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Monitoring unintentional air leaks in continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) is essential for therapy success. While leaks are often attributed to improperly sealed masks, mouth openings may also cause them, requiring interventions. Recent studies demonstrated distinctive mandibular jaw movement (MJM) signal patterns during sleep related to respiratory events and sleep stages. Analysing MJM during CPAP treatment reveals air leak peaks coinciding with maximal MJM amplitude during obstructive events, and air leak decreases corresponding to arousals. Examining leaks with MJM offers valuable insights into their origins and might open new avenues for CPAP management.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Rationale: Oral appliances are second-line treatments after continuous positive airway pressure for obstructive sleep apnea (OSA) management. However, the need for oral appliance titration limits their use as a result of monitoring challenges to assess the treatment effect on OSA. Objectives: To assess the validity of mandibular jaw movement (MJM) automated analysis compared with polysomnography (PSG) and polygraphy (PG) in evaluating the effect of oral appliance treatment and the effectiveness of MJM monitoring for oral appliance titration at home in patients with OSA. Methods: This observational, prospective study included 135 patients with OSA eligible for oral appliance therapy. The primary outcome was the apnea-hypopnea index (AHI), measured through in-laboratory PSG/PG and MJM-based technology. Additionally, MJM monitoring at home was conducted at regular intervals during the titration process. The agreement between PSG/PG and MJM automated analysis was revaluated using Bland-Altman analysis. Changes in AHI during the home-based oral appliance titration process were evaluated using a generalized linear mixed model and a generalized estimating equation model. Results: The automated MJM analysis demonstrated strong agreement with PG in assessing AHI at the end of titration, with a median bias of 0.24/h (limits of agreement, -11.2 to 12.8/h). The improvement of AHI from baseline in response to oral appliance treatment was consistent across three evaluation conditions: in-laboratory PG (-59.6%; 95% confidence interval, -59.8% to -59.5%), in-laboratory automated MJM analysis (-59.2%; -65.2% to -52.2%), and at-home automated MJM analysis (-59.7%; -67.4% to -50.2%). Conclusions: Incorporating MJM automated analysis into the oral appliance titration process has the potential to optimize oral appliance therapy outcomes for OSA.

BACKGROUND: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. METHODS: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). FINDINGS: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. INTERPRETATION: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. FUNDING: Biophytis.

Abstract The mpox outbreak of 2022–2023 represented a new global health challenge and recognition of mpox as a sexually transmitted disease. The majority of cases were reported in men who have sex with men (MSM), but women are also susceptible, especially during pregnancy. We evaluated the reproductive tracts of a subset of macaques from a large rechallenge study of mpox infection with virus from the 2022 outbreak and identified intraabdominal mpox replication associated with endometriosis. Mpox virus (MPXV) was found not only in skin, but in the cervix, the uterus, and periovarian endometriotic lesions of the affected macaque. Mpox replication preferentially targeted vimentin-positive poorly differentiated endometriotic stromal tissue and infiltrating macrophages in the reproductive tract. Mpox tropism for stromal cells and macrophages has broad implications for mpox pathogenesis and associated clinical syndromes. In addition, women with endometriosis may be at heightened risk for adverse outcomes associated with mpox infection. The rhesus macaque provides rare insight into this disease and the potential complications of mpox infection in the context of genitourinary tract disease.

Abstract Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of the variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

In academic contexts, failure, as compared to success, is likely to threaten self-esteem and thus, to increase the risk of psychological disengagement from one's studies. The goal of the present research is to examine whether belief in school meritocracy (BSM) increases (vs. decreases) the effect of academic performance on self-esteem and psychological disengagement. In two pre-registered studies, university students reported their BSM. Their self-esteem and psychological disengagement were assessed following a manipulated (Study 1, N = 465) or actual (Study 2, N = 375) academic performance. Results indicated that, in both studies, BSM was positively related to performance self-esteem and negatively related to psychological disengagement. However, BSM also increased the effect of performance (manipulated or actual) on psychological disengagement. Indeed, failure led to more disengagement than success, but more so at a high level of BSM than at a lower level of BSM. The double-edge effects of belief in meritocracy are discussed.

Abstract Adolescents exhibit remarkable heterogeneity in the structural architecture of brain development. However, due to limited large-scale longitudinal neuroimaging studies, existing research has largely focused on population averages, and the neurobiological basis underlying individual heterogeneity remains poorly understood. Here we identify, using the IMAGEN adolescent cohort followed up over 9 years (14–23 y), three groups of adolescents characterized by distinct developmental patterns of whole-brain gray matter volume (GMV). Group 1 show continuously decreasing GMV associated with higher neurocognitive performances than the other two groups during adolescence. Group 2 exhibit a slower rate of GMV decrease and lower neurocognitive performances compared with Group 1, which was associated with epigenetic differences and greater environmental burden. Group 3 show increasing GMV and lower baseline neurocognitive performances due to a genetic variation. Using the UK Biobank, we show these differences may be attenuated in mid-to-late adulthood. Our study reveals clusters of adolescent neurodevelopment based on GMV and the potential long-term impact.

Adolescence is a crucial period for physical and psychological development. The impact of negative life events represents a risk factor for the onset of neuropsychiatric disorders. This study aims to investigate the relationship between negative life events and structural brain connectivity, considering both graph theory and connectivity strength. A group (n = 487) of adolescents from the IMAGEN Consortium was divided into Low and High Stress groups. Brain networks were extracted at an individual level, based on morphological similarity between grey matter regions with regions defined using an atlas-based region of interest (ROI) approach. Between-group comparisons were performed with global and local graph theory measures in a range of sparsity levels. The analysis was also performed in a larger sample of adolescents (n = 976) to examine linear correlations between stress level and network measures. Connectivity strength differences were investigated with network-based statistics. Negative life events were not found to be a factor influencing global network measures at any sparsity level. At local network level, between-group differences were found in centrality measures of the left somato-motor network (a decrease of betweenness centrality was seen at sparsity 5%), of the bilateral central visual and the left dorsal attention network (increase of degree at sparsity 10% at sparsity 30% respectively). Network-based statistics analysis showed an increase in connectivity strength in the High stress group in edges connecting the dorsal attention, limbic and salience networks. This study suggests negative life events alone do not alter structural connectivity globally, but they are associated to connectivity properties in areas involved in emotion and attention.

Introduction:A growing literature has shown that exposure to adverse life events during childhood or adolescence is associated with the presence of psychotic-like experiences (PLEs), which is in turn associated with the risk of psychotic outcomes. Ruminative thinking, i.e., the tendency to dwell on particular issues or ideas, may affect the perceived aversiveness and ability to cope with adverse life events. However, the role that rumination plays in the relationship between adverse life events and the presence of PLEs remains unclear. The purpose of this study is to assess the association between adverse life events and PLEs in a longitudinal sample of young adults and adolescents, and to investigate whether this relationship is mediated by ruminative thinking.MethodsWe used a longitudinal naturalistic sample of 706 volunteers assessed at ages 18 and 22 years, within the Imagen consortium. Lifetime occurrence of adverse life events (i.e., events perceived as strongly negative by participants) was investigated using the Life Events Questionnaire. The Community Assessment of Psychic Experience (CAPE-42) served to assess the presence of PLEs, while ruminative thinking was investigated through the Ruminative Response Scale.ResultsResults showed that both frequency of PLEs and their persistence over time were associated with greater adverse life events exposure (r = 0.32, p < 0.001 and F1 = 9.8; p < 0.001, respectively) and greater ruminative response (r = 0.66, p < 0.001 and F1 = 94.9; p < 0.001, respectively). Mediation analyses showed that relationship between adverse life events and PLEs frequency was partially mediated by rumination (direct effect Z: 5.4, p < 0.001; indirect effect Z: 6.9, p < 0.001; total effect Z: 5.9, p < 0.001). Considering changes between the two assessment timepoints, relationship between PLEs variation between 18 and 22 years and adverse life events occurred during the same period was partially mediated by changes in rumination (direct effect Z: 2.8, p < 0.005; indirect effect Z: 4.3, p < 0.001; total effect Z: 4.3; p < 0.001).DiscussionOverall, our findings confirm that the presence of adverse life events may increase the risk of experiencing PLEs in healthy individuals and suggest that dysfunctional coping strategies, such as ruminative thinking, may be related to psychosis proneness. Results do not disentangle whether individuals with greater risk for psychosis tend to ruminate more or whether rumination exacerbates psychosis risk.

Structural brain aging has demonstrated strong inter-individual heterogeneity and mirroring patterns with brain development. However, due to the lack of large-scale longitudinal neuroimaging studies, most of the existing research focused on the cross-sectional changes of brain aging. In this investigation, we present a data-driven approach that incorporate both cross-sectional changes and longitudinal trajectories of structural brain aging and identified two brain aging patterns among 37,013 healthy participants from UK Biobank. Participants with accelerated brain aging also demonstrated accelerated biological aging, cognitive decline and increased genetic susceptibilities to major neuropsychiatric disorders. Further, by integrating longitudinal neuroimaging studies from a multi-center adolescent cohort, we validated the ‘last in, first out’ mirroring hypothesis and identified brain regions with manifested mirroring patterns between brain aging and brain development. Genomic analyses revealed risk loci and genes contributing to accelerated brain aging and delayed brain development, providing molecular basis for elucidating the biological mechanisms underlying brain aging and related disorders.

Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance use or a marker of the inclination to engage in such behavior. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1000 participants. Behaviors and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use.

AimTo determine the association between total sleep time (TST) spent in increased respiratory effort (RE) and the prevalence of type 2 diabetes in a large cohort of individuals with suspected obstructive sleep apnoea (OSA) referred for in-laboratory polysomnography (PSG).Materials and methodsWe conducted a retrospective cross-sectional study using the clinical data of 1128 patients. Non-invasive measurements of RE were derived from the sleep mandibular jaw movements (MJM) bio-signal. An explainable machine-learning model was built to predict prevalent type 2 diabetes from clinical data, standard PSG indices, and MJM-derived parameters (including the proportion of TST spent with increased respiratory effort [REMOV [%TST]).ResultsOriginal data were randomly assigned to training (n = 853) and validation (n = 275) subsets. The classification model based on 18 input features including REMOV showed good performance for predicting prevalent type 2 diabetes (sensitivity = 0.81, specificity = 0.89). Post hoc interpretation using the Shapley additive explanation method found that a high value of REMOV was the most important risk factor associated with type 2 diabetes after traditional clinical variables (age, sex, body mass index), and ahead of standard PSG metrics including the apnoea-hypopnea and oxygen desaturation indices.ConclusionsThese findings show for the first time that the proportion of sleep time spent in increased RE (assessed through MJM measurements) is an important predictor of the association with type 2 diabetes in individuals with OSA.

Abstract At the start of the Zika virus (ZIKV) epidemic in 2015, ZIKV spread across South and Central America, and reached parts of the southern United States placing pregnant women at risk for fetal microcephaly, fetal loss, and other adverse pregnancy outcomes associated with congenital ZIKA syndrome (CZS). For this reason, testing of a safe and efficacious ZIKV vaccine remains a global health priority. Here we report that a single immunization with Ad26.M.Env ZIKV vaccine, when administered prior to conception, fully protects pregnant rhesus macaques from ZIKV viral RNA in blood and tissues with no adverse effects in dams and fetuses. Furthermore, vaccination prevents ZIKV distribution to fetal tissues including the brain. ZIKV associated neuropathology was absent in offspring of Ad26.M.Env vaccinated dams, although pathology was limited in fetuses from non-immunized, challenged dams. Vaccine efficacy is associated with induction of ZIKV neutralizing antibodies in pregnant rhesus macaques. These data suggest the feasibility of vaccine prevention of CZS in humans.

Abstract Background The National Health Promotion Intervention Program by Student (HPIPS) is a French government educational program introduced in 2018, aiming at developing all health students’ health promotion knowledge and abilities, as well as implementing health promotion interventions for specific subpopulations in the general public. Its pedagogical framework was elaborated in 2018 and then evaluated by the French Council for Public Health in 2022, highlighting certain difficulties for the program to be homogeneously implemented in France. The aim of this study was to explore and describe the experiences and feedback of university lecturers in charge of this HPIPS training. Methods Semi-structured interviews were conducted with HPIPS lecturers from various health fields and from French universities, and a qualitative content analysis was carried out. Results Fourteen interviews were conducted during the autumn of 2022 with HPIPS program university lecturers including five doctors, three dentists, two nurses, two pharmacists, one midwife, and one physiotherapist from eight different towns belonging to six regions. Depending on the professional background, the component, and the local resources available, the teaching experience varied from one lecturer to another. A number of difficulties arose in setting up this educational program and complying with the latter legislation. The work overload was considerable, and the lecturers’ heavy commitments some lecturers to be discouraged, especially since some lecturers were not trained in health promotion abilities. Although interprofessionality was a strength of this HPIPS, it was also its main challenge. Pedagogical innovations were developed, notably through the use of digital technology; cross-disciplinary collaboration was established; and lecturers–students specific boundaries have emerged thanks to this health promotion project. Conclusions In France, setting up the HPIPS rapidly was experienced as a real pedagogical challenge for the interviewed university lecturers. While most of them noted the positive and beneficial contributions made by the introduction of prevention and health promotion intervention skills for health students, they also shared recommendations in order to match the ambitions and increase the HPIPS impact on the development of a culture of prevention and health promotion among health students.

Abstract Male sexual function can be disrupted by exposure to exogenous compounds that cause testicular physiological alterations. The constitutive androstane receptor (Car) is a receptor for both endobiotics and xenobiotics involved in detoxification. However, its role in male fertility, particularly in regard to the reprotoxic effects of environmental pollutants, remains unclear. This study aims to investigate the role of the Car signaling pathway in male fertility. In vivo, in vitro, and pharmacological approaches are utilized in wild‐type and Car‐deficient mouse models. The results indicate that Car inhibition impaired male fertility due to altered sperm quality, specifically histone retention, which is correlated with an increased percentage of dying offspring in utero. The data highlighted interactions among Car, Akt, Foxo1, and histone acetylation. This study demonstrates that Car is crucial in germ cell homeostasis and male fertility. Further research on the Car signaling pathway is necessary to reveal unidentified causes of altered fertility and understand the harmful impact of environmental molecules on male fertility and offspring health.

Background: Bipolar Disorder (BD) is associated with alterations of circadian rhythms of activity (CRA). Experimental research suggests that lithium (Li) modifies CRA, but this has been rarely explored in BD using actigraphy. Methods: The sample comprised 88 euthymic BD-I cases with 3 weeks of actigraphy. We used a Principal Component Analysis (PCA) to generate CRA dimensions. We then used linear regression analyses to compare these dimensions between groups of individuals defined according to prescribed mood stabilizers: Li monotherapy (“Li” group, n = 28), anticonvulsant or atypical antipsychotic monotherapy (“AC or AAP” group, n = 27) or combined treatments (“Li+AC or Li+AAP” group, n = 33). Analyses were adjusted for potential confounders (gender, age, body mass index, depressive symptoms, co-prescribed benzodiazepines and antidepressants, smoking status and past alcohol use disorder). Results: The PCA identified two dimensions: “robust CRA” (high amplitude and interdaily stability, with low intradaily variability) and “late chronotype”. Univariate analyses showed higher scores for “robust CRA” in the “Li” versus the “AC or AAP” (p = 0.021) or “Li+AC or Li+AAP” groups (p = 0.047). These findings remained significant after adjustments (respectively p = 0.010 and p = 0.019). Post-hoc analyses suggested lower variability, higher stability and higher amplitude of CRA in the “Li” group. Medication groups were similar for the “late chronotype” dimension (p = 0.92). Conclusions: This actigraphy study is the first to show more favorable CRA in BD-I individuals receiving a Li monotherapy when compared with those receiving other classes or combinations of mood stabilizers. Replications in larger samples are required. Prospective studies are also warranted to elucidate whether the introduction of Li or other mood stabilizers might influence CRA in BD-I.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Objectives Telemonitoring (TM) of home non-invasive ventilation (NIV) has been shown to facilitate home/outpatient therapy set-up. However, the impact of long-term TM on therapy dropouts, compliance and leak control has not yet been clearly determined. This study evaluated whether the NIV dropout rate was reduced by TM combined with remote patient support compared with a non-telemonitoring (NTM) pathway.Design Retrospective cohort study.Setting Data were obtained from all agencies of a single home care provider in France.Participants Adults with chronic respiratory failure (n=659) who started nocturnal NIV between January 2017 and December 2019 and had ≥8 days of NIV therapy (51% male; mean age 68.5±13.8 years; 35.5% on long-term oxygen therapy) were included. The TM group included 275 patients who spent ≥80% of the follow-up using TM, and the NTM group included 384 patients who had 0 to ≤10 days of telemonitoring during follow-up.Primary and secondary outcome measures The primary outcome was the rate of NIV dropouts at 1 year (ie, treatment discontinuation, excluding deaths). Secondary outcomes included therapy compliance and leaks.Results 82 patients died during follow-up. Significantly fewer patients in the TM vs NTM group had dropped out of NIV therapy at 1 year (13% vs 34%; p4 hours/day and control of leaks.Conclusions In patients starting home NIV, TM with home care provider first-line support was associated with a lower therapy dropout rate at 1 year, and better compliance and leak control, compared with standard follow-up.

Abstract Monitoring unintentional air leaks in continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) is essential for therapy success. While leaks are often attributed to improperly sealed masks, mouth openings may also cause them, requiring interventions. Recent studies demonstrated distinctive mandibular jaw movement (MJM) signal patterns during sleep related to respiratory events and sleep stages. Analysing MJM during CPAP treatment reveals air leak peaks coinciding with maximal MJM amplitude during obstructive events, and air leak decreases corresponding to arousals. Examining leaks with MJM offers valuable insights into their origins and might open new avenues for CPAP management.

Over recent years, positive airway pressure (PAP) remote monitoring has transformed the management of OSA and produced a large amount of data. Accumulated PAP data provide valuable and objective information regarding patient treatment adherence and efficiency. However, the majority of studies that have analyzed longitudinal PAP remote monitoring have summarized data trajectories in static and simplistic metrics for PAP adherence and the residual apnea-hypopnea index by the use of mean or median values. The aims of this article are to suggest directions for improving data cleaning and processing and to address major concerns for the following data science applications: (1) conditions for residual apnea-hypopnea index reliability, (2) lack of standardization of indicators provided by different PAP models, (3) missing values, and (4) consideration of treatment interruptions. To allow fair comparison among studies and to avoid biases in computation, PAP data processing and management should be conducted rigorously with these points in mind. PAP remote monitoring data contain a wealth of information that currently is underused in the field of sleep research. Improving the quality and standardizing data handling could facilitate data sharing among specialists worldwide and enable artificial intelligence strategies to be applied in the field of sleep apnea.

BackgroundMechanisms underlying blood pressure changes in obstructive sleep apnoea (OSA) are incompletely understood. Increased respiratory effort is one of the main features of OSA and is associated with sympathetic overactivity, leading to increased vascular wall stiffness and remodelling. This study investigated associations between a new measure of respiratory effort (percentage of total sleep time spent with increased respiratory effort based on measurement of mandibular jaw movements (MJM): REMOV, %TST) and prevalent hypertension in adults referred for evaluation of suspected OSA.MethodsA machine learning model was built to predict hypertension from clinical data, conventional polysomnography (PSG) indices and MJM-derived parameters (including REMOV). The model was evaluated in a training subset and a test subset.ResultsThe analysis included 1127 patients: 901 (80%) in the training subset and 226 (20%) in the test subset. The prevalence of hypertension was 31% and 30%, respectively, in the training and test subsets. A risk stratification model based on 18 input features including REMOV had good accuracy for predicting prevalent hypertension (sensitivity 0.75 and specificity 0.83). Using the Shapley additive explanation method, REMOV was the best predictor of hypertension after clinical risk factors (age, sex, body mass index and neck circumference) and time with oxygen saturation

This study explored the generality versus specificity of two trait-liability factors for externalizing problems-disinhibition and callousness-in the concurrent and prospective prediction of symptoms of conduct disorder, attention-deficit/hyperactivity disorder (ADHD), and substance use (i.e., alcohol use disorder and history of illicit substance use). Disinhibition involves an impulsive, unrestrained cognitive-behavioral style; callousness entails a dispositional lack of social-emotional sensitivity. Participants were European adolescents from the multisite IMAGEN project who completed questionnaires and clinical interviews at ages 14 (N = 1,504, Mage = 14.41, 51.13% female) and 16 (N = 1,407, Mage = 16.46, 51.88% female). Disinhibition was related concurrently and prospectively to greater symptoms of conduct disorder, ADHD, and alcohol use disorder; higher scores on a general externalizing factor; and greater likelihood of having tried an illicit substance. Callousness was selectively related to greater conduct disorder symptoms. These findings indicate disinhibition confers broad liability for externalizing spectrum disorders, perhaps due to its affiliated deficits in executive function. In contrast, callousness appears to represent more specific liability for antagonistic (aggressive/exploitative) forms of externalizing, as exemplified by antisocial behavior. Results support the utility of developmental-ontogenetic and hierarchical-dimensional models of psychopathology and have important implications for early assessment of risk for externalizing problems. (PsycInfo Database Record (c) 2022 APA, all rights reserved).