A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence.

Cellular senescence is an irreversible state of cell-cycle arrest induced by various stresses, including aberrant oncogene activation, telomere shortening, and DNA damage. Through a genome-wide screen, we discovered a conserved small nucleolar RNA (snoRNA), SNORA13, that is required for multiple forms of senescence in human cells and mice. Although SNORA13 guides the pseudouridylation of a conserved nucleotide in the ribosomal decoding center, loss of this snoRNA minimally impacts translation. Instead, we found that SNORA13 negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. SNORA13 interacts directly with RPL23, decreasing its incorporation into maturing 60S subunits and, consequently, increasing the pool of free RPs, thereby promoting p53-mediated senescence. Thus, SNORA13 regulates ribosome biogenesis and the p53 pathway through a non-canonical mechanism distinct from its role in guiding RNA modification. These findings expand our understanding of snoRNA functions and their roles in cellular signaling.

Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo.

SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.

Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis.

BACKGROUND: Patient-reported outcomes measures (PROM) are self-reflections of an individual's physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS). METHODS: The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed. RESULTS: In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients' cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38). CONCLUSION: Patient's SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication.

Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype.

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

Cost-effectiveness of ivosidenib versus chemotherapy for previously treated IDH1-mutant advanced intrahepatic cholangiocarcinoma in Taiwan.

BACKGROUND: International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV. METHODS: A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios. RESULTS: Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty. CONCLUSIONS: At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.

From Compressed-Sensing to Deep Learning MR: Comparative Biventricular Cardiac Function Analysis in a Patient Cohort.

BACKGROUND: Conventional segmented, retrospectively gated cine (Conv-cine) is challenged in patients with breath-hold difficulties. Compressed sensing (CS) has shown values in cine imaging but generally requires long reconstruction time. Recent artificial intelligence (AI) has demonstrated potential in fast cine imaging. PURPOSE: To compare CS-cine and AI-cine with Conv-cine in quantitative biventricular functions, image quality, and reconstruction time. STUDY TYPE: Prospective human studies. SUBJECTS: 70 patients (age, 39 ± 15 years, 54.3% male). FIELD STRENGTH/SEQUENCE: 3T; balanced steady state free precession gradient echo sequences. ASSESSMENT: Biventricular functional parameters of CS-, AI-, and Conv-cine were measured by two radiologists independently and compared. The scan and reconstruction time were recorded. Subjective scores of image quality were compared by three radiologists. STATISTICAL TESTS: Paired t-test and two related-samples Wilcoxon sign test were used to compare biventricular functional parameters between CS-, AI-, and Conv-cine. Intraclass correlation coefficient (ICC), Bland-Altman analysis, and Kendall's W method were applied to evaluate agreement of biventricular functional parameters and image quality of these three sequences. A P-value <0.05 was considered statistically significant, and standardized mean difference (SMD) < 0. 100 was considered no significant difference. RESULTS: Compared to Conv-cine, no statistically significant differences were identified in CS- and AI-cine function results (all P > 0.05), except for very small differences in left ventricle end-diastole volumes of 2.5 mL (SMD = 0.082) and 4.1 mL (SMD = 0.096), respectively. Bland-Altman scatter plots revealed that biventricular function results were mostly distributed within the 95% confidence interval. All parameters had acceptable to excellent interobserver agreements (ICC: 0.748-0.989). Compared with Conv-cine (84 ± 13 sec), both CS (14 ± 2 sec) and AI (15 ± 2 sec) techniques reduced scan time. Compared with CS-cine (304 ± 17 sec), AI-cine (24 ± 4 sec) reduced reconstruction time. CS-cine demonstrated significantly lower quality scores than Conv-cine, while AI-cine demonstrated similar scores (P = 0.634). CONCLUSION: CS- and AI-cine can achieve whole-heart cardiac cine imaging in a single breath-hold. Both CS- and AI-cine have the potential to supplement the gold standard Conv-cine in studying biventricular functions and benefit patients having difficulties with breath-holds. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Using machine learning on new feature sets extracted from three-dimensional models of broken animal bones to classify fragments according to break agent.

Distinguishing agents of bone modification at paleoanthropological sites is an important means of understanding early hominin evolution. Fracture pattern analysis is used to help determine site formation processes, including whether hominins were hunting or scavenging for animal food resources. Determination of how these behaviors manifested in ancient human sites has major implications for our biological and behavioral evolution, including social and cognitive abilities, dietary impacts of having access to in-bone nutrients like marrow, and cultural variation in butchering and food processing practices. Nevertheless, previous analyses remain inconclusive, often suffering from lack of replicability, misuse of mathematical methods, and/or failure to overcome equifinality. In this paper, we present a new approach aimed at distinguishing bone fragments resulting from hominin and carnivore breakage. Our analysis is founded on a large collection of scanned three-dimensional models of fragmentary bone broken by known agents, to which we apply state of the art machine learning algorithms. Our classification of fragments achieves an average mean accuracy of 77% across tests, thus demonstrating notable, but not overwhelming, success for distinguishing the agent of breakage. We note that, while previous research applying such algorithms has claimed higher success rates, fundamental errors in the application of machine learning protocols suggest that the reported accuracies are unjustified and unreliable. The systematic, fully documented, and proper application of machine learning algorithms leads to an inherent reproducibility of our study, and therefore our methods hold great potential for deciphering when and where hominins first began exploiting marrow and meat, and clarifying their importance and influence on human evolution.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Leptomeningeal carcinomatosis and brain metastases in gastroesophageal carcinoma: a real-world analysis of clinical and pathologic characteristics and outcomes.

BACKGROUND: Brain metastasis (BrM) and Leptomeningeal Carcinomatosis (LMC) are uncommon complications in gastroesophageal carcinoma (GEC) patients. These patients have a poor prognosis and are challenging to treat. We described the clinicopathologic features and outcomes in the largest cohort of Central Nervous System (CNS) metastasis in GEC patients. METHODS: single-center retrospective study of GEC treated from 2007 to 2021. Clinicopathologic characteristics and treatment modalities were reviewed. Survival was calculated from the date of CNS diagnosis until date of death/last follow-up using the Kaplan-Meier method. A multivariable Cox proportional hazards regression model was used. RESULTS: Of 3283 GEC patients, 100 (3.04%) were diagnosed with BrM and 20 with LMC (0.61%). Patients with known human epidermal growth factor receptor 2 (HER2) status (N = 48), 60% were HER2 positive (defined as IHC 3 + or IHC 2+/FISH+). Among LMC patients most were signet-ring subtype (85%), and only 15% (2/13) were HER2 positive. Median survival was 0.7; 3.8; and 7.7 months in BrM patients treated with best supportive care, radiation, and surgery, respectively (p < 0.001). In LMC, median survival was 0.7 month in patients who had best supportive care (7/19) and 2.8 months for those who had whole brain radiation therapy (p = 0.015). Multivariate analysis showed worse outcomes in ECOG ≥ 2 (p = 0.002), number of BrM ≥ 4 (p < 0.001) and number of metastatic sites (p = 0.009). CONCLUSION: HER2 expression were enriched in patients with BrM, while it is uncommon in LMC. Patients treated with surgery followed by radiation had an improved OS in BrM and WBRT benefited patients with LMC.

Individual and Interactive Effects of Housing and Neighborhood Quality on Mental Health in Hong Kong: A Retrospective Cohort Study.

Existing literature has widely explored the individual roles of housing and neighborhood quality, and there is limited research examining their interactive effects on mental health. This 3-year cohort study utilized a longitudinal design to investigate the individual and interactive effects of housing and neighborhood quality on mental health among 962 community-dwelling adults in Hong Kong. Participants were asked to rate their residential qualities over the 3-year period. Mental health outcomes, including levels of psychological distress and common mental disorders (CMD), were assessed using the Revised Clinical Interview Schedule (CIS-R). Logistic regression and generalized linear models were used to examine the association between housing and neighborhood quality and CMD/psychological distress, adjusting for sociodemographic and residential characteristics and baseline mental disorders. Housing quality was associated with the 3-year CMD (adjusted OR 0.95; 95% CI 0.91 to 0.98). Likewise, neighborhood quality was associated with CMD over 3 years (adjusted OR 0.92; 95% CI 0.87 to 0.96). In a separate model including both quality measures, the effect of housing quality on CMD was attenuated, whereas the neighborhood impact remained significant (adjusted OR 0.92; 95% CI 0.87 to 0.98). Generalized linear models indicated that for participants residing in substandard housing, those with high neighborhood quality had lower CIS-R scores at follow-up compared to those with low neighborhood quality (p = 0.041). Better neighborhood quality alleviated the detrimental effects of poor housing quality on mental health. Planning for an enhanced neighborhood would improve population mental health in an urban environment.

Age-related differences in the impact of resilience on mental health outcomes during the COVID-19 pandemic in Hong Kong.

OBJECTIVE: This study investigated changes in mental health in Hong Kong over two years and examined the role of resilience and age in mitigating the negative effects of public health emergencies, particularly the COVID-19 pandemic. METHODS: Complete data of interest from two telephone surveys conducted in 2020 (n = 1182) and 2021 (n = 1108) were analysed. Participants self-reported depressive and anxiety symptoms using the Patient Health Questionnaire 4-item version (PHQ), psychotic-like experiences (PLEs) using three items from the Prodromal Questionnaire Brief (PQB), and resilience using the Connor-Davidson Resilience Scale 2-item version (CD-RISC-2). RESULTS: We observed an increase in the percentage of participants with high depressive and anxiety symptoms and PLEs from 1.6% to 6.5% between 2020 and 2021. The likelihood of having high depressive and anxiety symptoms or PLEs depended on resilience and age, with no significant between-year differences. Resilience and age interaction effects were significant when comparing the high PHQ-high PQB group to the low PHQ-low PQB group only in 2021 but not in 2020. CONCLUSIONS: This study provides valuable insights into the impact of the COVID-19 pandemic on mental health in Hong Kong, emphasising the age-dependent nature of resilience in mitigating negative effects. Future research should explore the mechanisms by which resilience promotes mental health and well-being and identify ways to enhance resilience among older individuals during public health crises.

Mentalizing impairments and hypermentalizing bias in individuals with first-episode schizophrenia-spectrum disorder and at-risk mental state: the differential roles of neurocognition and social anxiety.

Mentalizing, or theory of mind (ToM), impairments and self-referential hypermentalizing bias are well-evident in schizophrenia. However, findings compared to individuals with at-risk mental states (ARMS) are inconsistent, and investigations into the relationship between social cognitive impairments and social anxiety in the two populations are scarce. This study aimed to examine and compare these deficits in first-episode schizophrenia-spectrum disorder (FES) and ARMS, and to explore potential specific associations with neurocognition and symptomatology. Forty patients with FES, 40 individuals with ARMS, and 40 healthy controls (HC) completed clinical assessments, a battery of neurocognitive tasks, and three social cognitive tasks. The comic strip and hinting tasks were used to measure non-verbal and verbal mentalizing abilities, and the gaze perception task was employed to assess self-referential hypermentalizing bias. FES and ARMS showed comparable mentalizing impairments and self-referential hypermentalizing bias compared to HC. However, only ambiguous self-referential gaze perception (SRGP) bias remained significantly different between three groups after controlling for covariates. Findings suggested that self-referential hypermentalizing bias could be a specific deficit and may be considered a potential behavioral indicator in early-stage and prodromal psychosis. Moreover, working memory and social anxiety were related to the social cognitive impairments in ARMS, whereas higher-order executive functions and positive symptoms were associated with the impairments in FES. The current study indicates the presence of stage-specific mechanisms of mentalizing impairments and self-referential hypermentalizing bias, providing insights into the importance of personalized interventions to improve specific neurocognitive domains, social cognition, and clinical outcomes for FES and ARMS.

MANAGEMENT OF LARGE FULL-THICKNESS MACULAR HOLES: Long-Term Outcomes of Internal Limiting Membrane Flaps and Internal Limiting Membrane Peels.

BACKGROUND/PURPOSE: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes. METHODS: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200. RESULTS: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3. CONCLUSION: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.

Comparison of Four Clinical Prognostic Scores in Patients with Advanced Gastric and Esophageal Cancer.

BACKGROUND: Prognostic scores that can identify patients at risk for early death are needed to aid treatment decision-making and patient selection for clinical trials. We compared the accuracy of four scores to predict early death (within 90 days) and overall survival (OS) in patients with metastatic gastric and esophageal (GE) cancer. METHODS: Advanced GE cancer patients receiving first-line systemic therapy were included. Prognostic risks were calculated using: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune (GRIm-Score), and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) scores. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to analyze associations between prognostic scores and OS. The predictive discrimination was estimated using Harrell's c-index. Predictive ability for early death was measured using time-dependent AUCs. RESULTS: In total, 451 patients with metastatic GE cancer were included. High risk patients had shorter OS for all scores (RMH high- vs. low-risk median OS 7.9 vs. 12.2 months, P < .001; MDACC 6.8 vs. 11.9 months P < .001; GRIm-Score 5.3 vs. 13 months, P < .001; MDA-ICI 8.2 vs. 12.2 months, P < .001). On multivariable analysis, each prognostic score was significantly associated with OS. The GRIm-Score had the highest predictive discrimination and predictive ability for early death. CONCLUSIONS: The GRIm-Score had the highest accuracy in predicting early death and OS. Clinicians may use this score to identify patients at higher risk of early death to guide treatment decisions including clinical trial enrolment. This score could also be used as a stratification factor in future clinical trial designs.

The emergence of primary negative symptoms: relevance of timing?

Negative symptoms are an important symptom dimension in schizophrenia that are often least responsive to antipsychotic medications. We revisit the current practice of identifying 'primary' negative symptoms and suggest that its concept would benefit from a further elaboration of their timing of emergence in relation to the dynamic neurobiological changes to enhance their utility in clinical decision-making and research.

Effect of high-endurance exercise intervention on sleep-dependent procedural memory consolidation in individuals with schizophrenia: a randomized controlled trial.

BACKGROUND: Little is known about the effects of physical exercise on sleep-dependent consolidation of procedural memory in individuals with schizophrenia. We conducted a randomized controlled trial (RCT) to assess the effectiveness of physical exercise in improving this cognitive function in schizophrenia. METHODS: A three-arm parallel open-labeled RCT took place in a university hospital. Participants were randomized and allocated into either the high-intensity-interval-training group (HIIT), aerobic-endurance exercise group (AE), or psychoeducation group for 12 weeks, with three sessions per week. Seventy-nine individuals with schizophrenia spectrum disorder were contacted and screened for their eligibility. A total of 51 were successfully recruited in the study. The primary outcome was sleep-dependent procedural memory consolidation performance as measured by the finger-tapping motor sequence task (MST). Assessments were conducted during baseline and follow-up on week 12. RESULTS: The MST performance scored significantly higher in the HIIT (n = 17) compared to the psychoeducation group (n = 18) after the week 12 intervention (p < 0.001). The performance differences between the AE (n = 16) and the psychoeducation (p = 0.057), and between the AE and the HIIT (p = 0.999) were not significant. Yet, both HIIT (p < 0.0001) and AE (p < 0.05) showed significant within-group post-intervention improvement. CONCLUSIONS: Our results show that HIIT and AE were effective at reverting the defective sleep-dependent procedural memory consolidation in individuals with schizophrenia. Moreover, HIIT had a more distinctive effect compared to the control group. These findings suggest that HIIT may be a more effective treatment to improve sleep-dependent memory functions in individuals with schizophrenia than AE alone.

Prevalence and correlates of suicidal behaviours in a representative epidemiological youth sample in Hong Kong: the significance of suicide-related rumination, family functioning, and ongoing population-level stressors.

BACKGROUND: Young people are most vulnerable to suicidal behaviours but least likely to seek help. A more elaborate study of the intrinsic and extrinsic correlates of suicidal ideation and behaviours particularly amid ongoing population-level stressors and the identification of less stigmatising markers in representative youth populations is essential. METHODS: Participants (n = 2540, aged 15-25) were consecutively recruited from an ongoing large-scale household-based epidemiological youth mental health study in Hong Kong between September 2019 and 2021. Lifetime and 12-month prevalence of suicidal ideation, plan, and attempt were assessed, alongside suicide-related rumination, hopelessness and neuroticism, personal and population-level stressors, family functioning, cognitive ability, lifetime non-suicidal self-harm, 12-month major depressive disorder (MDD), and alcohol use. RESULTS: The 12-month prevalence of suicidal ideation, ideation-only (no plan or attempt), plan, and attempt was 20.0, 15.4, 4.6, and 1.3%, respectively. Importantly, multivariable logistic regression findings revealed that suicide-related rumination was the only factor associated with all four suicidal outcomes (all p < 0.01). Among those with suicidal ideation (two-stage approach), intrinsic factors, including suicide-related rumination, poorer cognitive ability, and 12-month MDE, were specifically associated with suicide plan, while extrinsic factors, including coronavirus disease 2019 (COVID-19) stressors, poorer family functioning, and personal life stressors, as well as non-suicidal self-harm, were specifically associated with suicide attempt. CONCLUSIONS: Suicide-related rumination, population-level COVID-19 stressors, and poorer family functioning may be important less-stigmatising markers for youth suicidal risks. The respective roles played by not only intrinsic but also extrinsic factors in suicide plan and attempt using a two-stage approach should be considered in future preventative intervention work.

Effectiveness and optimal duration of early intervention treatment in adult-onset psychosis: a randomized clinical trial.

BACKGROUND: Contrasting the well-described effects of early intervention (EI) services for youth-onset psychosis, the potential benefits of the intervention for adult-onset psychosis are uncertain. This paper aims to examine the effectiveness of EI on functioning and symptomatic improvement in adult-onset psychosis, and the optimal duration of the intervention. METHODS: 360 psychosis patients aged 26-55 years were randomized to receive either standard care (SC, n = 120), or case management for two (2-year EI, n = 120) or 4 years (4-year EI, n = 120) in a 4-year rater-masked, parallel-group, superiority, randomized controlled trial of treatment effectiveness (Clinicaltrials.gov: NCT00919620). Primary (i.e. social and occupational functioning) and secondary outcomes (i.e. positive and negative symptoms, and quality of life) were assessed at baseline, 6-month, and yearly for 4 years. RESULTS: Compared with SC, patients with 4-year EI had better Role Functioning Scale (RFS) immediate [interaction estimate = 0.008, 95% confidence interval (CI) = 0.001-0.014, p = 0.02] and extended social network (interaction estimate = 0.011, 95% CI = 0.004-0.018, p = 0.003) scores. Specifically, these improvements were observed in the first 2 years. Compared with the 2-year EI group, the 4-year EI group had better RFS total (p = 0.01), immediate (p = 0.01), and extended social network (p = 0.05) scores at the fourth year. Meanwhile, the 4-year (p = 0.02) and 2-year EI (p = 0.004) group had less severe symptoms than the SC group at the first year. CONCLUSIONS: Specialized EI treatment for psychosis patients aged 26-55 should be provided for at least the initial 2 years of illness. Further treatment up to 4 years confers little benefits in this age range over the course of the study.

Antipsychotic utilization patterns in pregnant women with psychotic disorders: a 16-year population-based cohort study.

Despite growing concern about reproductive safety of antipsychotics, there is a paucity of research specifically assessing prenatal antipsychotic prescribing practices for psychotic disorders. This population-based cohort study identified women aged 15-50 years with diagnosis of psychotic disorders, who delivered their first and singleton child between 2003-2018 in Hong Kong, with an aim to examine temporal trends and predictors of prenatal antipsychotic use as well as antipsychotic utilization patterns before and during pregnancy. Data were retrieved from territory-wide medical-record database of public healthcare services. Of 804 women, 519 (65%) redeemed at least one prescription for antipsychotics during pregnancy. Older age at conception (25-34 years: OR 2.12 [95% CI 1.22-3.67]; 35-50 years: 2.52 [1.38-4.61]; 15-24 years as reference category) and antipsychotic treatment within 12 months pre-pregnancy (24.22 [16.23-36.16]) were significantly associated with prenatal antipsychotic use. Second-generation-antipsychotic (SGA) use during pregnancy increased over 16-year study period, while prenatal first-generation-antipsychotic (FGA) use showed declining trend. Overall antipsychotic and SGA use progressively decreased across pre-pregnancy and trimesters of pregnancy. Further analyses on antipsychotic use trajectories revealed that 87.4% (n = 459) of 529 women receiving antipsychotics in 12-month pre-pregnancy redeemed antipsychotic prescription during pregnancy, and 63.4% (n = 333) continued antipsychotic treatment throughout pregnancy. Only 7.5% of the cohort (n = 60) commenced antipsychotics in pregnancy. This is one of the few studies evaluating real-world prenatal antipsychotic utilization among women with psychotic disorders. Future research delineating risk conferred by illness-related factors and antipsychotic exposure on adverse maternal and fetal outcomes is warranted to facilitate treatment guideline development.

Visual-stress-related cortical excitability as a prospective marker for symptoms of depression and anxiety in young people.

Visual stress is thought to reflect cortical excitability and has been associated with many neurological, neuropsychiatric, and neurodevelopmental conditions. However, its relationships with symptoms of depression and anxiety have not yet been elucidated. We conducted two separate studies to first examine visual stress in a longitudinal community sample of 104 participants (aged 12-24) in association with prospective symptoms of depression, anxiety, and distress after 3 months, and subsequently in a cross-sectional epidemiological sample of 530 participants (aged 15-24) to validate its associations with current mood and distress symptoms. The Pattern Glare Test was used to examine visual stress to three grating patterns with the spatial frequencies (SF) of 0.3, 2.3, and 9.4 cycles per degree (cpd). Other known factors of mental health, including functioning, as well as resilience, hopelessness, and loneliness, were also assessed at baseline. In both studies, we showed that perceptual distortions were highest toward the pattern with mid-SF (2.3 cpd). Multiple linear regression analyses revealed that greater visual stress was significantly associated with not only baseline but also 3-month symptom outcomes, even when accounting for age, years of education, days of no functioning, resilience, hopelessness, and loneliness. Our findings suggest the importance of visual stress in understanding and predicting poor mental health outcomes. As mental health can lead to far-reaching consequences that extend to adulthood, our findings may inform state-of-the-art innovative strategies for the prediction of poor mental health outcomes and suggest visual stress as a potential marker for early risk detection among young people.