Trace amine-associated receptor 1 (TAAR1) agonists offer a new approach, but there is uncertainty regarding their effects, exact mechanism of action and potential role in treating psychosis.

To evaluate the available evidence on TAAR1 agonists in psychosis, using triangulation of the output of living systematic reviews (LSRs) of animal and human studies, and provide recommendations for future research prioritisation.

This study is part of GALENOS (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis). In the triangulation process, a multidisciplinary group of experts, including those with lived experience, met and appraised the first co-produced living systematic reviews from GALENOS, on TAAR1 agonists.

The animal data suggested a potential antipsychotic effect, as TAAR1 agonists reduced locomotor activity induced by pro-psychotic drug treatment. Human studies showed few differences for ulotaront and ralmitaront compared with placebo in improving overall symptoms in adults with acute schizophrenia (four studies, n = 1291 participants, standardised mean difference (SMD) 0.15, 95% CI −0.05 to 0.34). Large placebo responses were seen in ulotaront phase three trials. Ralmitaront was less efficacious than risperidone (one study, n = 156 participants, SMD = −0.53, 95% CI −0.86 to −0.20). The side-effect profile of TAAR1 agonists was favourable compared with existing antipsychotics. Priorities for future studies included (a) using different animal models of psychosis with greater translational validity; (b) animal and human studies with wider outcomes including cognitive and affective symptoms and (c) mechanistic studies and investigations of other potential applications, such as adjunctive treatments and long-term outcomes. Recommendations for future iterations of the LSRs included (a) meta-analysis of individual human participant data, (b) including studies that used different methodologies and (c) assessing other disorders and symptoms.

This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research.

Carbapenem-resistant Enterobacterales (CRE) are an urgent threat to healthcare, but the epidemiology of these antimicrobial-resistant organisms may be evolving in some settings since the COVID-19 pandemic. An updated analysis of hospital-acquired CRE (HA-CRE) incidence in community hospitals is needed.

We retrospectively analyzed data on HA-CRE cases and antimicrobial utilization (AU) from two community hospital networks, the Duke Infection Control Outreach Network (DICON) and the Duke Antimicrobial Stewardship Outreach Network (DASON) from January 2013 to June 2023. The zero-inflated negative binomial regression model was used owing to excess zeros.

126 HA-CRE cases from 36 hospitals were included in the longitudinal analysis. The pooled incidence of HA CRE was 0.69 per 100,000 patient days (95% confidence interval [95% CI], 0.57–0.82 HA-CRE rate significantly decreased over time before COVID-19 (rate ratio [RR], 0.94 [95% CI, 0.89–0.99]; p = 0.02), but there was a significant slope change indicating a trend increase in HA-CRE after COVID-19 (RR, 1.32 [95% CI, 1.06–1.66]; p = 0.01). In 21 hospitals participating in both DICON and DASON from January 2018 to June 2023, there was a correlation between HA-CRE rates and AU for CRE treatment (Spearman’s coefficient = 0.176; p < 0.01). Anti-CRE AU did not change over time, and there was no level or slope change after COVID.

The incidence of HA-CRE decreased before COVID-19 in a network of community hospitals in the southeastern United States, but this trend was disrupted by the COVID-19 pandemic.

Suicide has a complex relationship with several factors, and it is known that identifying high-risk groups of suicide and managing crisis in advance can help prevent suicide. Moreover in a previous study, it showed that people with chronic diseases often suffer from psychological difficulties such as depression and anxiety, which can influence one to commit suicide. Based on many studies about the relationship between diabetes and depression, 10% of diabetic patients experience major depression, and diabetic patients experience twice as much depression as the general population. But, there are few studies examining the relationship between diabetes and suicide risk, and most of them were targeted for type 1 diabetes only.

The objectives of this study were to investigate the suicide risk in diabetic patients, and evaluate the suicide risk varies by the duration of diabetes, using a large population sample in South Korea

Using the 2019 Korea National Health and Nutrition Examination Survey data, 6,296 adults (aged 19 years or older) were included. Suicidal ideation, suicidal plan, and suicidal behavior of diabetic patients were compared with the general population. After classifying the patients into ≤ 1 year, 2 to 9 years, and 10 years ≤ for the duration of diabetes, we evaluated the relationship between the duration of diabetes and the risk of suicide.

Diabetic patients had higher prevalence of suicidal ideation (9.1%, P<0.001) and suicidal plan (3.6%, P<0.001) than general population. After adjusting for potential confounding factors, suicidal plan (aOR = 3.011, 95% CI = 1.392-6.512) was significantly associated with diabetes. In the 2 to 9 year group of diabetes, we found an increase in risk of suicidal ideation (aOR=2.068, 95% CI=1.219-3.510), suicidal plan (aOR=3.640, 95% CI=1.592-8.320), and suicidal behavior (aOR=6.222, 95% CI=1.759-22.008) after adjusting covariates. However, increase in suicide risk was not observed in the ≤1 year and 10 years ≤ groups after diagnosis of diabetes.

In adults, diabetes is associated with increase in suicide risk. Suicide risk in diabetic patients shows an ‘inverted U-shaped’ depending on the duration of diabetes.

None Declared

The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer’s disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships.

64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction.

Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p = .004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p = .005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased.

LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies.

This meta-analysis aimed to consolidate existing data from randomised controlled trials on hypoplastic left heart syndrome.

Hypoplastic left heart syndrome specific randomised controlled trials published between January 2005 and September 2021 in MEDLINE, EMBASE, and Cochrane databases were included. Regardless of clinical outcomes, we included all randomised controlled trials about hypoplastic left heart syndrome and categorised them according to their results. Two reviewers independently assessed for eligibility, relevance, and data extraction. The primary outcome was mortality after Norwood surgery. Study quality and heterogeneity were assessed. A random-effects model was used for analysis.

Of the 33 included randomised controlled trials, 21 compared right ventricle-to-pulmonary artery shunt and modified Blalock–Taussig-Thomas shunt during the Norwood procedure, and 12 regarded medication, surgical strategy, cardiopulmonary bypass tactics, and ICU management. Survival rates up to 1 year were superior in the right ventricle-to-pulmonary artery shunt group; this difference began to disappear at 3 years and remained unchanged until 6 years. The right ventricle-to-pulmonary artery shunt group had a significantly higher reintervention rate from the interstage to the 6-year follow-up period. Right ventricular function was better in the modified Blalock–Taussig-Thomas shunt group 1–3 years after the Norwood procedure, but its superiority diminished in the 6-year follow-up. Randomised controlled trials regarding medical treatment, surgical strategy during cardiopulmonary bypass, and ICU management yielded insignificant results.

Although right ventricle-to-pulmonary artery shunt appeared to be superior in the early period, the two shunts applied during the Norwood procedure demonstrated comparable long-term prognosis despite high reintervention rates in right ventricle-to-pulmonary artery shunt due to pulmonary artery stenosis. For medical/perioperative management of hypoplastic left heart syndrome, further randomised controlled trials are needed to deliver specific evidence-based recommendations.

Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD).

To investigate the genomic architecture of ASD in terms of non-coding de novo mutations and 3-dimensional chromatin interactions

We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions.

Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development.

Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

None Declared

Lamina-specific alterations of inhibitory circuitries have been considered the crucial pathogenesis of perceptual, cognitive and behavioral symptoms presented in schizophrenia and mood disorders. Especially, with emerging evidences indicating the close lamina-specific relationship between synaptic defects and γ-Aminobutyric acid (GABA)-related gene dysfunctions, it has been suggested the mRNA dysregulations of Tyrosine kinase B (TrkB) and Glutamate decarboxylase 67 (GAD67) could particularly be implicated in middle and deep layers of neocortex of patients with major psychiatric disorders.

Giving inquiries of whether defects of these mRNA levels in Orbitofrontal cortex (OFC) would be involved as lamina-specific patterns in individuals with schizophrenia and mood disorders.

We examined mRNA levels of BDNF, TrkB and GAD67 in each OFC layer I through VI. We analyzed data from postmortem brain tissue of the Stanley Neuropathology Consortium Integrative Database (SNCID). SNCID consists of 15 subjects in each of four groups (schizophrenia, bipolar disorder, major depression without psychotic features, and unaffected controls). All groups were matched for age, sex, race, brain pH and post-mortem interval.

We found TrkB mRNA levels to be significantly reduced in layer VI in both groups with schizophrenia (25.8%) and bipolar disorder (35.7%) compared with controls. GAD67 mRNA levels were also significantly reduced in layer III and IV in patients with schizophrenia (23.4% and 22.7%, respectively) and bipolar disorder (31.2% and 24.9%, respectively) compared with controls. Individuals with major depression showed only trends toward decreased mRNA levels of GAD67 in layer III and IV and of TrkB in layer VI compared with controls. TrkB mRNA levels in layer VI were significantly correlated with GAD67 mRNA levels in layer III (ρ=0.581, p=0.037) and IV (ρ=0.857, p<0.001) in subjects with bipolar disorder, but not in those with schizophrenia. When analyzed with partial correlation controlling the effects of pH and PMI, significance of correlation remained only between GAD67 mRNA in layer IV and TrkB mRNA in layer VI in individuals with bipolar disorder (ρ=0.768, p=0.006).

The resulting lamina-specific decreases in inhibitory tone across layers of OFC may contribute to the unrestrained irritability and violent behaviors in common shared by both patients with schizophrenia and bipolar disorder. Nonetheless, our findings indicate the obvious correlations between lamina-specifically altered TrkB and GAD67 mRNA levels in OFC might be a candidate for endophenotype of bipolar disorder.

None Declared

We assessed the implementation of telehealth-supported stewardship activities in acute-care units and long-term care (LTC) units in Veterans’ Administration medical centers (VAMCs).

Before-and-after, quasi-experimental implementation effectiveness study with a baseline period (2019–2020) and an intervention period (2021).

The study was conducted in 3 VAMCs without onsite infectious disease (ID) support.

The study included inpatient providers at participating sites who prescribe antibiotics.

During 2021, an ID physician met virtually 3 times per week with the stewardship pharmacist at each participating VAMC to review patients on antibiotics in acute-care units and LTC units. Real-time feedback on prescribing antibiotics was given to providers. Additional implementation strategies included stakeholder engagement, education, and quality monitoring.

The reach–effectiveness–adoption–implementation–maintenance (RE-AIM) framework was used for program evaluation. The primary outcome of effectiveness was antibiotic days of therapy (DOT) per 1,000 days present aggregated across all 3 sites. An interrupted time-series analysis was performed to compare this rate during the intervention and baseline periods. Electronic surveys, periodic reflections, and semistructured interviews were used to assess other RE-AIM outcomes.

The telehealth program reviewed 502 unique patients and made 681 recommendations to 24 providers; 77% of recommendations were accepted. After program initiation, antibiotic DOT immediately decreased in the LTC units (−30%; P < .01) without a significant immediate change in the acute-care units (+16%; P = .22); thereafter DOT remained stable in both settings. Providers generally appreciated feedback and collaborative discussions.

The implementation of our telehealth program was associated with reductions in antibiotic use in the LTC units but not in the smaller acute-care units. Overall, providers perceived the intervention as acceptable. Wider implementation of telehealth-supported stewardship activities may achieve reductions in antibiotic use.

The Mini International Neuropsychiatric Interview 7.0.2 (MINI-7) is a widely used tool and known to have sound psychometric properties; but very little is known about its use in low and middle-income countries (LMICs). This study aimed to examine the psychometric properties of the MINI-7 psychosis items in a sample of 8609 participants across four countries in Sub-Saharan Africa.

We examined the latent factor structure and the item difficulty of the MINI-7 psychosis items in the full sample and across four countries.

Multiple group confirmatory factor analyses (CFAs) revealed an adequate fitting unidimensional model for the full sample; however, single group CFAs at the country level revealed that the underlying latent structure of psychosis was not invariant. Specifically, although the unidimensional structure was an adequate model fit for Ethiopia, Kenya, and South Africa, it was a poor fit for Uganda. Instead, a 2-factor latent structure of the MINI-7 psychosis items provided the optimal fit for Uganda. Examination of item difficulties revealed that MINI-7 item K7, measuring visual hallucinations, had the lowest difficulty across the four countries. In contrast, the items with the highest difficulty were different across the four countries, suggesting that MINI-7 items that are the most predictive of being high on the latent factor of psychosis are different for each country.

The present study is the first to provide evidence that the factor structure and item functioning of the MINI-7 psychosis vary across different settings and populations in Africa.

Obsessive-compulsive disorder (OCD) and schizophrenia are often reported as co-morbid conditions. However, the evidence of an association between OCD and the risk of schizophrenia is limited. This study investigated the risk of schizophrenia in patients newly diagnosed with OCD using a nationally representative sample cohort in South Korea.

Data were obtained from the 2002–2013 Korean National Health Insurance Service-National Sample Cohort of the National Health Insurance Service. Using propensity score matching, 2509 patients with OCD and a control group of 7527 patients were included in the analysis. Chi-squared tests were used to investigate and compare the general characteristics of the study population. The risk of schizophrenia was analysed using the Cox proportional hazard model.

The incidence rate was 45.79/10 000 person-year for patients with OCD and 4.19/10 000 person-year for patients without OCD. Patients with OCD had a higher risk of schizophrenia compared to the control group after adjusting for covariates (hazard ratio = 10.46, 95% confidence interval = 6.07–18.00).

This study identified an association between the diagnosis of OCD and the risk of schizophrenia in a South Korean national representative cohort. Further research using a prospective design to clarify the causality of OCD in schizophrenia in a controlled environment should be conducted to validate these findings.

General medical conditions (GMCs) often co-occur with mental and substance use disorders (MSDs).

To explore the contribution of GMCs to the burden of disease in people with MSDs, and investigate how this varied by age.

A population-based cohort of 6 988 507 persons living in Denmark during 2000–2015 followed for up to 16 years. Danish health registers were used to identify people with MSDs and GMCs. For each MSD, years lived with disability and health loss proportion (HeLP) were estimated for comorbid MSDs and GMCs, using a multiplicative model for disability weights.

Those with any MSD lost the equivalent of 43% of healthy life (HeLP = 0.43, 95% CI 0.40–0.44) after including information on GMCs, which was an increase from 25% before including GMCs (HeLP = 0.25, 95% CI 0.23–0.27). Schizophrenia was associated with the highest burden of disease (HeLP = 0.77, 95% CI 0.68–0.85). However, within each disorder, the relative contribution of MSDs and GMCs varied. For example, in those diagnosed with schizophrenia, MSDs and GMCs accounted for 86% and 14% of the total health loss; in contrast, in those with anxiety disorders, the same proportions were 59% and 41%. In general, HeLP increased with age, and was mainly associated with increasing rates of pulmonary, musculoskeletal and circulatory diseases.

In those with mental disorders, the relative contribution of comorbid GMCs to the non-fatal burden of disease increases with age. GMCs contribute substantially to the non-fatal burden of disease in those with MSDs.