Does HPA-axis activity mediate the relationship between obstetric complications and externalizing behavior problems? The TRAILS study

To examine whether HPA-axis activity mediates the relationship between obstetric complications (OCs) and externalizing behavior problems, and to investigate whether this model is different for boys and girls. In a population-based cohort of 1,768 10- to 12-year-old early adolescents, we assessed the cortisol awakening response and evening cortisol levels. Externalizing behavior problems were assessed using the Child Behavior Checklist and the Youth Self-Report. OCs were retrospectively assessed in a parent interview. OCs significantly predicted externalizing behavior problems, but OCs did not predict HPA-axis activity. Thus, the mediation model was not supported. In addition to the relationship between HPA-axis activity and externalizing behavior problems, which is specific for girls, there is also a relationship between OCs and externalizing behavior problems. However, these two mechanisms are not related to each other indicating that HPA-axis activity is not a mediator in the relationship between OCs and externalizing behavior problems. Future research should focus on understanding the mechanism through which OCs cause externalizing behavior problems

The lethal response to Cdk1 inhibition depends on sister chromatid alignment errors generated by KIF4 and isoform 1 of PRC1

Cyclin-dependent kinase 1 (Cdk1) is absolutely essential for cell division. Complete ablation of Cdk1 precludes the entry of G2 phase cells into mitosis, and is early embryonic lethal in mice. Dampening Cdk1 activation, by reducing gene expression or upon treatment with cell-permeable Cdk1 inhibitors, is also detrimental for proliferating cells, but has been associated with defects in mitotic progression, and the formation of aneuploid daughter cells. Here, we used a large-scale RNAi screen to identify the human genes that critically determine the cellular toxicity of Cdk1 inhibition. We show that Cdk1 inhibition leads to fatal sister chromatid alignment errors and mitotic arrest in the spindle checkpoint. These problems start early in mitosis and are alleviated by depletion of isoform 1 of PRC1 (PRC1-1), by gene ablation of its binding partner KIF4, or by abrogation of KIF4 motor activity. Our results show that, normally, Cdk1 activity must rise above the level required for mitotic entry. This prevents KIF4-dependent PRC1-1 translocation to astral microtubule tips and safeguards proper chromosome congression. We conclude that cell death in response to Cdk1 inhibitors directly relates to chromosome alignment defects generated by insufficient repression of PRC1-1 and KIF4 during prometaphase

HPA-axis activity and externalizing behavior problems in early adolescents from the general population:the role of comorbidity and gender The TRAILS study

Contradictory findings on the relationship between hypothalamus-pituitary-adrenal (HPA)-axis activity and externalizing behavior problems could be due to studies not accounting for issues of comorbidity and gender. In a population-based cohort of 1768 (10- to 12-year-old) early adolescents, we used a person-oriented approach and a variable-oriented approach to investigate whether comorbidity with internalizing behavior problems and gender moderate the relationship between HPA-axis activity (cortisol awakening response and evening cortisol levels) and externalizing behavior problems. We found that: (1) in early adolescents with pure externalizing behavior problems, there was a particularly strong effect of gender, in that girls showed significantly higher total cortisol levels after awakening (AUC(G) levels) and a significantly higher cortisol awakening response (AUC(I) levels) than boys. (2) Girls with pure externalizing behavior problems showed a significantly higher cortisol awakening response (AUC(I) levels) than girls without behavior problems or girls with comorbid internalizing behavior problems. This effect was absent in boys. (3) Externalizing behavior problems, in contrast to internalizing behavior problems, were associated with higher evening cortisol levels. This effect might, however, result from girls with externalizing behavior problems showing the highest evening cortisol levels. Overall, we were unable to find the expected relationships between comorbidity and HPA-axis activity, and found girls with pure externalizing behavior problems to form a distinct group with regard to their HPA-axis activity. There is need for prospective longitudinal studies of externalizing behavior problems in boys and girls in relation to their HPA-axis activity. It would be useful to consider how other risk factors such as life events and family and parenting factors as well as genetic risks affect the complex relationship between externalizing behavior problems and HPA-axis activity

A variant of the castor zinc finger 1 (CASZ1) gene is differentially associated with the clinical classification of chronic venous disease

Recent reports have suggested a reproducible association between the rs11121615 SNP, located within an intron of the castor zinc finger 1 (CASZ1) gene, and varicose veins. This study aimed to determine if this variant is also differentially associated with the various clinical classifications of chronic venous disease (CVD). The rs11121615 SNP was genotyped in two independent cohorts from New Zealand (n = 1876 controls /1606 CVD cases) and the Netherlands (n = 1626/2966). Participants were clinically assessed using well-established CVD criteria. The association between the rs11121615 C-allele and varicose veins was validated in both cohorts. This was strongest in those with higher clinical severity classes and was not significant in those with non-varicose vein CVD. Functional analysis of the rs11121615 variant demonstrated that the risk allele was associated with increased enhancer activity. This study demonstrates that the CASZ1 gene associated C-allele of rs11121615 has a significant, reproducible, association with CVD (CEAP C ≥ 2 meta-odds ratio 1.31, 95% CI 1.27-1.34, P = 1 × 10-98, PHet = 0.25), but not with non-varicose vein (CEAP C1, telangiectasia or reticular veins) forms of venous disease. The effect size of this association therefore appears to be susceptible to influence by phenotypic heterogeneity, particularly if a cohort includes a large number of cases with lower severity CVD

Subanesthetic ketamine treatment promotes abnormal interactions between neural subsystems and alters the properties of functional brain networks

Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia

DNA methylation profiling identifies a high effect genetic variant for lipoprotein(a) levels

Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF <0.02) at the CpG site that largely explained the observed methylation effect. Rs76735376 is an expression quantitative trait loci for the LPA gene and could affect expression by altering enhancer activity. This EWAS for plasma Lp(a) identified a single CpG site within LPA. This association is due to an uncommon, but highly effective genetic variant, which was not in significant linkage disequilibrium with other variants known to influence Lp(a) levels or apo(a) isoform size. This study highlights the utility of CpG site methylation to identify potentially important genetic associations that would not be readily apparent in a comparable size genetic association study

Cohort profile of PLUTO: a perioperative biobank focusing on prediction and early diagnosis of postoperative complications

Purpose Although elective surgery is generally safe, some procedures remain associated with an increased risk of complications. Improved preoperative risk stratification and earlier recognition of these complications may ameliorate postoperative recovery and improve long-term outcomes. The perioperative longitudinal study of complications and long-term outcomes (PLUTO) cohort aims to establish a comprehensive biorepository that will facilitate research in this field. In this profile paper, we will discuss its design rationale and opportunities for future studies.Participants Patients undergoing elective intermediate to high-risk non-cardiac surgery are eligible for enrolment. For the first seven postoperative days, participants are subjected to daily bedside visits by dedicated observers, who adjudicate clinical events and perform non-invasive physiological measurements (including handheld spirometry and single-channel electroencephalography). Blood samples and microbiome specimens are collected at preselected time points. Primary study outcomes are the postoperative occurrence of nosocomial infections, major adverse cardiac events, pulmonary complications, acute kidney injury and delirium/acute encephalopathy. Secondary outcomes include mortality and quality of life, as well as the long-term occurrence of psychopathology, cognitive dysfunction and chronic pain.Findings to date Enrolment of the first participant occurred early 2020. During the inception phase of the project (first 2 years), 431 patients were eligible of whom 297 patients consented to participate (69%). Observed event rate was 42% overall, with the most frequent complication being infection.Future plans The main purpose of the PLUTO biorepository is to provide a framework for research in the field of perioperative medicine and anaesthesiology, by storing high-quality clinical data and biomaterials for future studies. In addition, PLUTO aims to establish a logistical platform for conducting embedded clinical trials.Trial registration number NCT05331118

Cost-effectiveness of laparoscopic ileocaecal resection versus infliximab treatment of terminal ileitis in Crohn's disease: The LIR!C Trial

Objective Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy. Design A multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty. Results In total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €-8931; 95% CI €-12 087 to €-5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €-5729, 95% CI €-10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score. Conclusion Laparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab. Clinical trial registration number Dutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015)