increasing lift and reducing drag, ensuring high lift-drag ratio and providing wing trim moment. The deformable wing dry wind tunnel test platform designed by this method is structurally reliable, easy to operate, and can accurately reflect the influence of wing deformation on its aerodynamic force, which provides a verification means for the development of the design method and the design of practical aircraft in the future.
Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
Large gatherings of people on cruise ships and warships are often at high risk of COVID-19 infections. To assess the transmissibility of SARS-CoV-2 on warships and cruise ships and to quantify the effectiveness of the containment measures, the transmission coefficient (β), basic reproductive number (R0), and time to deploy containment measures were estimated by the Bayesian Susceptible-Exposed-Infected-Recovered model. A meta-analysis was conducted to predict vaccine protection with or without non-pharmaceutical interventions (NPIs). The analysis showed that implementing NPIs during voyages could reduce the transmission coefficients of SARS-CoV-2 by 50%. Two weeks into the voyage of a cruise that begins with 1 infected passenger out of a total of 3,711 passengers, we estimate there would be 45 (95% CI:25-71), 33 (95% CI:20-52), 18 (95% CI:11-26), 9 (95% CI:6-12), 4 (95% CI:3-5), and 2 (95% CI:2-2) final cases under 0%, 10%, 30%, 50%, 70%, and 90% vaccine protection, respectively, without NPIs. The timeliness of strict NPIs along with implementing strict quarantine and isolation measures is imperative to contain COVID-19 cases in cruise ships. The spread of COVID-19 on ships was predicted to be limited in scenarios corresponding to at least 70% protection from prior vaccination, across all passengers and crew.
Human monkeypox (mpox) virus is a viral zoonosis that belongs to the Orthopoxvirus genus of the Poxviridae family, which presents with similar symptoms as those seen in human smallpox patients. Mpox is an increasing concern globally, with over 80,000 cases in non-endemic countries as of December 2022. In this review, we provide a brief history and ecology of mpox, its basic virology, and the key differences in mpox viral fitness traits before and after 2022. We summarize and critique current knowledge from epidemiological mathematical models, within-host models, and between-host transmission models using the One Health approach, where we distinguish between models that focus on immunity from vaccination, geography, climatic variables, as well as animal models. We report various epidemiological parameters, such as the reproduction number, R0, in a condensed format to facilitate comparison between studies. We focus on how mathematical modelling studies have led to novel mechanistic insight into mpox transmission and pathogenesis. As mpox is predicted to lead to further infection peaks in many historically non-endemic countries, mathematical modelling studies of mpox can provide rapid actionable insights into viral dynamics to guide public health measures and mitigation strategies.
It is unknown how much variation in adult mental health problems is associated with differences between societal/cultural groups, over and above differences between individuals.
To test these relative contributions, a consortium of indigenous researchers collected Adult Self-Report (ASR) ratings from 16 906 18- to 59-year-olds in 28 societies that represented seven culture clusters identified in the Global Leadership and Organizational Behavioral Effectiveness study (e.g. Confucian, Anglo). The ASR is scored on 17 problem scales, plus a personal strengths scale. Hierarchical linear modeling estimated variance accounted for by individual differences (including measurement error), society, and culture cluster. Multi-level analyses of covariance tested age and gender effects.
Across the 17 problem scales, the variance accounted for by individual differences ranged from 80.3% for DSM-oriented anxiety problems to 95.2% for DSM-oriented avoidant personality (mean = 90.7%); by society: 3.2% for DSM-oriented somatic problems to 8.0% for DSM-oriented anxiety problems (mean = 6.3%); and by culture cluster: 0.0% for DSM-oriented avoidant personality to 11.6% for DSM-oriented anxiety problems (mean = 3.0%). For strengths, individual differences accounted for 80.8% of variance, societal differences 10.5%, and cultural differences 8.7%. Age and gender had very small effects.
Overall, adults' self-ratings of mental health problems and strengths were associated much more with individual differences than societal/cultural differences, although this varied across scales. These findings support cross-cultural use of standardized measures to assess mental health problems, but urge caution in assessment of personal strengths.
Common adolescent psychiatric symptoms cluster into two dominant domains: internalizing and externalizing. Both domains are linked to self-esteem, which serves as a protective factor against a wide range of internalizing and externalizing problems. This study examined trends in US adolescents' self-esteem and externalizing symptoms, and their correlation, by sex and patterns of time use.
Using Monitoring the Future data (N = 338 896 adolescents, grades:8/10/12, years:1991–2020), we generated six patterns of time use using latent profile analysis with 17 behavior items (e.g. sports participation, parties, paid work). Groups were differentiated by high/low engagement in sports and either paid work or high/low peer socialization. Within each group, we mapped annual, sex-stratified means of (and correlation between) self-esteem and externalizing factors. We also examined past-decade rates of change for factor means using linear regression and mapped proportions with top-quartile levels of poor self-esteem, externalizing symptoms, or both.
We found consistent increases in poor self-esteem, decreases in externalizing symptoms, and a positive correlation between the two across nearly all activity groups. We also identified a relatively constant proportion of those with high levels of both in every group. Increases in poor self-esteem were most pronounced for female adolescents with low levels of socializing, among whom externalizing symptoms also increased.
Rising trends in poor self-esteem are consistent across time use groups, as is the existence of a group facing poor self-esteem and externalizing symptoms. Effective interventions for adolescents' poor self-esteem/co-occurring symptoms are needed broadly, but especially among female adolescents with low peer socialization.
Imbalance and gait disturbances are common in patients with vestibular schwannoma (VS) and can result in significant morbidity. Current methods for quantitative gait analysis are cumbersome and difficult to implement. Here, we use custom-engineered instrumented insoles to evaluate the gait of patients diagnosed with VS.
Twenty patients with VS were recruited from otology, neurosurgery, and radiation oncology clinics at a tertiary referral center. Functional gait assessment (FGA), 2-minute walk test (2MWT), and uneven surface walk test (USWT) were performed. Custom-engineered instrumented insoles, equipped with an 8-cell force sensitive resistor (FSR) and a 9-degree-of-freedom inertial measurement unit (IMU), were used to collect stride-by-stride spatiotemporal gait parameters, from which mean values and coefficients of variation (CV) were determined for each patient.
FGA scores were significantly correlated with gait metrics obtained from the 2MWT and USWT, including stride length, stride velocity, normalized stride length, normalized stride velocity, stride length CV, and stride velocity CV. Tumor diameter was negatively associated with stride time and swing time on the 2MWT; no such association existed between tumor diameter and FGA or DHI.
Instrumented insoles may unveil associations between VS tumor size and gait dysfunction that cannot be captured by standardized clinical assessments and self-reported questionnaires.
OBJECTIVES/GOALS: Although gut fungi have been implicated in the immunopathogenesis of inflammatory bowel disease, the fungal microbiome has not been deeply explored across endo-histologic activity and treatment-exposure in ulcerative colitis. METHODS/STUDY POPULATION: Our retrospective cohort was derived from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease. We evaluated the fungal composition of fecal samples from 98 ulcerative colitis patients across endoscopic activity (n=43), endo-histologic activity (n=41), and biologic-exposure (n=98). Across all subgroups, we assessed fungal diversity and differential abundance of specific taxonomic groups. RESULTS/ANTICIPATED RESULTS: We identified 504 unique fungal amplicon sequence variants across the cohort of 98 patients, dominated by phylum Ascomycota. Compared to endoscopic remission, patients with endoscopic activity had an increased global fungus load (p DISCUSSION/SIGNIFICANCE: Endoscopic inflammation in ulcerative colitis is associated with altered fungal diversity driven by expansion of Saccharomyces and Candida compared to remission. The role of these fungal taxa as potential biomarkers and targets for personalized approaches to therapeutics in ulcerative colitis should be evaluated.
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.
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).
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%).
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.
Colliding collisionless shocks appear in a great variety of astrophysical phenomena and are thought to be possible sources of particle acceleration in the Universe. We have previously investigated particle acceleration induced by single super-critical shocks (whose magnetosonic Mach number is higher than the critical value of 2.7) (Yao et al., Nat. Phys., vol. 17, issue 10, 2021, pp. 1177–1182; Yao et al., Matter Radiat. Extrem., vol. 7, issue 1, 2022, 014402), as well as the collision of two sub-critical shocks (Fazzini et al., Astron. Astrophys., vol. 665, 2022, A87). Here, we propose to make measurements of accelerated particles from interpenetrating super-critical shocks to observe the ‘phase-locking effect’ (Fazzini et al., Astron. Astrophys., vol. 665, 2022, A87) from such an event. This effect is predicted to significantly boost the energy spectrum of the energized ions compared with a single super-critical collisionless shock. We thus anticipate that the results obtained in the proposed experiment could have a significant impact on our understanding of one type of primary source (acceleration of thermal ions as opposed to secondary acceleration mechanisms of already energetic ions) of ion energization of particles in the Universe.
Prior evidence indicates that negative symptom severity and cognitive deficits, in people with schizophrenia (PSZ), relate to measures of reward-seeking and loss-avoidance behavior (implicating the ventral striatum/VS), as well as uncertainty-driven exploration (reliant on rostrolateral prefrontal cortex/rlPFC). While neural correlates of reward-seeking and loss-avoidance have been examined in PSZ, neural correlates of uncertainty-driven exploration have not. Understanding neural correlates of uncertainty-driven exploration is an important next step that could reveal insights to how this mechanism of cognitive and negative symptoms manifest at a neural level.
We acquired fMRI data from 29 PSZ and 36 controls performing the Temporal Utility Integration decision-making task. Computational analyses estimated parameters corresponding to learning rates for both positive and negative reward prediction errors (RPEs) and the degree to which participates relied on representations of relative uncertainty. Trial-wise estimates of expected value, certainty, and RPEs were generated to model fMRI data.
Behaviorally, PSZ demonstrated reduced reward-seeking behavior compared to controls, and negative symptoms were positively correlated with loss-avoidance behavior. This finding of a bias toward loss avoidance learning in PSZ is consistent with previous work. Surprisingly, neither behavioral measures of exploration nor neural correlates of uncertainty in the rlPFC differed significantly between groups. However, we showed that trial-wise estimates of relative uncertainty in the rlPFC distinguished participants who engaged in exploratory behavior from those who did not. rlPFC activation was positively associated with intellectual function.
These results further elucidate the nature of reinforcement learning and decision-making in PSZ and healthy volunteers.
This systematic literature review aimed to provide an overview of the characteristics and methods used in studies applying the disability-adjusted life years (DALY) concept for infectious diseases within European Union (EU)/European Economic Area (EEA)/European Free Trade Association (EFTA) countries and the United Kingdom. Electronic databases and grey literature were searched for articles reporting the assessment of DALY and its components. We considered studies in which researchers performed DALY calculations using primary epidemiological data input sources. We screened 3053 studies of which 2948 were excluded and 105 studies met our inclusion criteria. Of these studies, 22 were multi-country and 83 were single-country studies, of which 46 were from the Netherlands. Food- and water-borne diseases were the most frequently studied infectious diseases. Between 2015 and 2022, the number of burden of infectious disease studies was 1.6 times higher compared to that published between 2000 and 2014. Almost all studies (97%) estimated DALYs based on the incidence- and pathogen-based approach and without social weighting functions; however, there was less methodological consensus with regards to the disability weights and life tables that were applied. The number of burden of infectious disease studies undertaken across Europe has increased over time. Development and use of guidelines will promote performing burden of infectious disease studies and facilitate comparability of the results.
This study aimed to investigate the relationship between bone quality in terms of metabolism, homeostasis of elements, bone mineral density (BMD), and microstructure and keel-bone fractures in laying hens (Gallus gallus domesticus). One hundred and twenty 17 week old Lohmann White laying hens with normal keel bones were individually housed in furnished cages for 25 weeks. Birds were then euthanased and dissected to assess keel-bone status at 42 weeks. Serum and keel-bone samples from normal keel (NK) and fractured keel (FK) hens were collected to determine the previously mentioned bone quality parameters. The results showed FK hens to have higher levels of the components of osteocalcin, greater alkaline phosphatase activity in serum and keel bones, and greater tartrate-resistant acid phosphatase (TRAP) activity in keel bones, compared to NK hens. Additionally, FK hens also had higher concentrations of Li, B, K, Cu, As, Se, Sn, Hg, and Pb, but lower concentrations of Na, P, and Ca. Moreover, FK hens showed decreased bone microstructural parameters including bone volume/tissue volume, trabecular number, degree of anisotropy, connectivity density, and BMD, but increased trabecular separation. Meanwhile, no differences were detected in serum TRAP activity, trabecular thickness, bone surface, or bone surface/bone volume. Results showed laying hens with keel-bone fractures to have differences in bone metabolism, elements of home-ostasis, bone microstructure parameters, and BMD. These results suggest that keel-bone fractures may be associated with bone quality.
Policymakers and researchers have little evidence on prevalence rates of intellectual disability (ID) or their changes over time to tailor healthcare interventions. Prevalence rates and trends of ID are especially lacking in regions with lower socio-demographic development. Additionally, the assessment of inequalities in the prevalence of ID across regions with varying socio-demographic development is understudied. This study assessed variations in prevalence rates of ID from 1990 to 2019 and the related inequalities between low and high socio-demographic index (SDI) regions.
This study used global data from 1990 to 2019 for individuals with ID from the 2019 Global Burden of Diseases study. Data analyses were performed from September 2021 to January 2022. Prevalence for individuals with ID was extracted by sex, age groups and SDI regions. Annual percentage change (APC) was estimated for each demographic group within SDI regions to assess their prevalence trends over 30 years. Relative and absolute inequalities were calculated between low and high SDI regions for the various age groups.
In 2019, there were 107.62 million (1.74%) individuals with ID, with an APC of −0.80 (−0.88 to −0.72). There was a slightly higher prevalence among males (1.42%) than females (1.37%). The highest prevalence rates were found in the low-middle SDI regions (2.42%) and the lowest prevalence rates were in the high SDI regions (0.33%). There was a large reduction in the prevalence rate between the youngest age group v. the oldest age group in all the SDI regions and at all time points. The relative inequalities between low and high SDI regions increased over three decades.
While an overall decrease in global prevalence rate for ID was found, relative inequalities continue to increase with lower SDI regions needing more comprehensive support services. The demographic trends indicate a significantly higher mortality rate among those with ID v. the rest of the population. Our study highlights the necessity for policies and interventions targeting lower SDI regions to mobilise resources that better support individuals with ID and achieve sustainable development goals proposed by the United Nations.
There is no doubt that the political economy of contemporary China has received significant attention, both in academic disciplines and in the real world. The role of the state in the economy and the relations between government and business actors have always been central concerns of classic social science works about China. There are, however, several crucial challenges in studying this topic. The complicated landscape of a multilayered, fragmented Chinese state and numerous state-owned, private, foreign, or mixed-type businesses has made it difficult to tease out their interactions and establish a comprehensive theoretical model. The fast-changing nature of state–market relations and their vast subnational and sectoral variation has often prevented scholars from generalizing those lessons beyond the case or issue area. Yet, among all these, the most daunting challenge is: How can studies of a particularly interesting phenomenon in China’s political economy contribute to broader discussions of state–society relations, regime durability, and state-led development without losing respectable country expertise?