It remains unclear which individuals with subthreshold depression benefit most from psychological intervention, and what long-term effects this has on symptom deterioration, response and remission.

To synthesise psychological intervention benefits in adults with subthreshold depression up to 2 years, and explore participant-level effect-modifiers.

Randomised trials comparing psychological intervention with inactive control were identified via systematic search. Authors were contacted to obtain individual participant data (IPD), analysed using Bayesian one-stage meta-analysis. Treatment–covariate interactions were added to examine moderators. Hierarchical-additive models were used to explore treatment benefits conditional on baseline Patient Health Questionnaire 9 (PHQ-9) values.

IPD of 10 671 individuals (50 studies) could be included. We found significant effects on depressive symptom severity up to 12 months (standardised mean-difference [s.m.d.] = −0.48 to −0.27). Effects could not be ascertained up to 24 months (s.m.d. = −0.18). Similar findings emerged for 50% symptom reduction (relative risk = 1.27–2.79), reliable improvement (relative risk = 1.38–3.17), deterioration (relative risk = 0.67–0.54) and close-to-symptom-free status (relative risk = 1.41–2.80). Among participant-level moderators, only initial depression and anxiety severity were highly credible (P > 0.99). Predicted treatment benefits decreased with lower symptom severity but remained minimally important even for very mild symptoms (s.m.d. = −0.33 for PHQ-9 = 5).

Psychological intervention reduces the symptom burden in individuals with subthreshold depression up to 1 year, and protects against symptom deterioration. Benefits up to 2 years are less certain. We find strong support for intervention in subthreshold depression, particularly with PHQ-9 scores ≥ 10. For very mild symptoms, scalable treatments could be an attractive option.

The Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic and mechanistic aspects of psychopathology. We used a multi-omics approach to examine how HiTOP’s psychopathology spectra (externalizing [EXT], internalizing [INT], and shared EXT + INT) map onto RDoC’s units of analysis.

We conducted analyses across five RDoC units of analysis: genes, molecules, cells, circuits, and physiology. Using genome-wide association studies from the companion Part I article, we identified genes and tissue-specific expression patterns. We used drug repurposing analyses that integrate gene annotations to identify potential therapeutic targets and single-cell RNA sequencing data to implicate brain cell types. We then used magnetic resonance imaging data to examine brain regions and circuits associated with psychopathology. Finally, we tested causal relationships between each spectrum and physical health conditions.

Using five gene identification methods, EXT was associated with 1,759 genes, INT with 454 genes, and EXT + INT with 1,138 genes. Drug repurposing analyses identified potential therapeutic targets, including those that affect dopamine and serotonin pathways. Expression of EXT genes was enriched in GABAergic, cortical, and hippocampal neurons, while INT genes were more narrowly linked to GABAergic neurons. EXT + INT liability was associated with reduced gray matter volume in the amygdala and subcallosal cortex. INT genetic liability showed stronger causal effects on physical health – including chronic pain and cardiovascular diseases – than EXT.

Our findings revealed shared and distinct pathways underlying psychopathology. Integrating genomic insights with the RDoC and HiTOP frameworks advanced our understanding of mechanisms that underlie EXT and INT psychopathology.

There is considerable comorbidity between externalizing (EXT) and internalizing (INT) psychopathology. Understanding the shared genetic underpinnings of these spectra is crucial for advancing knowledge of their biological bases and informing empirical models like the Research Domain Criteria (RDoC) and Hierarchical Taxonomy of Psychopathology (HiTOP).

We applied genomic structural equation modeling to summary statistics from 16 EXT and INT traits in individuals genetically similar to European reference panels (EUR-like; n = 16,400 to 1,074,629). Traits included clinical (e.g. major depressive disorder, alcohol use disorder) and subclinical measures (e.g. risk tolerance, irritability). We tested five confirmatory factor models to identify the best fitting and most parsimonious genetic architecture and then conducted multivariate genome-wide association studies (GWAS) of the resulting latent factors.

A two-factor correlated model, representing EXT and INT spectra, provided the best fit to the data. There was a moderate genetic correlation between EXT and INT (r = 0.37, SE = 0.02), with bivariate causal mixture models showing extensive overlap in causal variants across the two spectra (94.64%, SE = 3.27). Multivariate GWAS identified 409 lead genetic variants for EXT, 85 for INT, and 256 for the shared traits.

The shared genetic liabilities for EXT and INT identified here help to characterize the genetic architecture underlying these frequently comorbid forms of psychopathology. The findings provide a framework for future research aimed at understanding the shared and distinct biological mechanisms underlying psychopathology, which will help to refine psychiatric classification systems and potentially inform treatment approaches.

Borderline personality disorder (BPD) is a debilitating psychiatric illness whose symptoms frequently emerge during adolescence. Critically, self-injury and suicide attempts in BPD are often precipitated by interpersonal discord. Initial studies in adults suggest that the interpersonal difficulties common in BPD may emerge from disrupted processing of socioemotional stimuli. Less is known about these processes in adolescents with BPD symptoms, despite substantial changes in socioemotional processing during this developmental period.

Eighty-six adolescents and young adults with and without BPD symptoms completed an emotional interference task involving the identification of a facial emotion expression in the presence of a conflicting or congruent emotion word. We used hierarchical drift diffusion modeling to index speed of processing and decision boundary. Using Bayesian multilevel regression, we characterized age-related differences in facial emotion processing. We examined whether BPD symptom dimensions were associated with alterations in facial emotion processing. To determine the specificity of our effects, we analyzed behavioral data from a corresponding nonemotional interference task.

Emotion-related impulsivity, but not negative affectivity or interpersonal dysfunction, predicted inefficient processing when presented with conflicting negative emotional stimuli. Across both tasks, emotion-related impulsivity in adolescents, but not young adults, was further associated with a lower decision boundary – resulting in fast but inaccurate decisions.

Impulsive adolescents with BPD symptoms are prone to making errors when appraising facial emotion expressions, which may potentiate or worsen interpersonal conflicts. Our findings highlight the role of lower-level social cognitive processes in interpersonal difficulties among vulnerable youth during a sensitive developmental window.

In acute ischemic stroke, a longer time from onset to endovascular treatment (EVT) is associated with worse clinical outcome. We investigated the association of clinical outcome with time from last known well to arrival at the EVT hospital and time from hospital arrival to arterial access for anterior circulation large vessel occlusion patients treated > 6 hours from last known well.

Retrospective analysis of the prospective, multicenter cohort study ESCAPE-LATE. Patients presenting > 6 hours after last known well with anterior circulation large vessel occlusion undergoing EVT were included. The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were good (mRS 0–2) and poor clinical outcomes (mRS 5–6) at 90 days, as well as the National Institutes of Health Stroke Scale at 24 hours. Associations of time intervals with outcomes were assessed with univariable and multivariable logistic regression.

Two hundred patients were included in the analysis, of whom 85 (43%) were female. 90-day mRS was available for 141 patients. Of the 150 patients, 135 (90%) had moderate-to-good collaterals, and the median Alberta Stroke Program Early CT Score (ASPECTS) was 8 (IQR = 7–10). No association between ordinal mRS and time from last known well to arrival at the EVT hospital (odds ratio [OR] = 1.01, 95% CI = 1.00–1.02) or time from hospital arrival to arterial access (OR = -0.01, 95% CI = -0.02–0.00) was seen in adjusted regression models.

No relationship was observed between pre-hospital or in-hospital workflow times and clinical outcomes. Baseline ASPECTS and collateral status were favorable in the majority of patients, suggesting that physicians may have chosen to predominantly treat slow progressors in the late time window, in whom prolonged workflow times have less impact on outcomes.

Previous studies identified clusters of first-episode psychosis (FEP) patients based on cognition and premorbid adjustment. This study examined a range of socio-environmental risk factors associated with clusters of FEP, aiming a) to compare clusters of FEP and community controls using the Maudsley Environmental Risk Score for psychosis (ERS), a weighted sum of the following risks: paternal age, childhood adversities, cannabis use, and ethnic minority membership; b) to explore the putative differences in specific environmental risk factors in distinguishing within patient clusters and from controls.

A univariable general linear model (GLS) compared the ERS between 1,263 community controls and clusters derived from 802 FEP patients, namely, low (n = 223) and high-cognitive-functioning (n = 205), intermediate (n = 224) and deteriorating (n = 150), from the EU-GEI study. A multivariable GLS compared clusters and controls by different exposures included in the ERS.

The ERS was higher in all clusters compared to controls, mostly in the deteriorating (β=2.8, 95% CI 2.3 3.4, η2 = 0.049) and the low-cognitive-functioning cluster (β=2.4, 95% CI 1.9 2.8, η2 = 0.049) and distinguished them from the cluster with high-cognitive-functioning. The deteriorating cluster had higher cannabis exposure (meandifference = 0.48, 95% CI 0.49 0.91) than the intermediate having identical IQ, and more people from an ethnic minority (meandifference = 0.77, 95% CI 0.24 1.29) compared to the high-cognitive-functioning cluster.

High exposure to environmental risk factors might result in cognitive impairment and lower-than-expected functioning in individuals at the onset of psychosis. Some patients’ trajectories involved risk factors that could be modified by tailored interventions.

Urgent care centers (UCCs) have reported high rates of antibiotic prescribing for acute respiratory tract infections. Prior UCC studies have generally been limited to single networks. Broadly generalizable stewardship efforts targeting common diagnoses are needed. This study examines the effectiveness of an antibiotic stewardship intervention in reducing inappropriate prescribing for bronchitis and viral upper respiratory tract infections (URTIs) in UCCs.

A quality improvement study comparing inappropriate antibiotic prescribing rates in UCCs after the introduction of an antibiotic stewardship intervention.

Forty-nine UCCs in 27 different networks from 18 states, including 1 telemedicine site.

Urgent care clinicians from a national collaborative of UCCs, all members of the Urgent Care Association.

The intervention included signing a commitment statement and selecting from 5 different intervention options during 3 plan-do-study-act cycles. The primary outcome was the percentage of urgent care encounters for viral URTIs or bronchitis with inappropriate prescribing, stratified by clinician engagement and diagnosis. A 3-month baseline and 9-month intervention period were compared using a regression model using a generalized estimating equation.

Among 15,385 encounters, the intervention was associated with decreases in inappropriate antibiotic prescribing for bronchitis (48% relative decrease, aOR = 0.52; 95% CI, 0.33–0.83) and viral URTIs (33%, aOR = 0.67; 95% CI, 0.55–0.82) among actively engaged clinicians compared to baseline. The intervention did not result in significant changes for clinicians not actively engaged.

This intervention was associated with reductions in inappropriate prescribing among actively engaged clinicians. Implementing stewardship interventions in UCCs may reduce inappropriate antibiotic prescriptions for common diagnoses; however, active clinician engagement may be necessary.

Successfully educating urgent care patients on appropriate use and risks of antibiotics can be challenging. We assessed the conscious and subconscious impact various educational materials (informational handout, priming poster, and commitment poster) had on urgent care patients’ knowledge and expectations regarding antibiotics.

Stratified Block Randomized Control Trial.

Urgent care centers (UCCs) in Colorado, Florida, Georgia, and New Jersey.

Urgent care patients.

We randomized 29 UCCs across six study arms to display specific educational materials (informational handout, priming poster, and commitment poster). The primary intention-to-treat (ITT) analysis evaluated whether the materials impacted patient knowledge or expectations of antibiotic prescribing by assigned study arm. The secondary as-treated analysis evaluated the same outcome comparing patients who recalled seeing the assigned educational material and patients who either did not recall seeing an assigned material or were in the control arm.

Twenty-seven centers returned 2,919 questionnaires across six study arms. Only 27.2% of participants in the intervention arms recalled seeing any educational materials. In our primary ITT analysis, no difference in knowledge or expectations of antibiotic prescribing was noted between groups. However, in the as-treated analysis, the handout and commitment poster were associated with higher antibiotic knowledge scores.

Educational materials in UCCs are associated with increased antibiotic-related knowledge among patients when they are seen and recalled; however, most patients do not recall passively displayed materials. More emphasis should be placed on creating and drawing attention to memorable patient educational materials.