Molecular Mechanisms Involved in MAFLD in Cholecystectomized Patients: A Cohort Study.

Gallstone disease and metabolic dysfunction-associated fatty liver disease (MAFLD) share numerous common risk factors and progression determinants in that they both manifest as organ-specific consequences of metabolic dysfunction. Nevertheless, the precise molecular mechanisms underlying fibrosis development in cholecystectomized MAFLD patients remain inadequately defined. This study aimed to investigate the involvement of farnesoid X receptor 1 (FXR1) and fibroblast growth factor receptor 4 (FGFR4) in the progression of fibrosis in cholecystectomized MAFLD patients. A meticulously characterized cohort of 12 patients diagnosed with MAFLD, who had undergone liver biopsies during programmed cholecystectomies, participated in this study. All enrolled patients underwent a follow-up regimen at 1, 3, and 6 months post-cholecystectomy, during which metabolic biochemical markers were assessed, along with elastography, which served as indirect indicators of fibrosis. Additionally, the hepatic expression levels of FGFR4 and FXR1 were quantified using quantitative polymerase chain reaction (qPCR). Our findings revealed a robust correlation between hepatic FGFR4 expression and various histological features, including the steatosis degree (r = 0.779, p = 0.023), ballooning degeneration (r = 0.764, p = 0.027), interphase inflammation (r = 0.756, p = 0.030), and steatosis activity score (SAS) (r = 0.779, p = 0.023). Conversely, hepatic FXR1 expression did not exhibit any significant correlations with these histological features. In conclusion, our study highlights a substantial correlation between FGFR4 expression and histological liver damage, emphasizing its potential role in lipid and glucose metabolism. These findings suggest that FGFR4 may play a crucial role in the progression of fibrosis in cholecystectomized MAFLD patients. Further research is warranted to elucidate the exact mechanisms through which FGFR4 influences metabolic dysfunction and fibrosis in this patient population.

Information-Rich, Dual-Function 13C/2H-Isotopic Crosstalk NMR Assay for Human Serine Racemase (hSR) Provides a PLP-Enzyme "Partitioning Fingerprint" and Reveals Disparate Chemotypes for hSR Inhibition.

The first dual-function assay for human serine racemase (hSR), the only bona fide racemase in human biology, is reported. The hSR racemization function is essential for neuronal signaling, as the product, d-serine (d-Ser), is a potent N-methyl d-aspartate (NMDA) coagonist, important for learning and memory, with dysfunctional d-Ser-signaling being observed in some neuronal disorders. The second hSR function is ß-elimination and gives pyruvate; this activity is elevated in colorectal cancer. This new NMR-based assay allows one to monitor both α-proton-exchange chemistry and ß-elimination using only the native l-Ser substrate and hSR and is the most sensitive such assay. The assay judiciously employs segregated dual 13C-labeling and 13C/2H crosstalk, exploiting both the splitting and shielding effects of deuterium. The assay is deployed to screen a 1020-compound library and identifies an indolo-chroman-2,4-dione inhibitor family that displays allosteric site binding behavior (noncompetitive inhibition vs l-Ser substrate; competitive inhibition vs adenosine 5'-triphosphate (ATP)). This assay also reveals important mechanistic information for hSR; namely, that H/D exchange is ∼13-fold faster than racemization, implying that K56 protonates the carbanionic intermediate on the si-face much faster than does S84 on the re-face. Moreover, the 13C NMR peak pattern seen is suggestive of internal return, pointing to K56 as the likely enamine-protonating residue for ß-elimination. The 13C/2H-isotopic crosstalk assay has also been applied to the enzyme tryptophan synthase and reveals a dramatically different partition ratio in this active site (ß-replacement: si-face protonation ∼6:1 vs ß-elimination: si-face protonation ∼1:3.6 for hSR), highlighting the value of this approach for fingerprinting the pyridoxal phosphate (PLP) enzyme mechanism.

Telehealth services for cardiac neurodevelopmental care during the COVID-19 pandemic: a site survey from the Cardiac Neurodevelopmental Outcome Collaborative.

OBJECTIVE: COVID-19 has markedly impacted the provision of neurodevelopmental care. In response, the Cardiac Neurodevelopmental Outcome Collaborative established a Task Force to assess the telehealth practices of cardiac neurodevelopmental programmes during COVID-19, including adaptation of services, test protocols and interventions, and perceived obstacles, disparities, successes, and training needs. STUDY DESIGN: A 47-item online survey was sent to 42 Cardiac Neurodevelopmental Outcome Collaborative member sites across North America within a 3-week timeframe (22 July to 11 August 2020) to collect cross-sectional data on practices. RESULTS: Of the 30 participating sites (71.4% response rate), all were providing at least some clinical services at the time of the survey and 24 sites (80%) reported using telehealth. All but one of these sites were offering new telehealth services in response to COVID-19, with the most striking change being the capacity to offer new intervention services for children and their caregivers. Only a third of sites were able to carry out standardised, performance-based, neurodevelopmental testing with children and adolescents using telehealth, and none had completed comparable testing with infants and toddlers. Barriers associated with language, child ability, and access to technology were identified as contributing to disparities in telehealth access. CONCLUSIONS: Telehealth has enabled continuation of at least some cardiac neurodevelopmental services during COVID-19, despite the challenges experienced by providers, children, families, and health systems. The Cardiac Neurodevelopmental Outcome Collaborative provides a unique platform for sharing challenges and successes across sites, as we continue to shape an evidence-based, efficient, and consistent approach to the care of individuals with CHD.

Biomacromolecule-Assisted Screening for Reaction Discovery and Catalyst Optimization.

Reaction discovery and catalyst screening lie at the heart of synthetic organic chemistry. While there are efforts at de novo catalyst design using computation/artificial intelligence, at its core, synthetic chemistry is an experimental science. This review overviews biomacromolecule-assisted screening methods and the follow-on elaboration of chemistry so discovered. All three types of biomacromolecules discussed─enzymes, antibodies, and nucleic acids─have been used as "sensors" to provide a readout on product chirality exploiting their native chirality. Enzymatic sensing methods yield both UV-spectrophotometric and visible, colorimetric readouts. Antibody sensors provide direct fluorescent readout upon analyte binding in some cases or provide for cat-ELISA (Enzyme-Linked ImmunoSorbent Assay)-type readouts. DNA biomacromolecule-assisted screening allows for templation to facilitate reaction discovery, driving bimolecular reactions into a pseudo-unimolecular format. In addition, the ability to use DNA-encoded libraries permits the barcoding of reactants. All three types of biomacromolecule-based screens afford high sensitivity and selectivity. Among the chemical transformations discovered by enzymatic screening methods are the first Ni(0)-mediated asymmetric allylic amination and a new thiocyanopalladation/carbocyclization transformation in which both C-SCN and C-C bonds are fashioned sequentially. Cat-ELISA screening has identified new classes of sydnone-alkyne cycloadditions, and DNA-encoded screening has been exploited to uncover interesting oxidative Pd-mediated amido-alkyne/alkene coupling reactions.

Integrating Telehealth Into Neurodevelopmental Assessment: A Model From the Cardiac Neurodevelopmental Outcome Collaborative.

OBJECTIVE: In the wake of the COVID-19 pandemic, psychologists were pushed to look beyond traditional in-person models of neurodevelopmental assessment to maintain continuity of care. A wealth of data demonstrates that telehealth is efficacious for pediatric behavioral intervention; however, best practices for incorporating telehealth into neurodevelopmental assessment are yet to be developed. In this topical review, we propose a conceptual model to demonstrate how telehealth can be incorporated into various components of neurodevelopmental assessment. METHODS: Harnessing existing literature and expertise from a multidisciplinary task force comprised of clinicians, researchers, and patient/parent representatives from the subspecialty of cardiac neurodevelopmental care, a conceptual framework for telehealth neurodevelopmental assessment was developed. Considerations for health equity and access to care are discussed, as well as general guidelines for clinical implementation and gaps in existing literature. RESULTS: There are opportunities to integrate telehealth within each stage of neurodevelopmental assessment, from intake to testing, through to follow-up care. Further research is needed to determine whether telehealth mitigates or exacerbates disparities in access to care for vulnerable populations as well as to provide evidence of validity for a wider range of neurodevelopmental measures to be administered via telehealth. CONCLUSIONS: While many practices are returning to traditional, face-to-face neurodevelopmental assessment services, psychologists have a unique opportunity to harness the momentum for telehealth care initiated during the pandemic to optimize the use of clinical resources, broaden service delivery, and increase access to care for pediatric neurodevelopmental assessment.

Accounting for variation in temperature and oxygen availability when quantifying marine ecosystem metabolism.

It is critical to understand how human modifications of Earth's ecosystems are influencing ecosystem functioning, including net and gross community production (NCP and GCP, respectively) and community respiration (CR). These responses are often estimated by measuring oxygen production in the light (NCP) and consumption in the dark (CR), which can then be combined to estimate GCP. However, the method used to create "dark" conditions-either experimental darkening during the day or taking measurements at night-could result in different estimates of respiration and production, potentially affecting our ability to make integrative predictions. We tested this possibility by measuring oxygen concentrations under daytime ambient light conditions, in darkened tide pools during the day, and during nighttime low tides. We made measurements every 1-3 months over one year in southeastern Alaska. Daytime respiration rates were substantially higher than those measured at night, associated with higher temperature and oxygen levels during the day and leading to major differences in estimates of GCP calculated using daytime versus nighttime measurements. Our results highlight the potential importance of measuring respiration rates during both day and night to account for effects of temperature and oxygen-especially in shallow-water, constrained systems-with implications for understanding the impacts of global change on ecosystem metabolism.

The Effect of Size and Asymmetry at Birth on Brain Injury and Neurodevelopmental Outcomes in Congenital Heart Disease.

Poor and asymmetric fetal growth have been associated with neonatal brain injury (BI) and worse neurodevelopmental outcomes (NDO) in the growth-restricted population due to placental insufficiency. We tested the hypothesis that postnatal markers of fetal growth (birthweight (BW), head circumference (HC), and head to body symmetry) are associated with preoperative white matter injury (WMI) and NDO in infants with single ventricle physiology (SVP) and d-transposition of great arteries (TGA). 173 term newborns (106 TGA; 67 SVP) at two sites had pre-operative brain MRI to assess for WMI and measures of microstructural brain development. NDO was assessed at 30 months with the Bayley Scale of Infant Development-II (n = 69). We tested the association between growth parameters at birth with the primary outcome of WMI on the pre-operative brain MRI. Secondary outcomes included measures of NDO. Newborns with TGA were more likely to have growth asymmetry with smaller heads relative to weight while SVP newborns were symmetrically small. There was no association between BW, HC or asymmetry and WMI on preoperative brain MRI or with measures of microstructural brain development. Similarly, growth parameters at birth were not associated with NDO at 30 months. In a multivariable model only cardiac lesion and site were associated with NDO. Unlike other high-risk infant populations, postnatal markers of fetal growth including head to body asymmetry that is common in TGA is not associated with brain injury or NDO. Lesion type appears to play a more important role in NDO in CHD.

Defeat and Entrapment Mediate the Relationship Between Insomnia Symptoms and Suicidal Ideation in Young Adults.

AIM: In recent years, there has been a growing interest in understanding the relationship between sleep disturbance and suicide. The current study aimed to advance understanding of the psychological processes driving these relationships by examining whether insomnia symptoms are related to suicidal ideation via perceptions of defeat and entrapment. METHODS: Young adults (n = 259; 202 students [78.0%], 45 employed [17.4%], 12 unemployed [4.6%]) completed an anonymous self-report survey that was advertised via social media, university participant pools, and fliers. The survey was described as being related to sleep and mood/mental health. Validated measures were used to assess insomnia symptoms, chronotype, defeat, entrapment, suicidal ideation, and affective covariates. RESULTS: Bivariate associations found insomnia severity to be related to poorer affective outcomes including severity of suicidal ideation. Insomnia and depression were significant independent variables in multiple linear regression with suidical ideation as the dependent variable. The relationship between insomnia and suicidal ideation was mediated by perceptions of defeat and entrapment. CONCLUSION: Taken together, these findings shed light on the psychological mechanisms linking sleep disturbance and suicidal ideation by highlighting the role of defeat and entrapment. These findings have the potential to improve suicide risk assessment and prevention in young adults experiencing difficulties initiating or maintaining sleep.HighlightsDefeat and entrapment mediate relationship between insomnia and suicidal ideationEvidence for Integrated Motivational-Volitional Model of Suicidal Behavior in community sampleUses validated multi-item suicide measure.

Insomnia symptoms mediate the association between eveningness and suicidal ideation, defeat, entrapment, and psychological distress in students.

Chronotype describes a person's general preference for mornings, evenings, or neither. It is typically conceptualized as a continuous unidimensional spectrum from morningness to eveningness. Eveningness is associated with poorer outcomes across a myriad of physical and mental health outcomes. This preference for later sleep and wake times is associated with increased risk of depression, anxiety, and suicidal ideation in both clinical and community samples. However, the mechanisms underlying the negative consequences of this preference for evenings are not fully understood. Previous research has found that sleep disturbances may act as a mediator of this relationship. The present study aimed to explore the associations between chronotype and affective outcomes in a sample of students. Additionally, it aimed to investigate the potential role of insomnia as a mediator within these relationships. Participants (n = 190) completed an anonymous self-report survey of validated measures online which assessed chronotype, insomnia symptoms, and a range of affective outcomes (defeat, entrapment, suicide risk, stress, and depressive and anxious symptomology). Eveningness was associated with more severe or frequent experiences of these outcomes, with participants that demonstrated a preference for eveningness more likely to report poorer affective functioning and increased psychological distress. Mediation analysis found the relationship between chronotype and these outcome measures was completely or partially mediated by insomnia symptom severity measured by the validated Sleep Condition Indicator insomnia scale. Taken together, these findings add further evidence for the negative consequences of increased eveningness. Additionally, our results show that chronotype and sleep disturbances should be considered when assessing mental well-being. Implementing appropriate sleep-related behavior change or schedule alterations can offer a tool for mitigation or prevention of psychological distress in students that report a preference for later sleep and wake times.

The association between clinicians' initial judgments of feigning and outcomes on symptom validity measures among pretrial forensic psychiatric inpatients.

Research suggests the use of validated symptom validity tests to detect feigning is imperative to increase accuracy over unaided clinical judgment, especially in forensic settings. This study examined performance on the Miller Forensic Assessment of Symptoms (M-FAST) and Structured Interview of Reported Symptoms (SIRS) during 297 assessments of forensic inpatients. The risk of being identified as feigning on the M-FAST or SIRS was similar for those who were referred for evaluation of feigning compared to those who were not, but individuals with malingering designations prior to the evaluation scored significantly higher than those without on the M-FAST and several SIRS subscales. Findings support the importance of utilizing objective methods of data collection.

Nodding off but can't disconnect: development and validation of the iNOD index of Nighttime Offline Distress.

BACKGROUND: There is a pressing need to update sleep models, education and treatment to better reflect the realities of sleep in a 24/7 connected social world. Progress has been limited to date by available measurement tools, which have largely focused on the frequency or duration of individuals' social media use, without capturing crucial sleep-relevant aspects of this inherently social and interactive experience. METHODS: Survey data from 3008 adolescents (aged 10-18 years) was used to rigorously develop and validate a new self-report measure that quantifies difficulty disengaging from social media interactions at night: the index of Nighttime Offline Distress (iNOD). Exploratory and Confirmatory Factor analyses in a random split sample produced a ten-item two-factor solution, with subscales capturing concerns about Staying Connected and Following Etiquette (Cronbach's alphas = 0.91 and 0.92 respectively). RESULTS: Those with higher scores on these subscales tended to report using social media for longer after they felt they should be asleep (rs = 0.41 and 0.26, respectively), shorter sleep duration (rs = -0.24 and -0.17, respectively) and poorer sleep quality (rs = -0.33 and -0.31, respectively). Results also pointed towards a potentially fragmented process of sleep displacement for those who may struggle to disconnect - and to stay disconnected - from social interactions in order to allow sufficient uninterrupted sleep opportunity. CONCLUSIONS: These findings can inform current models for understanding normal and disordered sleep during adolescence, whilst highlighting specific social concerns as important potential targets for sleep education efforts.

Social media use and adolescent sleep patterns: cross-sectional findings from the UK millennium cohort study.

OBJECTIVES: This study examines associations between social media use and multiple sleep parameters in a large representative adolescent sample, controlling for a wide range of covariates. DESIGN: The authors used cross-sectional data from the Millennium Cohort Study, a large nationally representative UK birth cohort study. PARTICIPANTS: Data from 11 872 adolescents (aged 13-15 years) were used in analyses. METHODS: Six self-reported sleep parameters captured sleep timing and quality: sleep onset and wake times (on school days and free days), sleep onset latency (time taken to fall asleep) and trouble falling back asleep after nighttime awakening. Binomial logistic regressions investigated associations between daily social media use and each sleep parameter, controlling for a range of relevant covariates. RESULTS: Average social media use was 1 to <3 hours per day (31.6%, n=3720). 33.7% were classed as low users (<1 hour; n=3986); 13.9% were high users (3 to <5 hours; n=1602) and 20.8% were very high users (5+ hours; n=2203). Girls reported spending more time on social media than boys. Overall, heavier social media use was associated with poorer sleep patterns, controlling for covariates. For example, very high social media users were more likely than comparable average users to report late sleep onset (OR 2.14, 95% CI 1.83 to 2.50) and wake times (OR 1.97, 95% CI 1.32 to 2.93) on school days and trouble falling back asleep after nighttime awakening (OR 1.36, 95% CI 1.10 to 1.66). CONCLUSIONS: This study provides a normative profile of UK adolescent social media use and sleep. Results indicate statistically and practically significant associations between social media use and sleep patterns, particularly late sleep onset. Sleep education and interventions can focus on supporting young people to balance online interactions with an appropriate sleep schedule that allows sufficient sleep on school nights.

Identifying drivers for bedtime social media use despite sleep costs: The adolescent perspective.

OBJECTIVES: Bedtime social media use is associated with poor sleep during adolescence, which in turn contributes to poor mental health, impaired daytime functioning and lower academic achievement. However, the underlying drivers for these bedtime social media habits remain understudied. This study adds an adolescent perspective on motivations for bedtime social media use and perceived impact on sleep. METHODS: Adolescents aged 11-17 years (n = 24) participated in focus group discussions exploring their experiences of using social media, particularly at night. Inductive reflexive thematic analysis produced themes that captured underlying drivers for social media use and associated impact on sleep. RESULTS: Our analyses produced two overarching themes: Missing Out and Norms & Expectations. Adolescents' nighttime social media use was driven by concerns over negative consequences for real-world relationships if they disconnected (often reporting delayed bedtimes, insufficient sleep and daytime tiredness). These concerns included the risk of offline peer exclusion from missing out on online interactions, and the fear of social disapproval from violating norms around online availability and prompt responses. CONCLUSIONS: These findings offer novel insight into why adolescents may choose to prioritize social media over sleep. Researchers and practitioners can respond to the evolving needs of today's adolescents by approaching social media use not as a technology-based activity, but as an embedded social experience underpinned by the same concerns as offline interactions.

Management of Non-melanoma Skin Cancer in Transplant Recipients.

Transplant recipients have a significantly higher risk of developing non-melanoma skin cancers compared with the general population and squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most common post-transplant malignancies. Although in the general population BCC outnumbers SCC 4:1, in transplant patients this ratio is reversed and SCC is more common, with a 65- to 250-fold increased incidence. As patients in immunosuppressed states are living longer after transplants, the incidence of skin cancer in this population continues to increase. The skin cancers in transplant patients also tend to be more aggressive, with higher morbidity and mortality. Preventive strategies play an important role in transplant recipients given their increased frequency of developing both premalignant and malignant skin lesions. Sun protection and regular skin cancer screening are critical. In addition, chemoprophylaxis with systemic retinoids, nicotinamide and capecitabine can significantly reduce the development of new skin cancers. Topical 5-fluorouracil, imiquimod, photodynamic therapy and cyclooxygenase inhibitors have all been investigated in transplant patients for the treatment of field cancerisation. Adjusting the immunosuppressive regimen is also an important adjuvant therapeutic strategy for managing skin cancers in transplant recipients and requires integrated multidisciplinary care with the entire transplant team. This article reviews the epidemiology of non-melanoma skin cancer in transplant patients, discusses the prevention strategies and highlights the management and treatment strategies of both field cancerisation and non-melanoma skin cancers.

Creation of a multidisciplinary and multicenter study group for the use of 3D printing in general thoracic surgery: lessons learned in our first year experience.

Introduction: In recent years, the use of 3D printing in medicine has grown exponentially, but the use of 3D technology has not been equally adopted by the different medical specialties. Published 3D printing activity in general thoracic surgery is scarce and has been mostly limited to case reports. The aim of this report was to reflect on the results and lessons learned from a newly created multidisciplinary and multicenter 3D unit of the Spanish Society of Thoracic Surgery (SECT). Methods: This is a pilot study to determine the feasibility and usefulness of printing 3D models for patients with thoracic malignancy or airway complications, based on real data. We designed a point-of-care 3D printing workflow involving thoracic surgeons, radiologists with experience in intrathoracic pathology, and engineers with experience in additive manufacturing. Results: In the first year of operation we generated 26 three-dimensional models out of 27 cases received (96.3%). In 9 cases a virtual model was sufficient for optimal patient handling, while in 17 cases a 3D model was printed. Per pathology, cases were classified as airway stenosis after lung transplantation (7 cases, 25.9%), tracheal pathology (7 cases, 25.9%), chest tumors (6 cases, 22.2%) carcinoid tumors (4 cases, 14.8%), mediastinal tumors (2 cases, 7.4%) and Pancoast tumors (one case, 3.7%). Conclusion: A multidisciplinary 3D laboratory is feasible in a hospital setting, and working as a multicenter group increases the number of cases and diversity of pathologies thus providing further opportunity to study the benefits of the 3D printing technology in general thoracic surgery.

Genome-Wide Association Study of Circadian Rhythmicity in 71,500 UK Biobank Participants and Polygenic Association with Mood Instability.

BACKGROUND: Circadian rhythms are fundamental to health and are particularly important for mental wellbeing. Disrupted rhythms of rest and activity are recognised as risk factors for major depressive disorder and bipolar disorder. METHODS: We conducted a genome-wide association study (GWAS) of low relative amplitude (RA), an objective measure of rest-activity cycles derived from the accelerometer data of 71,500 UK Biobank participants. Polygenic risk scores (PRS) for low RA were used to investigate potential associations with psychiatric phenotypes. OUTCOMES: Two independent genetic loci were associated with low RA, within genomic regions for Neurofascin (NFASC) and Solute Carrier Family 25 Member 17 (SLC25A17). A secondary GWAS of RA as a continuous measure identified a locus within Meis Homeobox 1 (MEIS1). There were no significant genetic correlations between low RA and any of the psychiatric phenotypes assessed. However, PRS for low RA was significantly associated with mood instability across multiple PRS thresholds (at PRS threshold 0·05: OR = 1·02, 95% CI = 1·01-1·02, p = 9·6 × 10-5), and with major depressive disorder (at PRS threshold 0·1: OR = 1·03, 95% CI = 1·01-1·05, p = 0·025) and neuroticism (at PRS threshold 0·5: Beta = 0·02, 95% CI = 0·007-0·04, p = 0·021). INTERPRETATION: Overall, our findings contribute new knowledge on the complex genetic architecture of circadian rhythmicity and suggest a putative biological link between disrupted circadian function and mood disorder phenotypes, particularly mood instability, but also major depressive disorder and neuroticism. FUNDING: Medical Research Council (MR/K501335/1).

Association of disrupted circadian rhythmicity with mood disorders, subjective wellbeing, and cognitive function: a cross-sectional study of 91 105 participants from the UK Biobank.

BACKGROUND: Disruption of sleep and circadian rhythmicity is a core feature of mood disorders and might be associated with increased susceptibility to such disorders. Previous studies in this area have used subjective reports of activity and sleep patterns, but the availability of accelerometer-based data from UK Biobank participants permits the derivation and analysis of new, objectively ascertained circadian rhythmicity parameters. We examined associations between objectively assessed circadian rhythmicity and mental health and wellbeing phenotypes, including lifetime history of mood disorder. METHODS: UK residents aged 37-73 years were recruited into the UK Biobank general population cohort from 2006 to 2010. We used data from a subset of participants whose activity levels were recorded by wearing a wrist-worn accelerometer for 7 days. From these data, we derived a circadian relative amplitude variable, which is a measure of the extent to which circadian rhythmicity of rest-activity cycles is disrupted. In the same sample, we examined cross-sectional associations between low relative amplitude and mood disorder, wellbeing, and cognitive variables using a series of regression models. Our final model adjusted for age and season at the time that accelerometry started, sex, ethnic origin, Townsend deprivation score, smoking status, alcohol intake, educational attainment, overall mean acceleration recorded by accelerometry, body-mass index, and a binary measure of childhood trauma. FINDINGS: We included 91 105 participants with accelerometery data collected between 2013 and 2015 in our analyses. A one-quintile reduction in relative amplitude was associated with increased risk of lifetime major depressive disorder (odds ratio [OR] 1·06, 95% CI 1·04-1·08) and lifetime bipolar disorder (1·11, 1·03-1·20), as well as with greater mood instability (1·02, 1·01-1·04), higher neuroticism scores (incident rate ratio 1·01, 1·01-1·02), more subjective loneliness (OR 1·09, 1·07-1·11), lower happiness (0·91, 0·90-0·93), lower health satisfaction (0·90, 0·89-0·91), and slower reaction times (linear regression coefficient 1·75, 1·05-2·45). These associations were independent of demographic, lifestyle, education, and overall activity confounders. INTERPRETATION: Circadian disruption is reliably associated with various adverse mental health and wellbeing outcomes, including major depressive disorder and bipolar disorder. Lower relative amplitude might be linked to increased susceptibility to mood disorders. FUNDING: Lister Institute of Preventive Medicine.

Alterations in glutamatergic signaling contribute to the decline of circadian photoentrainment in aged mice.

Robust physiological circadian rhythms form an integral part of well-being. The aging process has been found to negatively impact systems that drive circadian physiology, typically manifesting as symptoms associated with abnormal/disrupted sleeping patterns. Here, we investigated the age-related decline in light-driven circadian entrainment in male C57BL/6J mice. We compared light-driven resetting of circadian behavioral activity in young (1-2 months) and old (14-18 months) mice and explored alterations in the glutamatergic pathway at the level of the circadian pacemaker, the suprachiasmatic nucleus (SCN). Aged animals showed a significant reduction in sensitivity to behavioral phase resetting by light. We show that this change was through alterations in N-Methyl-D-aspartate (NMDA) signaling at the SCN, where NMDA, a glutamatergic agonist, was less potent in inducing clock resetting. Finally, we show that this shift in NMDA sensitivity was through the reduced SCN expression of this receptor's NR2B subunit. Only in young animals did an NR2B antagonist attenuate behavioral resetting. These results can help target treatments that aim to improve both physiological and behavioral circadian entrainment in aged populations.

Psychopathy in the Medical Emergency Department.

Psychopathy is a personality disorder representing an admixture of a fearless and dominant temperament with an impulsive and antisocial orientation. A sample of 1,026 participants in the waiting room of the medical emergency department of a city hospital exhibited levels of fearless dominance similar to university undergraduates and federal inmates; their levels of impulsive antisociality fell between those of federal and state inmates. Both psychopathy factors were correlated with male gender, younger age, and more frequent average alcohol consumption. Fearless dominance was associated with agentic success (e.g., being employed, higher household income), fewer psychological problems, and less use of psychotropic medications, including anxiolytics. Impulsive antisociality was negatively related to both agentic and communal (e.g., ever being married) success and positively correlated with substance use and self-reported bipolar, ADHD, and psychotic psychiatric conditions. Further, only impulsive antisociality was associated with presenting to the emergency department for physical injury or psychological disturbance.