Bullying in clinical high risk for psychosis participants from the NAPLS-3 cohort.

PURPOSE: Bullying is associated with a heightened risk for poor outcomes, including psychosis. This study aimed to replicate previous findings on bullying prevalence in clinical high-risk (CHR) individuals, to assess the longitudinal course of clinical and functional variables between bullied and non-bullied CHR and the association of bullying with premorbid functioning, clinical outcome, transition to psychosis and risk of violence. METHODS: The sample consisted of 691 CHR participants and 96 healthy controls. Participants reported whether they had experienced bullying and how long it had lasted. Assessments included DSM-5 diagnoses, attenuated psychotic symptoms, negative symptoms, social and role functioning, depression, stress, premorbid functioning, and risk of violence. The bullied and non-bullied CHR groups were compared at baseline and further longitudinally on clinical and functioning variables and transition to psychosis. RESULTS: Bullying was more prevalent among CHR individuals than healthy controls. Bullied CHR had a higher prevalence of PTSD and more severe depression and stress at baseline than non-bullied CHR. There was no impact of bullying on clinical and functional variables over time. Bullying was not related to final clinical status or transition to psychosis. However, bullied participants had poorer premorbid functioning and a greater risk of violence. CONCLUSION: While bullying may not impact the likelihood of CHR individuals to transition to psychosis, it may be a risk factor for development of the at-risk state and may be related to a greater risk of violence. Future studies should consider bullying perpetration among CHR individuals.

Stereotypical alterations in cortical patterning are associated with maternal illness-induced placental dysfunction.

We have previously shown in mice that cytokine-mediated damage to the placenta can temporarily limit the flow of nutrients and oxygen to the fetus. The placental vulnerability is pronounced before embryonic day 11, when even mild immune challenge results in fetal loss. As gestation progresses, the placenta becomes increasingly resilient to maternal inflammation, but there is a narrow window in gestation when the placenta is still vulnerable to immune challenge yet resistant enough to allow for fetal survival. This gestational window correlates with early cortical neurogenesis in the fetal brain. Here, we show that maternal illness during this period selectively alters the abundance and laminar positioning of neuronal subtypes influenced by the Tbr1, Satb2, and Ctip2/Fezf2 patterning axis. The disturbances also lead to a laminar imbalance in the proportions of projection neurons and interneurons in the adult and are sufficient to cause changes in social behavior and cognition. These data illustrate how the timing of an illness-related placental vulnerability causes developmental alterations in neuroanatomical systems and behaviors that are relevant to autism spectrum disorders.

Unleash metformin: reconsideration of the contraindication in patients with renal impairment.

OBJECTIVE: To evaluate the expanded use of metformin in renal impairment. DATA SOURCES: The MEDLINE database via PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health were searched in August 2013 and included studies from 1950 onward. STUDY SELECTION AND DATA EXTRACTION: The search included comparative trials, observational cohort studies, and meta-analyses using the terms diabetes mellitus, metformin, renal insufficiency, and acidosis, lactic. DATA SYNTHESIS: One randomized controlled trial, 1 meta-analysis, 1 case-control, and 3 prospective-cohort studies, representing about 150 000 patients, revealed that metformin is safe in patients with stable mild-moderate renal impairment. The incidence of lactic acidosis is low and similar to sulfonylureas. In addition, reduced risks of cardiovascular disease, all-cause mortality, or any acidosis/serious infection were seen with metformin use in mild-to-moderate renal impairment. CONCLUSIONS: Data over the past decade refute the historical contraindication in patients with renal impairment and suggest that the risk of metformin-associated lactic acidosis is low in stable mild-to-moderate renal impairment and similar to the risk with other type 2 diabetes mellitus (DM2) medications with no renal impairment restrictions. Because of its unique impact on microvascular and macrovascular complications, it is advantageous to utilize metformin as the cornerstone in DM2 treatment for as long as possible, including in those patients with mild to moderate stages of renal impairment with no additional contraindications. A dosage reduction is recommended if estimated glomerular filtration rate (eGFR) is between 30 and 45 mL/min/1.73 m(2) and discontinuation if eGFR is <30 mL/min/1.73 m(2).

Patient-Reported Outcome Measures in Clinical High Risk for Psychosis: A Systematic Review.

A key issue in both research and clinical work with youth at clinical high risk (CHR) of psychosis is that there are clearly heterogenous clinical outcomes in addition to the development of psychosis. Thus, it is important to capture the psychopathologic outcomes of the CHR group and develop a core outcomes assessment set that may help in dissecting the heterogeneity and aid progress toward new treatments. In assessing psychopathology and often poor social and role functioning, we may be missing the important perspectives of the CHR individuals themselves. It is important to consider the perspectives of youth at CHR by using patient-reported outcome measures (PROMs). This systematic review of PROMs in CHR was conducted based on a comprehensive search of several databases and followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Sixty-four publications were included in the review examining PROMs for symptoms, functioning, quality of life, self-perceptions, stress, and resilience. Typically, PROMs were not the primary focus of the studies reviewed. The PROMs summarized here fit with results published elsewhere in the literature based on interviewer measures. However, very few of the measures used were validated for CHR or for youth. There are several recommendations for determining a core set of PROMs for use with CHR.

Cognitive-Behavioral Social Skills Training: Outcome of a Randomized Controlled Trial for Youth at Risk of Psychosis.

Aim: Difficulties in social functioning have been observed in youth at clinical high-risk (CHR) of psychosis even in those who do not go on to develop a psychotic illness. Few treatment studies have attempted to improve social functioning in this population. The aim of this study was to conduct a randomized trial comparing the effects of Cognitive-Behavioral Social Skills Training (CBSST) with a supportive therapy (ST). Methods: Both CBSST and ST were weekly group therapies, delivered over 18 weeks. This was a 2-arm trial with single-blinded ratings and intention-to-treat analyses. Assessments occurred at baseline, end-of-treatment, and 12 months after the baseline assessment. The primary outcome was social and role functioning and defeatist performance attitudes were the secondary outcome. Attenuated positive and negative symptoms, anxiety, depression, self-efficacy, and beliefs about self and others were examined as exploratory outcomes. Results: There were no significant differences between the 2 groups at baseline or either of the 2 follow-ups. However, at follow-ups, in each group there were significant improvements in clinical symptoms. These could not be attributed to group treatment since there was no control or wait-list group. Conclusions: Since poor social functioning is one of the most observed difficulties in CHR individuals, and a decline in social functioning may be a significant predictor of later transition to psychosis, future work will be needed to find effective treatments for this decline in functioning for CHR youth.

Bullying and social functioning, schemas, and beliefs among youth at clinical high risk for psychosis.

BACKGROUND: Individuals at clinical high-risk (CHR) for psychosis experience high rates of bullying. There is little research on the differences between CHR who did and did not experience bullying. However, there is evidence that bullying may be related to negative schemas and social impairment. OBJECTIVES: To examine differences in core schemas, asocial and defeatist beliefs, and social functioning between those who did and did not report bullying experiences in a large sample of CHR individuals. We hypothesized that bullying in CHR youth would be associated with poorer social functioning, increased maladaptive beliefs, and negative core schemas. METHODS: CHR participants (N = 203) were split into those who did and did not report experiencing bullying. The two groups were compared on demographic characteristics, social functioning, and belief variables, using the Brief Core Schemas Scale, the Asocial Beliefs Scale, the Defeatist Performance Attitudes Scale, and the First Episode Social Functioning Scale. RESULTS: 72.9% reported experiencing bullying. These participants had greater severity of negative schemas about others and asocial and defeatist performance beliefs, and lower social functioning scores. CONCLUSIONS: Prevalence of bullying among CHR participants is high. Bullying may be a risk factor for increased asocial and defeatist beliefs, negative core schemas, and poor social functioning. Targeting maladaptive schemas and beliefs during treatment may serve to improve functional outcomes in this group.

Sex at the interface: the origin and impact of sex differences in the developing human placenta.

The fetal placenta is a source of hormones and immune factors that play a vital role in maintaining pregnancy and facilitating fetal growth. Cells in this extraembryonic compartment match the chromosomal sex of the embryo itself. Sex differences have been observed in common gestational pathologies, highlighting the importance of maternal immune tolerance to the fetal compartment. Over the past decade, several studies examining placentas from term pregnancies have revealed widespread sex differences in hormone signaling, immune signaling, and metabolic functions. Given the rapid and dynamic development of the human placenta, sex differences that exist at term (37-42 weeks gestation) are unlikely to align precisely with those present at earlier stages when the fetal-maternal interface is being formed and the foundations of a healthy or diseased pregnancy are established. While fetal sex as a variable is often left unreported in studies performing transcriptomic profiling of the first-trimester human placenta, four recent studies have specifically examined fetal sex in early human placental development. In this review, we discuss the findings from these publications and consider the evidence for the genetic, hormonal, and immune mechanisms that are theorized to account for sex differences in early human placenta. We also highlight the cellular and molecular processes that are most likely to be impacted by fetal sex and the evolutionary pressures that may have given rise to these differences. With growing recognition of the fetal origins of health and disease, it is important to shed light on sex differences in early prenatal development, as these observations may unlock insight into the foundations of sex-biased pathologies that emerge later in life.

Longitudinal impact of trauma in the North American Prodrome Longitudinal Study-3.

AIM: Individuals at clinical high risk (CHR) for psychosis have been shown to experience more trauma than the general population. However, although the effects of trauma appear to impact some symptoms it does not seem to increase the risk of transition to psychosis. The aim of this article was to examine the prevalence of trauma, and its association with longitudinal clinical and functional outcomes in a large sample of CHR individuals. METHODS: From the North American Prodrome Longitudinal Study-3 (NAPLS-3) 690 CHR individuals and 91 healthy controls from nine study sites between 2015 and 2018 were assessed. Historical trauma experiences were captured at baseline. Participants completed longitudinal assessments measuring clinical outcomes including positive and negative symptoms, depression, social and role functioning and assessing transition to psychosis. RESULTS: From the 690 CHR participants and 96 healthy controls, 343 (49.6%) and 15 (15.6%), respectively, reported a history of trauma (p < .001). Emotional neglect (70.3%) was the most commonly reported type of trauma, followed by psychological abuse (57.4%). Among CHR participants, time to transition to psychosis was not associated with trauma. Baseline depression and suspiciousness/persecutory ideas were statistically significantly different between CHR individuals who did or did not experience trauma. However, when examining clinical and functional outcomes over 12-months of follow-up, there were no differences between those who experienced trauma and those who did not. CONCLUSION: Overall, trauma is a significantly prevalent among CHR individuals. The effects of trauma on transition and longitudinal clinical and functional outcomes were not significant.

LTP- and LTD-inducing stimulations cause opposite changes in arc/arg3.1 mRNA level in hippocampal area CA1 in vivo.

Immediate early genes (IEGs) typically are the first genetic responders to a variety of cellular activations. The IEG that encodes activity-regulated cytoskeleton-associated protein (arc/arg3.1) has attracted much interest because its mRNA is transported to and translated near activated synapses. Moreover, arc has been implicated in both long-term potentiation (LTP) and long-term depression (LTD). However, little is known about the time course of altered arc expression during LTP and LTD. Here we characterized arc mRNA levels in area CA1 of the adult rat hippocampus in vivo after LTP- and LTD-inducing stimulations that were identical, except for the temporal patterning of the stimulation pulses. We observed a persistent increase in arc mRNA level during LTP. In contrast, during LTD, arc mRNA level first was decreased and then transiently increased relative to control level. These findings demonstrate that arc mRNA is regulated differently during LTP and LTD, and they provide evidence for stimulation-induced downregulation of mRNA availability during LTD. Findings of abbreviated LTD when transcription was inhibited indicate that the prolonged maintenance of the type of N-methyl-D-aspartate receptor-dependent LTD studied here requires de novo transcription. Furthermore, lack of evidence for a LTD-associated change in the mRNA level of the IEG zif268 demonstrates that the decrease in arc mRNA during LTD is not a general genetic response. Thus, the regulation of arc expression not only differs between LTP and LTD, but also diverges from that of other IEGs implicated in activity-dependent synaptic plasticity.

Cognitive behavioural social skills training: Methods of a randomized controlled trial for youth at risk of psychosis.

AIM: Poor functioning has become a hallmark of many youth at clinical high-risk (CHR) of psychosis. Even for those who do not make the transition to psychosis remain troubled by functional deficits and a decline in functioning increases the odds of transitioning to psychosis. There are very few treatment studies that have attempted to improve social and role functioning. The aim of this paper is to describe the methods of a treatment study to address social and role functioning in CHR. METHODS: This was a randomized controlled trial of cognitive-behavioural social skills training (CBSST) versus a supportive therapy. CBSST combines elements of cognitive behaviour therapy (CBT) and social skills training (SST), two evidence-based treatments for schizophrenia. By adding CBT to SST to target functioning outcomes, SST can be used to train new social skills, and thoughts that interfere with skilled performance in the real world can be addressed using CBT. We developed an adapted version of CBSST, more appropriate for the age range and illness severity of typical CHR individuals, to attempt to show improvements in social and role functioning for these young people. RESULTS: Two hundred and three participants were recruited for this study. Results include initial baseline data. CONCLUSION: This article describes the baseline methodology of a CHR youth who have difficulties in social and/or role functioning. It is one of the first clinical trials to address this significant problem.

Social functioning and brain imaging in individuals at clinical high-risk for psychosis: A systematic review.

Impairments in social functioning are a core impairment in psychosis and are associated with poor outcomes. These deficits are found in those at clinical high-risk (CHR) for psychosis, and can persist even in the absence of transition. However, the neurobiological underpinnings of social functioning remain unclear, therefore we conducted a systematic review of brain metrics that have been associated with social functioning in youth at CHR for psychosis. Five databases (MEDLINE, CINAHL, EBM reviews, Embase, and PsycINFO) were searched from inception to May 5, 2020. Studies were selected if they examined brain imaging, and social functioning in youth at CHR for psychosis. Of the 9629 citations found through online database searching, 12 studies with 696 CHR participants met inclusion criteria. Too few studies were focused on the same brain region using the same methodology to perform a meta-analysis, however, loci within the prefrontal cortex were most often associated with social functioning. Few studies have linked social functioning to brain imaging metrics, suggesting that future work should focus on this relationship.

Examining Sex Differences in the Human Placental Transcriptome During the First Fetal Androgen Peak.

Sex differences in human placenta exist from early pregnancy to term, however, it is unclear whether these differences are driven solely by sex chromosome complement or are subject to differential sex hormonal regulation. Here, we survey the human chorionic villus (CV) transcriptome for sex-linked signatures from 11 to 16 gestational weeks, corresponding to the first window of increasing testis-derived androgen production in male fetuses. Illumina HiSeq RNA sequencing was performed on Lexogen Quantseq 3' libraries derived from CV biopsies (n = 11 females, n = 12 males). Differential expression (DE) was performed to identify sex-linked transcriptional signatures, followed by chromosome mapping, pathway analysis, predicted protein interaction, and post-hoc linear regressions to identify transcripts that trend over time. We observe 322 transcripts DE between male and female CV from 11 to 16 weeks, with 22 transcripts logFC > 1. Contrary to our predictions, the difference between male and female expression of DE autosomal genes was more pronounced at the earlier gestational ages. In females, we found selective upregulation of extracellular matrix components, along with a number of X-linked genes. In males, DE transcripts centered on chromosome 19, with mitochondrial, immune, and pregnancy maintenance-related transcripts upregulated. Among the highest differentially expressed autosomal genes were CCRL2, LGALS13, and LGALS14, which are known to regulate immune cell interactions. Our results provide insight into sex-linked gene expression in late first and early second trimester developing human placenta and lay the groundwork to understand the mechanistic origins of sex differences in prenatal development.

Negative Symptoms and Functioning in Youth at Risk of Psychosis: A Systematic Review and Meta-analysis.

LEARNING OBJECTIVE: After participating in this activity, learners should be better able to:• Evaluate the relationship between negative symptoms and functioning in youth at clinical high risk for psychosis. AIM: Youth at CHR for psychosis often demonstrate significant negative symptoms and poor functioning, though the magnitude and direction of the relationship between the two remains unknown. The objective of this systematic review is to summarize the relationship between negative symptoms and functioning in CHR samples. METHOD: Electronic databases CINAHL, EBM, Embase, MEDLINE, and PsycINFO were searched from inception. Studies were selected if they included any study that reported a relationship between negative symptoms and functioning in youth at clinical high risk (CHR). The correlation coefficient r was converted to Cohen's d, and all random-effects meta-analyses were performed using the transformed values. RESULTS: Forty-one studies met the inclusion criteria, including a total of 4574 individuals at CHR for psychosis. Negative symptom total scores were significantly associated with poorer global functioning (d, -1.40; 95% CI, -1.82 to -0.98; I = 79.4%; p < .001 [9 studies, n = 782]), social functioning (d, -1.10; 95% CI, -1.27 to -0.93; I = 10.40%; p < .001 [12 studies, n = 811]), and role functioning (d, -0.96; 95% CI, -1.17 to -0.76; I = 41.1%; p < .001 [9 studies, n = 881]). In addition, negative symptoms were consistently associated with poor premorbid functioning. When examining negative symptom domains, avolition, anhedonia, and blunted affect were each significantly and independently associated with poorer social functioning and role functioning. In terms of prediction models, negative symptoms contributed to the prediction of lower functioning across multiple studies. CONCLUSION: This meta-analysis demonstrates a strong relationship between negative symptoms and functioning in youth at clinical high risk for psychosis.

Brain changes associated with negative symptoms in clinical high risk for psychosis: A systematic review.

The negative symptoms of schizophrenia are linked to poorer functional outcomes and decreases in quality of life, and are often the first to develop in individuals who are at clinical high risk (CHR) for psychosis. However, the accompanying neurobiological changes are poorly understood. Therefore, we conducted a systematic review of the studies that have examined the brain metrics associated with negative symptoms in those at CHR. Electronic databases were searched from inception to August 2019. Studies were selected if they mentioned negative symptoms in youth at CHR for psychosis, and brain imaging. Of 261 citations, 43 studies with 2144 CHR participants met inclusion criteria. Too few studies were focused on the same brain regions using similar neuroimaging methods to perform a meta-analysis, however, the results of this systematic review suggest a relationship between negative symptom increases and decreases in grey matter. The paucity of studies linking changes in brain structure and function with negative symptoms in those at CHR suggests that future work should focus on examining these relationships.

"Females Are Not Just 'Protected' Males": Sex-Specific Vulnerabilities in Placenta and Brain after Prenatal Immune Disruption.

Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased toward male outcomes. An argument is made that males are more vulnerable to gestational complications and neurodevelopmental disorders, the implication being that an understanding of disrupted development in males is sufficient to understand causal mechanisms that are assumed to be similar but attenuated in females. Here we examine this assumption in the context of immune-driven alterations in fetal brain development and related outcomes in female and male mice. Pregnant C57BL/6 mice were treated with low-dose lipopolysaccharide at embryonic day 12.5. Placental pathology, acute fetal brain inflammation and hypoxia, long-term changes in adult cortex cytoarchitecture, altered densities and ratio of excitatory (Satb2+) to inhibitory (parvalbumin+) neuronal subtypes, postnatal growth, and behavior outcomes were compared between male and female offspring. We find that while males experience more pronounced placental pathology, fetal brain hypoxia, depleted PV and Satb2+ densities, and social and learning-related behavioral abnormalities, females exhibit unique acute inflammatory signaling in fetal brain, postnatal growth delay, opposite alterations in cortical PV densities, changes in juvenile behavior, delayed postnatal body growth, and elevated anxiety-related behavior as adults. While males are more severely impacted by prenatal immune disruption by several measures, females exposed to the same insult exhibit a unique set of vulnerabilities and developmental consequences that is not present in males. Our results clearly outline disparate sex-specific features of prenatal vulnerability to inflammatory insults and warn against the casual extrapolation of male disease mechanisms to females.