Aberrant connectivity in the hippocampus, bilateral insula and temporal poles precedes treatment resistance in first-episode psychosis: a prospective resting-state functional magnetic resonance imaging study with connectivity concordance mapping.

Functional connectivity resting-state functional magnetic resonance imaging has been proposed to predict antipsychotic treatment response in schizophrenia. However, only a few prospective studies have examined baseline resting-state functional magnetic resonance imaging data in drug-naïve first-episode schizophrenia patients with regard to subsequent treatment response. Data-driven approaches to conceptualize and measure functional connectivity patterns vary broadly, and model-free, voxel-wise, whole-brain analysis techniques are scarce. Here, we apply such a method, called connectivity concordance mapping to resting-state functional magnetic resonance imaging data acquired from an Asian sample (n = 60) with first-episode psychosis, prior to pharmaceutical treatment. Using a longitudinal design, 12 months after the resting-state functional magnetic resonance imaging, we measured and classified patients into two groups based on psychometric testing: treatment responsive and treatment resistant. Next, we compared the two groups' connectivity concordance maps that were derived from the resting-state functional magnetic resonance imaging data at baseline. We have identified consistently higher functional connectivity in the treatment-resistant group in a network including the left hippocampus, bilateral insula and temporal poles. These data-driven novel findings can help researchers to consider new regions of interest and facilitate biomarker development in order to identify treatment-resistant schizophrenia patients early, in advance of treatment and at the time of their first psychotic episode.

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.

Plasma versus tissue tumor mutational burden as biomarkers of durvalumab plus tremelimumab response in patients with metastatic colorectal cancer in the CO.26 trial.

PURPOSE: Tissue derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset on which this was validated lacked colorectal cancers (CRCs), and there is limited evidence for immunotherapy benefit in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients comparing durvalumab and tremelimumab (D+T, n=119 patients) versus best supportive care (BSC, n=61 patients). ctDNA sequencing was available for 168 patients (n=118 D+T, n=50), of which 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on overall survival were determined using a minimal p-value approach. This report includes the final overall survival analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D+T compared to BSC in microsatellite stable (MSS) metastatic CRC (HR 0.71 [95% CI:0.28-1.80], p=0.47). No tissue TMB threshold could identify a high TMB group that benefited from ICI. In contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D+T (HR=0.34 [95%CI:0.13-0.85], p=0.022), as was clonal pTMB ≥10.6 mutations/Mb (HR=0.10 [95%CI:0.014-0.79], p=0.029) and subclonal pTMB ≥25.9/Mb (HR=0.20 [95% CI:0.061-0.69], p=0.010). Higher pTMB was associated with length of time on cytotoxic agents (p=0.021) and prior anti-EGFR exposure (p=2.44x10-06). CONCLUSION: pTMB derived from either clonal or subclonal mutations may identify a group more likely to benefit from immunotherapy, though validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.

Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.

BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.

The Positively Charged Cluster in the N-terminal Disordered Region may Affect Prion Protein Misfolding: Cryo-EM Structure of Hamster PrP(23-144) Fibrils.

Prions, the misfolding form of prion proteins, are contagious proteinaceous macromolecules. Recent studies have shown that infectious prion fibrils formed in the brain and non-infectious fibrils formed from recombinant prion protein in a partially denaturing condition have distinct structures. The amyloid core of the in vitro-prepared non-infectious fibrils starts at about residue 160, while that of infectious prion fibrils formed in the brain involves a longer sequence (residues ∼90-230) of structural conversion. The C-terminal truncated prion protein PrP(23-144) can form infectious fibrils under certain conditions and cause disease in animals. In this study, we used cryogenic electron microscopy (cryo-EM) to resolve the structure of hamster sHaPrP(23-144) fibrils prepared at pH 3.7. This 2.88 Å cryo-EM structure has an amyloid core covering residues 94-144. It comprises two protofilaments, each containing five ß-strands arranged as a long hairpin plus an N-terminal ß-strand. This N-terminal ß-strand resides in a positively charged cluster region (named PCC2; sequence 96-111), which interacts with the turn region of the opposite protofilaments' hairpin to stabilize the fibril structure. Interestingly, this sHaPrP(23-144) fibril structure differs from a recently reported structure formed by the human or mouse counterpart at pH 6.5. Moreover, sHaPrP(23-144) fibrils have many structural features in common with infectious prions. Whether this structure is infectious remains to be determined. More importantly, the sHaPrP(23-144) structure is different from the sHaPrP(108-144) fibrils prepared in the same fibrillization buffer, indicating that the N-terminal disordered region, possibly the positively charged cluster, influences the misfolding pathway of the prion protein.

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.

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.

Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial.

BACKGROUND: Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8). METHODS: CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed. RESULTS: From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3-4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified. CONCLUSIONS: The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted. TRIAL REGISTRATION NUMBER: NCT03414983.

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.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Investigating inhibitors of 1-deoxy-d-xylulose 5-phosphate synthase in a mouse model of UTI.

The rising rate of antimicrobial resistance continues to threaten global public health. Further hastening antimicrobial resistance is the lack of new antibiotics against new targets. The bacterial enzyme, 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), is thought to play important roles in central metabolism, including processes required for pathogen adaptation to fluctuating host environments. Thus, impairing DXPS function represents a possible new antibacterial strategy. We previously investigated a DXPS-dependent metabolic adaptation as a potential target in uropathogenic Escherichia coli (UPEC) associated with urinary tract infection (UTI), using the DXPS-selective inhibitor butyl acetylphosphonate (BAP). However, investigations of DXPS inhibitors in vivo have not been conducted. The goal of the present study is to advance DXPS inhibitors as in vivo probes and assess the potential of inhibiting DXPS as a strategy to prevent UTI in vivo. We show that BAP was well-tolerated at high doses in mice and displayed a favorable pharmacokinetic profile for studies in a mouse model of UTI. Further, an alkyl acetylphosphonate prodrug (homopropargyl acetylphosphonate, pro-hpAP) was significantly more potent against UPEC in urine culture and exhibited good exposure in the urinary tract after systemic dosing. Prophylactic treatment with either BAP or pro-hpAP led to a partial protective effect against UTI, with the prodrug displaying improved efficacy compared to BAP. Overall, our results highlight the potential for DXPS inhibitors as in vivo probes and establish preliminary evidence that inhibiting DXPS impairs UPEC colonization in a mouse model of UTI.IMPORTANCENew antibiotics against new targets are needed to prevent an antimicrobial resistance crisis. Unfortunately, antibiotic discovery has slowed, and many newly FDA-approved antibiotics do not inhibit new targets. Alkyl acetylphosphonates (alkyl APs), which inhibit the enzyme 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), represent a new possible class of compounds as there are no FDA-approved DXPS inhibitors. To our knowledge, this is the first study demonstrating the in vivo safety, pharmacokinetics, and efficacy of alkyl APs in a urinary tract infection mouse model.

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.

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.

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Systematic review and meta-analysis of internalised stigma and stigma resistance in patients with psychosis: The impact of individualism-collectivism culture and other individual factors.

PURPOSE: This study aimed to meta-analysis the level of internalised stigma experienced by individuals with psychosis worldwide, and the impact of cultural differences, economic status of the studied regions and duration of illness on their levels of internalised stigma. Clinical and individual level factors associated with internalised stigma and stigma resistance were also systematically reviewed. METHODS: A systematic search of keywords on two scholarly databases were conducted. The individualism index of the countries or regions where the studies were conducted was retrieved from Hofstede's updated measurement of individualism. Economic status of regions was categorised based on their per capita gross national income. Meta-analysis and meta-regression were conducted using the 'metafor' package in R. Factors associated with internalised stigma and stigma resistance were also systematically consolidated. RESULTS: Seventy-three articles were included in the meta-analysis and the pooled score of both internalised stigma and stigma resistance of individuals with psychosis were within the mild range (2.20 and 2.44, respectively). The meta-regression analysis found high collectivism culture is significantly related to a higher level of internalised stigma. Economic status was not significant. Thirty-five articles were included in the systematic review and clinical, psychological, psychosocial variables, cognition and sociodemographic factors were found to be associated with internalised stigma. CONCLUSION: Internalised stigma in psychosis is ubiquitous worldwide and high collectivism culture may be related with high internalised stigma. With the presence of multiple individual factors related to internalised stigma, intervention programmes to reduce internalised stigma should consider focussing on both macro- and micro-level factors.

Asian American University Students' Experiences during the COVID-19 Pandemic: A Qualitative Study.

In addition to the unprecedented challenges and stressors that university students faced during the COVID-19 pandemic, Asian American students experienced specific hardships due to COVID-19-associated xenophobic attitudes, harassment, and assault against people of Asian complexions. This qualitative study aimed to explore the ways in which Asian American university students' experiences during the pandemic changed their views of their identities as Asian Americans by analyzing in-depth interviews of four case study participants. Secondary analysis of two waves of interviews, which were conducted during the initial outbreak of the COVID-19 pandemic and during a six-month follow-up, and primary analysis of a newly conducted third wave one year after the initial outbreak yielded 12 themes that captured the essence of the Asian American university students' experience and redefining of their identity during the pandemic. The four participants identified these themes across four categories: Experiences and Events during the Pandemic; Categorization of Asians in America; Confronting Asian Discrimination; and Renewed Sense of Identity. The longitudinal findings revealed direct experiences and perspectives regarding the influence of the COVID-19 pandemic on Asian communities, as well as the impact of the various social and political events during this time period, such as the Black Lives Matter Movement (2020) and the 2020 US presidential election. The implications, limitations, and future directions are discussed.

Development of an individualized risk calculator of treatment resistance in patients with first-episode psychosis (TRipCal) using automated machine learning: a 12-year follow-up study with clozapine prescription as a proxy indicator.

About 15-40% of patients with schizophrenia are treatment resistance (TR) and require clozapine. Identifying individuals who have higher risk of development of TR early in the course of illness is important to provide personalized intervention. A total of 1400 patients with FEP enrolled in the early intervention for psychosis service or receiving the standard psychiatric service between July 1, 1998, and June 30, 2003, for the first time were included. Clozapine prescriptions until June 2015, as a proxy of TR, were obtained. Premorbid information, baseline characteristics, and monthly clinical information were retrieved systematically from the electronic clinical management system (CMS). Training and testing samples were established with random subsampling. An automated machine learning (autoML) approach was used to optimize the ML algorithm and hyperparameters selection to establish four probabilistic classification models (baseline, 12-month, 24-month, and 36-month information) of TR development. This study found 191 FEP patients (13.7%) who had ever been prescribed clozapine over the follow-up periods. The ML pipelines identified with autoML had an area under the receiver operating characteristic curve ranging from 0.676 (baseline information) to 0.774 (36-month information) in predicting future TR. Features of baseline information, including schizophrenia diagnosis and age of onset, and longitudinal clinical information including symptoms variability, relapse, and use of antipsychotics and anticholinergic medications were important predictors and were included in the risk calculator. The risk calculator for future TR development in FEP patients (TRipCal) developed in this study could support the continuous development of data-driven clinical tools to assist personalized interventions to prevent or postpone TR development in the early course of illness and reduce delay in clozapine initiation.

Unique Challenges in Biomarkers for Psychotic Disorders.

Biomarkers are observations that provide information about the risk of certain conditions (predictive) or their underlying mechanisms (explanatory) [...].

Circulating Oncometabolite 2-hydroxyglutarate as a Potential Biomarker for Isocitrate Dehydrogenase (IDH1/2) Mutant Cholangiocarcinoma.

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

Evaluation of a Low-Intensity Online Intervention (LiON) for Reducing Distress and Mental Health Symptoms in Young People.

PURPOSE: Enhancing young people's mental health is crucial given that most adult mental disorders develop before age 24 years. However, it is unclear whether low-intensity interventions delivered online can be effective. This study aimed to provide preliminary evidence on whether a low-intensity online intervention (LiON) can effectively lower young people's distress levels and mental health symptoms. METHODS: We compared the preintervention and postintervention changes in distress level and severity of depression and anxiety symptoms in 137 young people aged 15-24 years who used the LiON service with the three-month changes in a 1:1 propensity score-matched control group of community young people who did not use the service. They participated in one of the following modules for the first time: (1) sleep and relaxation, (2) stress-coping, and (3) problem-solving. RESULTS: Participants who received LiON intervention (mean age 22.88 [standard deviation 3.67] years, 65.7% female) showed significantly greater reductions in distress level (Cohen's f2: 0.079), as well as the severity of depressive symptoms (Cohen's f2: 0.056) and anxiety symptoms (Cohen's f2: 0.044) compared to the control group. DISCUSSION: The findings suggest that the LiON intervention has the potential to effectively reduce distress and mental health symptoms in young people. Future research should aim to confirm these findings through randomized controlled trials and explore the cost-effectiveness of the intervention.