Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.

We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).

Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.

Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.

Giant coronary artery aneurysms are rare but potentially fatal complications of Kawasaki disease. The lack of evidence-based recommendations on their management and treatment cause guidelines and practices to differ. We aimed to assess these variations.

An anonymous online survey regarding surveillance, imaging, pharmacological management, and interventional practices was distributed among 134 physicians attending to Kawasaki disease patients worldwide. A p-value of <0.05 was deemed significant.

The majority (60%) of respondents were general paediatric cardiologists, and 29% interventional specialists. The average years in practice was 15 ± 9.6. Physicians from Asia had the most experience with giant coronary artery aneurysms. American practitioners preferred combining anticoagulants with aspirin. Beta-blockers and statins were more likely used in teenagers versus younger children. Cardiac catheterisation was most (52%) chosen for coronary surveillance in patients with echocardiogram anomalies, followed by Coronary CT-angiography. The indications for coronary intervention were split among respondents, regardless of geographic region or experience. The preferred treatment of coronary stenosis was percutaneous intervention (69%) versus bypass surgery. For thrombosis, thrombolytics (50%) were preferred over percutaneous (39%) and surgical (11%) interventions. Most (92%) preferred intervening in young children in a paediatric facility but were split between a paediatric and adult facility for older children. Most chose combined management by adult and paediatric specialists for either age-scenarios (70, 82%).

As identified by our study, the lack of large studies and evidence-based recommendations cause uncertainty and ambivalence towards certain treatments. International collaborative efforts are needed to provide more robust evidence in the management of these patients.

Major depressive disorder (MDD) is a prevalent and disabling condition. Approximately 30-50% of patients do not respond to first-line medication or psychotherapy. Therefore, several studies have investigated the predictive potential of pretreatment severity rating or neuroimaging features to guide clinical approaches that can speed optimal treatment selection.

To evaluate the performance of 1) severity ratings (scores of Hamilton Depression/Anxiety Scale, illness duration, and sleep quality, etc.) and demographic characteristic and 2) brain magnetic resonance imaging (MRI) features in predicting treatment outcomes for MDD. Second, to assess performance variations among varied modalities and interventions in MRI studies.

We searched studies in PubMed, Embase, Web of Science, and Science Direct databases before March 22, 2023. We extracted a confusion matrix for prediction in each study. Separate meta-analyses were performed for clinical and MRI studies. The logarithm of diagnostic odds ratio [log(DOR)], sensitivity, and specificity were conducted using Reitsma’s random effect model. The area under curve (AUC) of summary receiver operating characteristic (SROC) curve was calculated.

Subgroup analyses were conducted in MRI studies based on modalities: resting-state functional MRI (rsfMRI), task-based fMRI (tbfMRI), and structural MRI (sMRI), and interventions: antidepressant (including selective serotonin reuptake inhibitors [SSRI]) and electroconvulsive therapy (ECT). Meta-regression was conducted 1) between clinical and MRI studies and 2) among modality or intervention subgroups in MRI studies.

We included ten studies used clinical features covering 6494 patients, yielded a log(DOR) of 1.42, AUC of 0.71, sensitivity of 0.61, and specificity of 0.74. In terms of MRI, 44 studies with 2623 patients were included, revealing an overall log(DOR) of 2.53. The AUC, sensitivity, and specificity were 0.89, 0.78, and 0.75.

Studies using MRI features had a higher sensitivity (0.89 vs. 0.61) in predicting treatment outcomes than clinical features (P < 0.001). RsfMRI had higher specificity (0.79 vs. 0.69) than tbfMRI subgroup (P = 0.01). No significant differences were found between sMRI and other modalities, nor between antidepressants (SSRIs and others) and ECT. Antidepressant studies primarily identified predictive imaging features in limbic and default mode networks, while ECT mainly focused on limbic network.

Our findings suggest a robust promise for pretreatment brain MRI features in predicting treatment outcomes in MDD, offering higher accuracy than clinical studies. While tasks in tbfMRI studies differed, those studies overall had less predictive utility than rsfMRI data. For MRI studies, overlapping but distinct network level measures predicted outcomes for antidepressants and ECT.

None Declared

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder. It is considered that dysregulation of cytokine levels is related to the pathophysiological mechanism of OCD. However, the results of previous studies on cytokine levels in OCD are inconsistent.

To perform a meta-analysis assessing cytokine levels in peripheral blood of OCD patients.

We searched in PubMed, Web of Science, and Embase from inception to March 31, 2023 for eligible studies. We conducted multivariate meta-analysis in combined proinflammatory cytokines (interleukin-6 [IL-6], IL-1β, IL-2, tumor necrosis factor-α [TNF-α], and interferon-γ [IFN-γ]) and combined anti-inflammatory cytokines (IL-10 and IL-4) respectively, and calculated the same meta-analysis in each cytokine. We also performed sensitivity analysis and publication bias tests, as well as subgroup analysis (i.e. different age groups, varied cytokine measurement methods, medication treated or naïve, and presence of psychiatric comorbidities) and meta-regression analysis (variables including patients’ sex ratio, age, age at symptom onset, illness duration, scores of Y-BOCS, family history of psychiatric disorders, and BMI).

17 original studies (13, 13, 10, 5, 4, 3, 2 studies for IL-6, TNF-α, IL-1β, IL-10, IL-2, IL-4, and IFN-γ, respectively), 573 patients (mean age, 25.2; 50.3% female) and 498 healthy controls (HC; mean age, 25.3; 51.4% female) were included. The results showed that the levels of combined pro- or anti-inflammatory cytokines and each signle cytokine were not significantly different between OCD patients and HC (all P>0.05), with significant heterogeneities in all analyses (I2 from 79.1% to 91.7%). We did not find between-group differences in cytokine levels in all subgroup analyses. Meta-regression analysis suggested that age at onset (P=0.0003) and family history (P=0.0062) might be the source of heterogeneity in TNF-α level. Sensitivity analysis confirmed that all results were stable, except for IL-4 where different cytokine measurement methods may be the contributing factor. Egger test did not find publication bias.

Our study showed no difference in cytokine levels between OCD patients and HC, but age at onset and family history may affect TNF-α level. Confounding factors such as age at onset, family history, and cytokine measurement methods should be controlled in future studies to further explore the immune mechanism of OCD.

None Declared

Adolescence is a period marked by highest vulnerability to the onset of depression, with profound implications for adult health. Neuroimaging studies have revealed considerable atrophy in brain structure in these patients with depression. Of particular importance are regions responsible for cognitive control, reward, and self-referential processing. However, the causal structural networks underpinning brain region atrophies in adolescents with depression remain unclear.

This study aimed to investigate the temporal course and causal relationships of gray matter atrophy within the brains of adolescents with depression.

We analyzed T1-weighted structural images using voxel-based morphometry in first-episode adolescent patients with depression (n=80, 22 males; age = 15.57±1.78) and age, gender matched healthy controls (n=82, 25 males; age = 16.11±2.76) to identify the disease stage-specific gray matter abnormalities. Then, with granger causality analysis, we arranged the patients’ illness duration chronologically to construct the causal structural covariance networks that investigated the causal relationships of those atypical structures.

Compared to controls, smaller volumes in ventral medial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), middle cingulate cortex (MCC) and insula areas were identified in patients with less than 1 year illness duration, and further progressed to the subgenual ACC, regions of default, frontoparietal networks in longer duration. Causal network results revealed that dACC, vmPFC, MCC and insula were prominent nodes projecting exerted positive causal effects to regions of the default mode and frontoparietal networks. The dACC, vmPFC and insula also had positive projections to the reward network, which included mainly the thalamus, caudate and putamen, while MCC also exerted a positive causal effect on the insula and thalamus.

These findings revealed the progression of structural atrophy in adolescent patients with depression and demonstrated the causal relationships between regions involving cognitive control, reward and self-referential processes.

None Declared

There’s large heterogeneity present in major depressive disorder (MDD) and controversial evidence on alterations of brain functional connectivity (FC), making it hard to elucidate the neurobiological basis of MDD. Subtyping is one promising solution to characterize this heterogeneity.

To identify neurophysiological subtypes of MDD based on FC derived from resting-state functional magnetic resonance imaging using large multisite data and investigate the differences in genetic mechanisms and neurotransmitter basis of FC alterations, and the differences of FC-related cognition between each subtype.

Consensus clustering of FC patterns was applied to a population of 829 MDD patients from REST-Meta-MDD database after data cleaning and image quality control. Gene transcriptomic data derived from Allen Human Brain Atlas and neurotransmitter receptor/transporter density data acquired by using neuromap toolbox were used to characterize the molecular mechanism underlying each FC-based subtype by identifying the gene set and neurotransmitters/transporters showing high spatial similarity with the profiles of FC alterations between each subtype and 770 healthy controls. The FC-related cognition in each subtype was also selected by lasso regression.

Two stable neurophysiological MDD subtypes were found and labeled as hypoconnectivity (n=527) and hyperconnectivity (n=299) characterized by the FC differences in each subtype relative to controls, respectively. The two subtypes did not differ in age, sex, and scores of Hamilton Depression/Anxiety Scale.

The genes related to FC alterations were enriched in ion transmembrane transport, synaptic transmission/organization, axon development, and regulation of neurotransmitter level for both subtypes, but specifically enriched in glial cell differentiation for hypoconnectivity subtype, while enriched in regulation of presynaptic membrane and regulation of neuron differentiation for hyperconnectivity subtype.

FC alterations were associated with the density of 5-HT2a receptor in both subtypes. For hyperconnectivity subtype, FC alterations were also correlated with the density of norepinephrine transporter, glutamate receptor, GABA receptor, 5-HT1b receptor, and cannabinoid receptor.

Both subtypes showed correlations between FC and categorization, motor inhibition, and localization. The FC in hypoconnectivity subtype correlated with response inhibition, selective attention, face recognition, sleep, empathy, expertise, uncertainty, and anticipation, while that was related to inference, speech perception, and reward anticipation in hyperconnectivity subtype.

Our findings suggested the presence of two neuroimaging subtypes of MDD characterized by hypo or hyper-connectivity. The two subtypes had both shared and distinct genetic mechanisms, neurotransmitter receptor/transporter profiles, and cognition types.

None Declared

To examine the effectiveness of Self-Help Plus (SH+) as an intervention for alleviating stress levels and mental health problems among healthcare workers.

This was a prospective, two-arm, unblinded, parallel-designed randomised controlled trial. Participants were recruited at all levels of medical facilities within all municipal districts of Guangzhou. Eligible participants were adult healthcare workers experiencing psychological stress (10-item Perceived Stress Scale scores of ≥15) but without serious mental health problems or active suicidal ideation. A self-help psychological intervention developed by the World Health Organization in alleviating psychological stress and preventing the development of mental health problems. The primary outcome was psychological stress, assessed at the 3-month follow-up. Secondary outcomes were depression symptoms, anxiety symptoms, insomnia, positive affect (PA) and self-kindness assessed at the 3-month follow-up.

Between November 2021 and April 2022, 270 participants were enrolled and randomly assigned to either SH+ (n = 135) or the control group (n = 135). The SH+ group had significantly lower stress at the 3-month follow-up (b = −1.23, 95% CI = −2.36, −0.10, p = 0.033) compared to the control group. The interaction effect indicated that the intervention effect in reducing stress differed over time (b = −0.89, 95% CI = −1.50, −0.27, p = 0.005). Analysis of the secondary outcomes suggested that SH+ led to statistically significant improvements in most of the secondary outcomes, including depression, insomnia, PA and self-kindness.

This is the first known randomised controlled trial ever conducted to improve stress and mental health problems among healthcare workers experiencing psychological stress in a low-resource setting. SH+ was found to be an effective strategy for alleviating psychological stress and reducing symptoms of common mental problems. SH+ has the potential to be scaled-up as a public health strategy to reduce the burden of mental health problems in healthcare workers exposed to high levels of stress.

We identify a set of essential recent advances in climate change research with high policy relevance, across natural and social sciences: (1) looming inevitability and implications of overshooting the 1.5°C warming limit, (2) urgent need for a rapid and managed fossil fuel phase-out, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future contribution of natural carbon sinks, (5) intertwinedness of the crises of biodiversity loss and climate change, (6) compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems.

The Intergovernmental Panel on Climate Change Assessment Reports provides the scientific foundation for international climate negotiations and constitutes an unmatched resource for researchers. However, the assessment cycles take multiple years. As a contribution to cross- and interdisciplinary understanding of climate change across diverse research communities, we have streamlined an annual process to identify and synthesize significant research advances. We collected input from experts on various fields using an online questionnaire and prioritized a set of 10 key research insights with high policy relevance. This year, we focus on: (1) the looming overshoot of the 1.5°C warming limit, (2) the urgency of fossil fuel phase-out, (3) challenges to scale-up carbon dioxide removal, (4) uncertainties regarding future natural carbon sinks, (5) the need for joint governance of biodiversity loss and climate change, (6) advances in understanding compound events, (7) accelerated mountain glacier loss, (8) human immobility amidst climate risks, (9) adaptation justice, and (10) just transitions in food systems. We present a succinct account of these insights, reflect on their policy implications, and offer an integrated set of policy-relevant messages. This science synthesis and science communication effort is also the basis for a policy report contributing to elevate climate science every year in time for the United Nations Climate Change Conference.

We highlight recent and policy-relevant advances in climate change research – with input from more than 200 experts.

Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care.

This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as “too late” (death or declined for transplant due to being too sick) and/or “care escalation” (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. “Late referral” was defined as those referred too late and/or had care escalation.

Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8–21.5, p=0.004).

Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.