Mental health care utilization in individuals with high levels of psychosis-like experiences: Associations with race and potentially traumatic events.

Objective: Racial inequities in mental health care utilization (MHCU) are well documented. Marginalized racial groups are more likely to report psychosis-like experiences (PLEs) and are at elevated risk for racial discrimination and trauma, impacting PLE severity. Little is known about how factors associated with race impact treatment seeking among individuals reporting PLEs. The present study examined associations between race, trauma, discrimination, PLEs, and MHCU among people endorsing high levels of PLEs. Method: Participants were Asian/Asian American, Black/African American, or White/European American college students ages 18-25 years meeting PLE self-report measure cutoff scores (N = 177). Binary logistic and multiple linear regressions were used to examine associations between past, current, and prospective MHCU and race, potentially traumatic events, discrimination, and PLEs. Results: Participants endorsing more PLEs were more likely to report past and current treatment and to be considering future services. Asian/Asian American and Black/African American participants were less likely to endorse past, current, and prospective future mental health care. Potentially traumatic events predicted increased utilization of past treatment. Conclusions: Results suggest service differences among participants, such that Black/African American and Asian/Asian American young adults reporting PLEs were less likely than White/European American counterparts to seek treatment even when accounting for traumatic events and discrimination. These findings highlight the need to further elucidate MHCU among marginalized racial groups experiencing psychosis-like symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Advancing drug discovery using the power of the human genome.

Human genetics plays an increasingly important role in drug development and population health. Here we review the history of human genetics in the context of accelerating the discovery of therapies, present examples of how human genetics evidence supports successful drug targets, and discuss how polygenic risk scores could be beneficial in various clinical settings. We highlight the value of direct-to-consumer platforms in the era of fast-paced big data biotechnology, and how diverse genetic and health data can benefit society. © 2021 23andMe, Inc. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Telepsychotherapy with Youth at Clinical High Risk for Psychosis: Clinical Issues and Best Practices during the COVID-19 Pandemic.

Early detection and prevention of psychosis has become an international priority. Much of this work has focused on youth presenting with attenuated symptoms of psychosis-those at Clinical High Risk for psychosis (CHR)-given their elevated probability of developing the full disorder in subsequent years. Individuals at CHR may be prone to exacerbated psychological distress during the COVID-19 pandemic and its subsequent physical isolation measures, due to heightened stress sensitivity and comorbid mental health problems. Telepsychotherapy holds promise for reaching this population, especially during the current COVID-19 outbreak. However, there are limited evidence-based guidelines or interventions for use of telepsychotherapy with this population. In this paper, we review common clinical issues for individuals at CHR and how they might be exacerbated by the COVID-19 pandemic; best practices for treatment and adaptations for telepsychotherapy for individuals at CHR; and highlight real clinical issues that we are currently experiencing in a United States-based specialized CHR clinic as we conduct telepsychotherapy via videoconferencing. We conclude with questions for those in the field to contemplate, as well as potential challenges and benefits in using telepsychotherapy with individuals at CHR and their families.

Weight gain trajectories in hospital-based treatment of anorexia nervosa.

Weight gain is a primary treatment goal for anorexia nervosa (AN); however little is known about heterogeneity in weight gain pattern during treatment. Preliminary evidence suggests weight gain trajectory is associated with treatment outcome. This study grouped patients using mixture modeling into weight gain trajectories, and compared predictors and treatment outcomes between trajectory groups. Women diagnosed with AN or subthreshold AN (N = 211) completed self-report measures at admission and six-months after discharge from an integrated inpatient (IP)-partial hospitalization (PH) behavioral specialty eating disorders program. Gowned weights were measured daily. Three distinct trajectories emerged: negative quadratic (Optimal), negative quadratic with fast weight gain (Fast), and positive linear with slower weight gain (Slow). The majority of patients were assigned to the Optimal group. Trajectory groups differed on admission, discharge, and follow-up variables. The Fast group emerged as most distinct. Women in this group were more than twice as likely to binge and or vomit regularly compared with the other two groups and were most likely to achieve weight restoration by discharge and to have more positive weight outcomes at short-term follow-up. There were no group differences in eating disorder behavioral frequencies at follow-up when adjusting for behavioral severity at admission. Weight gain trajectory may serve as a personalized in-treatment marker of outcome and could inform research on moderators and mediators of treatment response. Randomized controlled treatment studies, utilizing weight gain trajectories to determine group membership, may help identify subgroups of patients with differential responses to treatment interventions.

Synthesis and evaluation of ether-linked demethylepipodophyllotoxin dimers.

A series of novel ether-linked dimers of demethylepipodophyllotoxin are topoisomerase II poisons that exhibit higher levels of double-stranded versus single-stranded DNA cleavage than their corresponding monomers. The dimers also have higher levels of tumor cell cytotoxicity than the monomers, lending support to the two-drug model for interaction of demethylepipodophyllotoxins with human topoisomerase IIα.

Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension.

Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.

Aging as accelerated accumulation of somatic variants: whole-genome sequencing of centenarian and middle-aged monozygotic twin pairs.

It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins.

Use of divalent metal ions in the DNA cleavage reaction of topoisomerase IV.

It has long been known that type II topoisomerases require divalent metal ions in order to cleave DNA. Kinetic, mutagenesis and structural studies indicate that the eukaryotic enzymes utilize a novel variant of the canonical two-metal-ion mechanism to promote DNA scission. However, the role of metal ions in the cleavage reaction mediated by bacterial type II enzymes has been controversial. Therefore, to resolve this critical issue, this study characterized the DNA cleavage reaction of Escherichia coli topoisomerase IV. We utilized a series of divalent metal ions with varying thiophilicities in conjunction with oligonucleotides that replaced bridging and non-bridging oxygen atoms at (and near) the scissile bond with sulfur atoms. DNA scission was enhanced when thiophilic metal ions were used with substrates that contained bridging sulfur atoms. In addition, the metal-ion dependence of DNA cleavage was sigmoidal in nature, and rates and levels of DNA cleavage increased when metal ion mixtures were used in reactions. Based on these findings, we propose that topoisomerase IV cleaves DNA using a two-metal-ion mechanism in which one of the metal ions makes a critical interaction with the 3'-bridging atom of the scissile phosphate and facilitates DNA scission by the bacterial type II enzyme.

Exploring the relation between psychosis-like experiences and suicidal ideation, plans, and attempts among college students in the United States.

AIM: The suicide rate among college students is particularly high, with evidence that psychosis-like experiences (PLEs) put these individuals at greater risk. The current study explored whether there are differential relations between four subtypes of PLEs and three suicide outcomes. METHODS: We analysed a large sample of college students from the Fall semester cohort of the 2020 Healthy Minds Study (HMS) (weighted N = 36727). PLEs and suicide outcomes were assessed using binary variables from the World Health Organization Composite International Diagnostic Interview. RESULTS: Findings revealed that reporting any of the subtypes of PLEs was associated with greater odds of suicidal ideation (SI), a suicide plan (SP) and a suicide attempt (SA) (signficant a ORs ranging from 1.30 to 3.30). For college students who endorsed SI or a SP in the past year, experiencing delusional mood (aOR [95% CI] = 1.30 [1.02-1.65]), suspiciousness (aOR [95% CI] = 1.31 [1.00-1.71]) and hallucinatory experiences (aOR [95% CI] = 2.76 [2.05-3.71]) in their lifetime increased their odds of reporting a SA in the past year. There was also evidence of a dose-dependent relation between the number of PLEs endorsed and all three suicide outcomes. CONCLUSIONS: Certain subtypes of PLEs including delusional mood, suspiciousness and hallucinatory experiences may contribute to an elevated risk of suicide outcomes in college students. Moreover, the odds of reporting suicide outcomes were greater for individuals who endorsed a greater number of PLEs. It may be helpful to assess for indicated subtypes when determining suicide risk among college students and to be particularly mindful of those who report three or more PLEs.

The influence of psychotic-like experiences on intent to seek treatment: Findings from a multi-site community survey of mental health experiences.

Psychotic-like experiences (PLEs) may reflect elevated risk for serious mental illness, including psychosis. Although some studies report an association between PLEs and increased service utilization, there is evidence of unmet need among individuals with PLEs, with few studies exploring the relation between PLEs and intent to seek treatment. Characterizing factors that underlie intent to seek treatment in individuals not otherwise engaged in treatment may assist in determining the role of PLEs and future intentions, and help prioritize symptoms of greatest significance. Non-help-seeking participants ages 16-30 years (nanalysis = 2529) in a multi-site study completed online questionnaires of PLEs (PRIME with distress), depression (CESD), anxiety (STAI), and intention to seek mental health treatment. Associations between PLEs and intent to seek treatment were analyzed through multiple linear regressions. PRIME scores predicted intent to seek treatment, and item-level analyses suggested that this association was driven by items 12 ("going crazy"), 7 (wondering if people may hurt me), 5 (confused if things are real or imagination/dreams), and 1 (odd/unusual things going on). When accounting for the effects of anxiety and depression, PLE sum scores as well as individual experiences remained statistically significant, although effect sizes were negligible. Findings suggest that PLEs can play a role in identifying individuals who intend to seek mental health services and warrant further research in independent samples.

Efficacy of contact intervention videos on college students' intentions toward mental health help-seeking.

ObjectiveUntreated mental health (MH) concerns have significant implications for college students. This study examined the efficacy of a video contact intervention targeting students' intentions to seek counseling. Participants: One-hundred and sixty-three college students (Mage = 21.05, SD = 2.20) from a Mid-Atlantic university participated. The sample was predominantly female (74%). Method: Students were randomly assigned to view a student-targeted contact video (ie, clips from college students who share their mental health experiences), a MH comparison contact video, or a non-MH comparison video. Intentions to seek counseling and psychological distress were measured pretest and post-test. Results: Intentions to seek counseling significantly increased from pretest to post-test in the student-targeted contact video condition (F[1, 156] = 22.75, p < .001, partial η2 = .13), but not in the comparison conditions. Further, this effect was only observed among participants who reported preexisting psychological distress (F[1, 153] = 28.00, p < .001, partial η2 = .16). Conclusions: This study provides initial support for the utility of a student-targeted contact intervention video for increasing help-seeking intentions among those reporting current psychological distress.

Psychometric Properties and Factor Analysis of a Short Form of the Multidimensional Measure of Emotional Abuse.

The 28-item Multidimensional Measure of Emotional Abuse (MMEA) assesses four common forms of emotional abuse in intimate relationships and has been used extensively to study the development of intimate partner violence (IPV), the consequences of emotional abuse, and the outcomes of IPV interventions. The current study provides psychometric analyses of a shortened version of the MMEA using self-report data from a sample of men receiving treatment at a community-based relationship violence intervention program (RVIP; N = 467) and reports from their relationship partners (N = 252), and data from a sample of undergraduate students (N = 194) who reported on their own and their partners' abusive behavior. Theoretical and statistical considerations, including internal consistency after item deletion, were used to select items for the shortened version. In the clinic sample (for self- and partner reports) and in the undergraduate sample (for self-report only), the 16-item MMEA-Short Form (MMEA-SF) retains the 4-factor structure of the 28-item MMEA. In both samples and across reporting methods (self and partner), the 16-item MMEA-SF has good internal consistency, good concurrent validity with the Revised Conflict Tactics Scales (CTS2) psychological aggression subscale, and similar correlations with CTS2 physical assault subscale as the original 28-item MMEA version. The MMEA-SF can reduce assessment burden while maintaining good domain coverage and strong psychometric properties and will be an asset to researchers and practitioners who need a brief, multifaceted measure of emotional relationship abuse in both clinic and undergraduate samples.

Internalized stigma mediates the relation between psychosis-risk symptoms and subjective quality of life in a help-seeking sample.

Subjective quality of life can be compromised in individuals with psychosis-risk symptoms, with poorer quality of life being associated with worse functioning and later transition to psychosis. Individuals who experience psychosis-related symptoms also tend to endorse more internalized (or self-) mental health stigma when compared to controls, potentially contributing to delays in seeking treatment and increased duration of untreated psychosis, as well as interfering with treatment engagement and retention in those already receiving care. Despite these findings, and the growing recognition for prevention in earlier phases of psychotic illness, few studies have examined the relation between psychosis-risk symptoms, internalized stigma, and subjective quality of life in a younger, help-seeking sample. The present study examined whether internalized stigma mediates the relation between psychosis-risk symptoms and subjective quality of life in a transdiagnostic sample of youth (M age = 17.93, SD = 2.90) at clinical high-risk for psychosis (CHR), with early psychosis, or with non-psychotic disorders (N = 72). Psychosis-risk symptom severity was assessed using the Structured Interview for Psychosis-Risk Syndromes (SIPS). Internalized stigma was assessed using the Internalized Stigma of Mental Illness Inventory (ISMI), and subjective quality of life was assessed using the Youth Quality of Life Instrument - Short Form (YQOL-SF). Internalized stigma fully mediated the relation between psychosis-risk symptoms and subjective quality of life across the full sample (p < .05, f2 = 0.06). Findings suggest that internalized stigma may be an important target in efforts to improve quality of life for individuals in early stages of psychosis.

Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage.

F14512 is a novel etoposide derivative that contains a spermine in place of the C4 glycosidic moiety. The drug was designed to exploit the polyamine transport system that is upregulated in some cancers. However, a preliminary study suggests that it is also a more efficacious topoisomerase II poison than etoposide [Barret et al. (2008) Cancer Res. 68, 9845-9853]. Therefore, we undertook a more complete study of the actions of F14512 against human type II topoisomerases. As determined by saturation transfer difference (1)H NMR spectroscopy, contacts between F14512 and human topoisomerase IIα in the binary enzyme-drug complex are similar to those of etoposide. Although the spermine of F14512 does not interact with the enzyme, it converts the drug to a DNA binder [Barret et al. (2008)]. Consequently, the influence of the C4 spermine on drug activity was assessed. F14512 is a highly active topoisomerase II poison and stimulates DNA cleavage mediated by human topoisomerase IIα or topoisomerase IIß. The drug is more potent and efficacious than etoposide or TOP-53, an etoposide derivative that contains a C4 aminoalkyl group that strengthens drug-enzyme binding. Unlike the other drugs, F14512 maintains robust activity in the absence of ATP. The enhanced activity of F14512 correlates with a tighter binding and an increased stability of the ternary topoisomerase II-drug-DNA complex. The spermine-drug core linkage is critical for these attributes. These findings demonstrate the utility of a C4 DNA binding group and provide a rational basis for the development of novel and more active etoposide-based topoisomerase II poisons.

Contributions of the D-Ring to the activity of etoposide against human topoisomerase IIα: potential interactions with DNA in the ternary enzyme--drug--DNA complex.

Etoposide is a widely prescribed anticancer drug that stabilizes covalent topoisomerase II-cleaved DNA complexes. The drug contains a polycyclic ring system (rings A-D), a glycosidic moiety at C4, and a pendant ring (E-ring) at C1. Interactions between human topoisomerase IIα and etoposide in the binary enzyme--drug complex appear to be mediated by substituents on the A-, B-, and E-rings of etoposide. These protein--drug contacts in the binary complex have predictive value for the actions of etoposide within the ternary topoisomerase IIα--drug--DNA complex. Although the D-ring of etoposide does not appear to contact topoisomerase IIα in the binary complex, etoposide derivatives with modified D-rings display reduced cytotoxicity against murine leukemia cells [Meresse, P., et al. (2003) Bioorg. Med. Chem. Lett. 13, 4107]. This finding suggests that alterations in the D-ring may affect etoposide activity toward topoisomerase IIα in the ternary enzyme--drug--DNA complex. Therefore, to address the potential contributions of the D-ring to the activity of etoposide, we characterized drug derivatives in which the C13 carbonyl was moved to the C11 position (retroetoposide and retroDEPT) or the D-ring was opened (D-ring diol). All of the D-ring alterations decreased the ability of etoposide to enhance DNA cleavage mediated by human topoisomerase IIα in vitro and in cultured cells. They also weakened etoposide binding in the ternary enzyme--drug--DNA complex and altered sites of enzyme-mediated DNA cleavage. On the basis of these findings, we propose that the D-ring of etoposide has important interactions with DNA in the ternary topoisomerase II cleavage complex.

Disease risk scores for skin cancers.

We trained and validated risk prediction models for the three major types of skin cancer- basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma-on a cross-sectional and longitudinal dataset of 210,000 consented research participants who responded to an online survey covering personal and family history of skin cancer, skin susceptibility, and UV exposure. We developed a primary disease risk score (DRS) that combined all 32 identified genetic and non-genetic risk factors. Top percentile DRS was associated with an up to 13-fold increase (odds ratio per standard deviation increase >2.5) in the risk of developing skin cancer relative to the middle DRS percentile. To derive lifetime risk trajectories for the three skin cancers, we developed a second and age independent disease score, called DRSA. Using incident cases, we demonstrated that DRSA could be used in early detection programs for identifying high risk asymptotic individuals, and predicting when they are likely to develop skin cancer. High DRSA scores were not only associated with earlier disease diagnosis (by up to 14 years), but also with more severe and recurrent forms of skin cancer.

Associations between Race, Discrimination, Community Violence, Traumatic Life Events, and Psychosis-Like Experiences in a Sample of College Students.

Self-report tools of psychosis-like experiences contribute to the understanding of psychosis and may aid in identification and prevention efforts across the severity spectrum. Current tools are likely limited by biases, leading to potential systematic health disparities. Principal component analyses in diverse samples of community participants reporting psychosis-like experiences may aid in the detection of measurement biases. The current study evaluated the fit of a two-component model for the Prime Screen, a self-report psychosis-like experiences measure, in a sample of Black (n = 82) and White (n = 162) community participants, and subsequently evaluated the relation of these components with measures of mental well-being, traumatic life experiences, community violence, and experiences of discrimination. Analyses indicated limited support for a two-component model of the Prime Screen, with four of the items showing high cross-loading across both components ("poor fit" items). Although many Prime Screen items correlated with mental well-being as expected, correlations between item scores and mental well-being were non-significant for poor fit items. Community violence emerged as a significant predictor of some individual item scores for both good and poor fit items, while discrimination predicted only some poor fit item scores. Results highlight the potential limitations of current self-report tools of psychosis-like experiences, as well as possible considerations for improvement for use in diverse populations.

Family functioning moderates the impact of psychosis-risk symptoms on social and role functioning.

BACKGROUND: Youth at clinical high-risk (CHR) for psychosis often experience difficulties in social and role functioning. Given evidence that family stress and support can impact psychosis-risk symptoms, as well as an individual's ability to fulfill social and role functions, family dynamics are hypothesized to moderate the effect of psychosis-risk symptoms on functioning. METHODS: Participants at CHR (N = 52) completed the clinician-administered Structured Interview for Psychosis-risk Syndromes (SIPS) and the Family Assessment Device (FAD) General Functioning Scale, a self-report measure of family functioning including cohesion and support. Interviewers rated participants' current social and role functioning using the Global Functioning: Social and Role Scales. RESULTS: Regression results indicated that positive symptoms, but not ratings of family functioning, statistically predicted social and role functioning. Perceived family functioning, however, moderated the effect of symptoms on social/role functioning. For individuals who perceived lower levels of family functioning, symptoms were moderately associated with social and role functioning (f2 = 0.17 and f2 = 0.23, respectively). In contrast, psychosis-risk symptoms were not significantly associated with social/role functioning for individuals with higher levels of perceived family functioning. Notably, positive symptoms and perceived family functioning were not associated with one another, suggesting that perceived family functioning did not directly impact symptom severity, or vice versa. CONCLUSIONS: Findings support the notion that family functioning may be a clinically meaningful factor for individuals at CHR. Although this cross-sectional data limits our discussion of potential mechanisms underlying the pattern of findings, results suggest that familial support may be beneficial for individuals at risk for psychosis.

The impact of age on the validity of psychosis-risk screening in a sample of help-seeking youth.

Self-report screening instruments offer promise in furthering early identification of at-risk youth, yet current efforts are limited by false positive rates. Identifying moderators of accuracy is a potential step towards improving identification and prevention efforts. We investigated the moderating effect of age on self-reported attenuated positive symptoms from the Prime Screen and clinician diagnosed clinical high-risk/early psychosis (CHR/EP) status. Participants (N = 134) were racially diverse, lower-income, help-seeking adolescents and young adults from a primarily urban community. The overall model predicting CHR/EP status was significant, with results suggesting the presence of a trending interaction between age and Prime Screen symptoms. Analyses indicated that number of items endorsed to predict CHR/EP decreased with age (youngest group [M = 12.99] cut off = 6 items; middle age group [M = 14.97] cut off = 3; oldest age group [M = 18.40] cut off = 1). Although younger participants endorsed more risk items on average, follow up analyses suggested that the Prime Screen was a more accurate predictor of clinician-diagnosed-risk among older participants relative to their younger peers. The current study builds on the literature identifying moderators of psychosis-risk screening measure accuracy, highlighting potential limitations of CHR/EP screening tools in younger populations.