Evidence of an interaction between FXR1 and GSK3 beta polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics

Background: Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3β (GSK3β), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3β, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. Methods: To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3β expression. Results: We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. Discussion: Our findings suggest that, like GSK3β, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3β pathway for NSs of SCZ

The Brief Negative Symptom Scale (BNSS): Independent validation in a large sample of Italian patients with schizophrenia

BACKGROUND: The Brief Negative Symptom Scale (BNSS) was developed to address the main limitations of the existing scales for the assessment of negative symptoms of schizophrenia. The initial validation of the scale by the group involved in its development demonstrated good convergent and discriminant validity, and a factor structure confirming the two domains of negative symptoms (reduced emotional/verbal expression and anhedonia/asociality/avolition). However, only relatively small samples of patients with schizophrenia were investigated. Further independent validation in large clinical samples might be instrumental to the broad diffusion of the scale in clinical research. METHODS: The present study aimed to examine the BNSS inter-rater reliability, convergent/discriminant validity and factor structure in a large Italian sample of outpatients with schizophrenia. RESULTS: Our results confirmed the excellent inter-rater reliability of the BNSS (the intraclass correlation coefficient ranged from 0.81 to 0.98 for individual items and was 0.98 for the total score). The convergent validity measures had r values from 0.62 to 0.77, while the divergent validity measures had r values from 0.20 to 0.28 in the main sample (n=912) and in a subsample without clinically significant levels of depression and extrapyramidal symptoms (n=496). The BNSS factor structure was supported in both groups. CONCLUSIONS: The study confirms that the BNSS is a promising measure for quantifying negative symptoms of schizophrenia in large multicenter clinical studies

Prospective Study on the Association between Harm Avoidance and Postpartum Depressive State in a Maternal Cohort of Japanese Women

BACKGROUND: Recent studies have displayed increased interest in examining the relationship between personality traits and the onset, treatment response patterns, and relapse of depression. This study aimed to examine whether or not harm avoidance (HA) was a risk factor for postpartum depression measured by the Edinburgh Postnatal Depression Scale (EPDS) and the state dependency of HA. METHODS: Pregnant women (n=460; mean age 31.9±4.2 years) who participated in a prenatal program completed the EPDS as a measure of depressive state and the Temperament and Character Inventory (TCI) as a measure of HA during three periods: early pregnancy (T1), late pregnancy (around 36 weeks), and 1 month postpartum (T2). Changes in EPDS and HA scores from T1 to T2 were compared between the non depressive (ND) group and the postpartum depressive (PD) group. RESULTS: There was no significant difference in the level of HA between the ND and PD groups at T1. In the ND group, EPDS and HA scores did not change significantly from T1 to T2. In the PD group, both scores increased significantly from T1 to T2 (EPDS, p<0.0001; HA, p<0.048). In the ND and PD groups, a significant positive correlation was observed in changes in EPDS and HA scores from T1 to T2 (r=0.31, p=0.002). CONCLUSIONS: These results suggest that HA cannot be considered a risk factor for the development of postpartum depression measured by EPDS. Furthermore, HA may be state dependent

Transdiagnostic subgroups of cognitive impairment in early affective and psychotic illness

Abstract: Cognitively impaired and spared patient subgroups were identified in psychosis and depression, and in clinical high-risk for psychosis (CHR). Studies suggest differences in underlying brain structural and functional characteristics. It is unclear whether cognitive subgroups are transdiagnostic phenomena in early stages of psychotic and affective disorder which can be validated on the neural level. Patients with recent-onset psychosis (ROP; N = 140; female = 54), recent-onset depression (ROD; N = 130; female = 73), CHR (N = 128; female = 61) and healthy controls (HC; N = 270; female = 165) were recruited through the multi-site study PRONIA. The transdiagnostic sample and individual study groups were clustered into subgroups based on their performance in eight cognitive domains and characterized by gray matter volume (sMRI) and resting-state functional connectivity (rsFC) using support vector machine (SVM) classification. We identified an impaired subgroup (N ROP = 79, N ROD = 30, N CHR = 37) showing cognitive impairment in executive functioning, working memory, processing speed and verbal learning (all p < 0.001). A spared subgroup (N ROP = 61, N ROD = 100, N CHR = 91) performed comparable to HC. Single-disease subgroups indicated that cognitive impairment is stronger pronounced in impaired ROP compared to impaired ROD and CHR. Subgroups in ROP and ROD showed specific symptom- and functioning-patterns. rsFC showed superior accuracy compared to sMRI in differentiating transdiagnostic subgroups from HC (BACimpaired = 58.5%; BACspared = 61.7%, both: p < 0.01). Cognitive findings were validated in the PRONIA replication sample (N = 409). Individual cognitive subgroups in ROP, ROD and CHR are more informative than transdiagnostic subgroups as they map onto individual cognitive impairment and specific functioning- and symptom-patterns which show limited overlap in sMRI and rsFC. Clinical trial registry name: German Clinical Trials Register (DRKS). Clinical trial registry URL: https://www.drks.de/drks_web/ . Clinical trial registry number: DRKS00005042

Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis

Cannabis use during adolescence is associated with an increased risk of developing psychosis. According to a current hypothesis, this results from detrimental effects of early cannabis use on brain maturation during this vulnerable period. However, studies investigating the interaction between early cannabis use and brain structural alterations hitherto reported inconclusive findings. We investigated effects of age of cannabis initiation on psychosis using data from the multicentric Personalized Prognostic Tools for Early Psychosis Management (PRONIA) and the Cannabis Induced Psychosis (CIP) studies, yielding a total sample of 102 clinically-relevant cannabis users with recent onset psychosis. GM covariance underlies shared maturational processes. Therefore, we performed source-based morphometry analysis with spatial constraints on structural brain networks showing significant alterations in schizophrenia in a previous multisite study, thus testing associations of these networks with the age of cannabis initiation and with confounding factors. Earlier cannabis initiation was associated with more severe positive symptoms in our cohort. Greater gray matter volume (GMV) in the previously identified cerebellar schizophrenia-related network had a significant association with early cannabis use, independent of several possibly confounding factors. Moreover, GMV in the cerebellar network was associated with lower volume in another network previously associated with schizophrenia, comprising the insula, superior temporal, and inferior frontal gyrus. These findings are in line with previous investigations in healthy cannabis users, and suggest that early initiation of cannabis perturbs the developmental trajectory of certain structural brain networks in a manner imparting risk for psychosis later in life

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity &gt; 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI