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DNA methylation in peripheral tissues may be a relevant biomarker of risk for developing mental disorders after exposure to early life adversity. Genes involved in HPA axis regulation, such as FKBP5 , might play a key role. In this study, we aimed to identify the main drivers of salivary FKBP5 methylation in a cohort of 162 maltreated and non-maltreated children aged 3-5 years at two measurement timepoints. We combined data from a targeted bisulfite sequencing approach for fine-mapping 49 CpGs in regulatory regions of FKBP5 and epigenetic scores for exposure to alcohol, cigarette smoke, and glucocorticoids derived from the EPICv1 microarray. Most variability of methylation in the FKBP5 locus was explained by estimated cell type proportions as well as epigenetic exposure scores, most prominently by the glucocorticoid exposure score. While not surviving correction for multiple testing, we replicated previously reported associations of FKBP5 methylation with CM. We also detected synergistic effects of both rs1360780 genotype and the glucocorticoid exposure score on FKBP5 hypomethylation. These effects were identified in the 3'TAD, a distal regulatory region of FKBP5 which is not extensively covered in Illumina arrays, emphasizing the need for fine mapping approaches. Additionally, the epigenetic glucocorticoid exposure score was associated with childhood maltreatment, maternal mental disorders, and pregnancy complications, thereby highlighting the role of glucocorticoid signaling in the epigenetic consequences of early adversity. These results underscore the need to assess cell type heterogeneity in targeted assessments of DNA methylation and show the impact of exposures beyond just childhood maltreatment such as glucocorticoid exposure., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elisabeth Binder has patent #FKBP5: a novel target for antidepressant therapy, European Patent #EP 1687443 B1 issued to the European Patent Office. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The brain and the intestinal microbiota are highly interconnected and especially vulnerable to disruptions in early life. Emerging evidence indicates that psychosocial adversity detrimentally impacts the intestinal microbiota, affecting both physical and mental health. This study aims to investigate the gut microbiome in young children in the immediate aftermath of maltreatment exposure., Methods: Maltreatment exposure was assessed in 88 children (ages 3-7) using the Maternal Interview for the Classification of Maltreatment [MICM]. Children were allocated to three groups according to the number of experienced maltreatment categories: no maltreatment, low maltreatment, and high maltreatment exposures. Stool samples were collected and analyzed by 16S rRNA sequencing., Results: Children subjected to high maltreatment exposure exhibited lower alpha diversity in comparison to those with both no and low maltreatment exposure (Simpson Index, Tukey post hoc, p = 0.059 and p = 0.007, respectively). No significant distinctions in beta diversity were identified. High maltreatment exposure was associated with the enrichment of several genera from the class Clostridia ( Clostridium, Intestinibacter, Howardella and Butyrivibrio ) and the depletion of the genus Phocaeicola (class Bacteriodia)., Conclusions: Severe maltreatment exposure is associated with alterations in the gut microbiota of young children. Longitudinal trajectories of intestinal microbiota composition in the context of maltreatment may reveal important insights related to psychiatric and somatic health outcomes.

Predicting future kidney allograft function is challenging. Novel biomarkers, such as urinary Dickkopf-3 (uDKK3), may help guide donor selection and improve allograft outcomes. In this prospective multicenter pilot trial, we investigated whether donor uDKK3 reflects organ quality and is associated with future allograft function. We measured uDKK3/crea ratios (uDKK3/crea) from 95 deceased and 46 living kidney donors. Prenephrectomy uDKK3/crea levels were 100× higher in deceased than in living donors (9888 pg/mg vs 113 pg/mg; P < .001). Among deceased donor transplantations, recipients were stratified by their corresponding uDKK3/crea donor levels ranging below (group A, n = 68) or above (group B, n = 65) median. The primary end point of best estimated glomerular filtration rate (eGFR) within the first 3 months after kidney transplantation was superior in group A (56.3 mL/min/1.73 m 2 ) than that in group B (44.2 mL/min/1.73 m 2 ; P = .0139). Second, the composite clinical end point consisting of death, allograft failure or eGFR decline >50% occurred less frequent in group A. By mixed linear regression modeling, donor uDKK3/crea remained an independent predictor of eGFR after transplantation, with a slope of -4.282 mL/min/1.73 m 2 per logarithmic increase in donor uDKK3/crea. In summary, uDKK3 may serve as a noninvasive, donor-dependent biomarker for assessing organ quality and future allograft function., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. J.de Fallois is a member of the European Reference Network for Rare Kidney Diseases (ERKNet). A. Günzel received a doctoral stipend from the RES. C. Daniel receives funding from German Research Foundation (DFG; TR374 project number C2). K. Amann receives funding from German Research Foundation (DFG; TR374 project number C2). J. Halbritter receives funding from the German Research Foundation (DFG; project number HA 6908/4-1, HA 6908/7-1, and HA 6908/8-1) and is a member of the European Reference Network for Rare Kidney Diseases (ERKNet). Other authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Coronary artery disease (CAD) often leads to adverse events resulting in significant disease burdens. Underlying risk factors often remain inapparent prior to disease incidence and the cardiovascular (CV) risk is not exclusively explained by traditional risk factors. Platelets inherently promote atheroprogression and enhanced platelet functions and distinct platelet lipid species are associated with disease severity in patients with CAD. Lipidomics data were acquired using mass spectrometry and processed alongside clinical data applying machine learning to model estimates of an increased CV risk in a consecutive CAD cohort (n = 595). By training machine learning models on CV risk measurements, stratification of CAD patients resulted in a phenotyping of risk groups. We found that distinct platelet lipids are associated with an increased CV or bleeding risk and independently predict adverse events. Notably, the addition of platelet lipids to conventional risk factors resulted in an increased diagnostic accuracy of patients with adverse CV events. Thus, patients with aberrant platelet lipid signatures and platelet functions are at elevated risk to develop adverse CV events. Machine learning combining platelet lipidome data and common clinical parameters demonstrated an increased diagnostic value in patients with CAD and might improve early risk discrimination and classification for CV events., (© 2024. The Author(s).)

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research., (© 2024. The Author(s).)

Background and Aims: Patients with cardiovascular disease (CVD) are at high risk to develop adverse events. The distinct risk of developing adverse cardiovascular (CV) events is not solely explained by traditional risk factors. Platelets are essentially involved in progression of CVD including coronary artery disease (CAD) and platelet hyperreactivity leads to development of adverse CV events. Alterations in the platelet lipidome lead to platelet hyperresponsiveness and thus might alter the individual risk profile. In this study, we investigate the platelet lipidome of CAD patients by untargeted lipidomics and elucidate alterations in the lipid composition of patients with adverse CV events., Methods: We characterized the platelet lipidome in a large consecutive CAD cohort (n = 1057) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry., Results: The platelet lipidome in this study identified 767 lipids and characteristic changes occurred in patients with adverse CV events. The most prominent upregulated lipids in patients with cardiovascular events primarily belong to the class of phospholipids and fatty acyls. Further, upregulated platelet lipids are associated with an increased cardiovascular or bleeding risk and independently associated with adverse events. In addition, alterations of the platelet lipidome are associated with modulation of in vitro platelet functions., Conclusions: Our results reveal that the composition of the platelet lipidome is altered in CVD patients with an increased cardiovascular risk and distinct platelet lipids may indicate adverse events. Results of this study may contribute to improved risk discrimination and classification for cardiovascular events in patients with CVD. Main findings of this study and hypothetical impact of altered platelet lipid signatures in patients with adverse cardiovascular events on platelet function and clinical outcome. LPE lysophosphatidylethanolamines, CAR acylcarnitines, FA fatty acids., (© 2023. The Author(s).)

Background: Maternal early-life maltreatment (ELM) increases the risk of subsequent child maltreatment, but the underlying mechanisms of these intergenerational effects remain largely unknown. Identifying these mechanisms is crucial for developing preventive interventions that can break the cycle of abuse. Notably, previous research has shown that ELM often results in attachment insecurity and altered anger characteristics. Therefore, this study determines whether these characteristics mediate the relationship between maternal history of ELM and child abuse potential., Methods: The study sample included 254 mothers, of whom 149 had experienced ELM to at least a moderate degree. Maternal ELM was assessed using the Childhood Experience of Care and Abuse (CECA) interview. Attachment insecurity, trait anger and anger expression, and maternal abuse potential were assessed using the Vulnerable Attachment Questionnaire (VASQ), State-Trait Anger Expression Inventory (STAXI), and Child Abuse Potential Inventory (CAPI), respectively., Results: The severity of maternal ELM predicted higher child abuse potential, with attachment insecurity and anger suppression mediating this effect. Specifically, higher levels of maternal ELM were associated with greater attachment insecurity and increased anger suppression, resulting in a higher child abuse potential. Although higher levels of trait anger were directly associated with higher child abuse potential, this parameter did not mediate the relationship with ELM. In addition, no significant associations were observed between outwardly expressed anger and ELM or child abuse potential. All analyses were adjusted for maternal mental disorders, years of education, and relationship status., Discussion: Attachment insecurity and anger suppression may serve as pathways linking the maternal history of ELM to the risk of child abuse, even when considering maternal psychopathology. Overall, our findings indicate that interventions aimed at strengthening attachment and improving anger suppression may be beneficial for all mothers with ELM history and high child abuse potential, not just those who suffer from mental illness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wuebken, Bermpohl, Boedeker, Hindi Attar, Schoofs, Kluczniok, Fuchs, Neukel, Herpertz, Brunner, Winter, Kaess, Jaite and Dittrich.)

Backgound: Branchiootorenal (BOR) syndrome is an autosomal dominant disorder caused by pathogenic EYA1 variants and clinically characterized by auricular malformations with hearing loss, branchial arch anomalies, and congenital anomalies of the kidney and urinary tract. BOR phenotypes are highly variable and heterogenous. While random monoallelic expression is assumed to explain this phenotypic heterogeneity, the potential role of modifier genes has not yet been explored., Methods: Through thorough phenotyping and exome sequencing, we studied one family with disease presentation in at least four generations in both clinical and genetic terms. Functional investigation of the single associated EYA1 variant c.1698+1G>A included splice site analysis and assessment of EYA1 distribution in patient-derived fibroblasts. The candidate modifier gene CYP51A1 was evaluated by histopathological analysis of murine Cyp51 +/ - and Cyp51 -/- kidneys. As the gene encodes the enzyme lanosterol 14α-demethylase, we assessed sterol intermediates in patient blood samples as well., Results: The EYA1 variant c.1698+1G>A resulted in functional deletion of the EYA domain by exon skipping. The EYA domain mediates protein-protein interactions between EYA1 and co-regulators of transcription. EYA1 abundance was reduced in the nuclear compartment of patient-derived fibroblasts, suggesting impaired nuclear translocation of these protein complexes. Within the affected family, renal phenotypes spanned from normal kidney function in adulthood to chronic kidney failure in infancy. By analyzing exome sequencing data for variants that potentially play roles as genetic modifiers, we identified a canonical splice site alteration in CYP51A1 as the strongest candidate variant., Conclusion: In this study, we demonstrate pathogenicity of EYA1 c.1698+1G>A, propose a mechanism for dysfunction of mutant EYA1, and conjecture CYP51A1 as a potential genetic modifier of renal involvement in BOR syndrome., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Introduction Procedural sedation is a common procedure conducted in emergency departments (ED) across the world, which requires patients to receive anesthesia/sedation medication in a controlled environment in order to alleviate pain, anxiety, and suffering, thereby allowing multiple procedures to be completed in a safe and timely manner. We deploy this technique for joint reductions, burns dressings, wound repairs, etc. in our ED. As a large tertiary referral hospital ED, we aimed to benchmark our practice for this high-acuity procedure against international standards. The main objective of our audit was to benchmark our current practice of procedural sedation against international standards from the Royal College of Emergency Medicine (RCEM), United Kingdom, and American College of Emergency Physicians (ACEP) guidelines. As a secondary objective, we aimed to design and implement a multi-lingual procedural sedation leaflet for our patients and their carers. Methods A retrospective electronic healthcare records review was conducted from January 2019 to August 2022 following which a convenience sample of 100 patients was selected. Records audited were obtained from the Hospital Quality and Pharmacy departments. We selected patients from the data provided by selecting sedation medication used (ketamine, midazolam, propofol) and frequency documented as 'pre-procedure' (Pre-Proc). We included patients of all age groups who received procedural sedation in the emergency department and excluded inpatient encounters. After reviewing RCEM and ACEP guidance, we studied 14 criteria and standards. A team comprising physicians and hospital interpreters was set up to draft a procedural sedation leaflet. After hospital marketing team approval, these were published in Arabic, English, Urdu, Hindi, Bengali, and Malayalam. Results Compliance percentages of the 14 criteria were calculated. A "traffic light" color scheme was used to inform the reader of areas of good practice and areas for improvement. Percentages of 90-100% (green) were considered compliant, 80-89% (amber) were partially compliant, and 79% or less (red) were non-compliant. Of the 14 criteria, 10 were fully compliant. One criterion was partially compliant and three criteria were non-compliant. Conclusion Overall, we performed well in in this audit with 100% compliance rates in many areas. We identified that we had no written discharge information leaflet for our patients and carers. We drafted a multi-lingual procedural sedation leaflet and stocked this in the department. Through face-to-face education, we re-trained physicians on the importance of documentation when adhering to safe practices around procedural sedation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Khamis AlBedwawi et al.)

Preschool mental disorders are often associated with significant interpersonal problems, related to impaired affect recognition, theory of mind (ToM), and empathy. To date, these skills have not been studied together in preschoolers with externalizing behavior problems (EBPs). The aim of the present study was to investigate whether and to what extent preschool children with EBPs show impairments in affect recognition, ToM, and empathy. Preschoolers with EBPs, defined by current psychiatric treatment and T-scores ≥ 60 on the externalizing problem scale of the Child Behavior Checklist (CBCL/1½-5 or 6-18R) were compared to non-clinical controls (HCs), defined by no past and no current psychiatric treatment and T-scores < 60 on all CBCL broad-band scales. Groups were compared on affect recognition (NEuroPSYchological Assessment-II), affective ToM (Test of Emotion Comprehension), cognitive ToM (Extended Theory-of-Mind Scale), parent-reported emotional contagion, attention to others' feelings, and prosocial action (Empathy Questionnaire), IQ and language (Wechsler Preschool and Primary Scale of Intelligence-III Matrices, Active and Passive Vocabulary test), controlling for age, sex, and language abilities. Compared to 28 HCs, 22 preschoolers with EBPs (total sample mean age = 5.5 years +/- 0.8 years, range= 4.2-6.9 years, males 66%) had significantly greater impairments in cognitive ToM ( p = 0.0012, η 2 = 0.266), attention to others' feelings ( p = 0.0049, η 2 = 0.222), and prosocial action ( p = 0.0070, η 2 = 0.210), each representing strong effect sizes. EBPs were significantly related to cognitive domains, like prosocial action ( r = -0.501), cognitive ToM ( r = -0.425), and attention to others' feelings ( r = -0.332), but not to affective domains of social cognition. Social cognitive development may be impaired as early as preschool age and should be promoted before the child starts school.

Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. A challenge that remains is selection of treatment to improve outcomes. The dogs in this study were part of a larger clinical trial evaluating the use of combinations of doxorubicin chemotherapy, anti-CD20 monoclonal antibody, and one of three small molecule inhibitors: KPT-9274, TAK-981, or RV1001. We hypothesized that significant differential expression of genes (DEGs) in the tumors at baseline could help predict which dogs would respond better to each treatment based on the molecular pathways targeted by each drug. To this end, we evaluated gene expression in lymph node aspirates from 18 trial dogs using the NanoString nCounter Canine Immuno-oncology (IO) Panel. We defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. We analyzed all dogs at baseline and compared poor responders to good responders, and found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. There was minimal DEG overlap between treatment arms, prompting separate analyses for each treatment cohort. Increased CREBBP and CDKN1A for KPT-9274, increased TLR3 for TAK-981, and increased PI3Kδ, AKT3, and PTEN, and decreased NRAS for RV1001 were associated with better prognoses. Trends for selected candidate biomarker genes were confirmed via qPCR. Our findings emphasize the heterogeneity in DLBCL, similarities and differences between canine and human DLBCL, and ultimately identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs., Competing Interests: JMR is an inventor on a use patent filed for “Diagnosis of skin conditions in veterinary and human patients” for CTCL; and on use patents for targeting CXCR3 (0#15/851,651) and IL15 (# 62489191) for the treatment of vitiligo. CAL received Grant/Research Support and Consulting Engagements from Fidocure. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Dittrich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background:  Platelets are key players in the pathophysiology of coronary artery disease (CAD) and platelet hyperreactivity leads to increased risk of developing adverse cardiovascular events. Further, significant changes in the platelet lipidome occur in patients with acute coronary syndrome (ACS) and critically regulated lipids lead to platelet hyperresponsiveness. Statin treatment is crucial in the treatment and prevention of patients with CAD by remodeling lipid metabolism., Objective:  In this study, we investigate the platelet lipidome of CAD patients by untargeted lipidomics, highlighting significant changes between statin-treated and naïve patients., Methods:  We characterized the platelet lipidome in a CAD cohort ( n  = 105) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry., Results:  Among the annotated lipids, 41 lipids were significantly upregulated in statin-treated patients, whereas 6 lipids were downregulated compared to naïve patients. The most prominent upregulated lipids in statin-treated patients belong to the class of triglycerides, cholesteryl esters, palmitic acid, and oxidized phospholipids, whereas mainly glycerophospholipids were downregulated compared to untreated patients. A more pronounced effect of statin treatment on the platelet lipidome was observed in ACS patients. We further highlight a dose-dependent influence on the platelet lipidome., Conclusion:  Our results reveal that the platelet lipidome is altered in CAD patients with statin treatment and upregulated lipids embody mainly characteristic triglycerides, whereas downregulated lipids mostly compromise glycerophospholipids, which may play a role in the pathophysiology of CAD. Results of this study may contribute to the understanding of statin treatment softening the lipid phenotype., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Antibody mediated rejection (ABMR) is the most common cause of long-term allograft loss in kidney transplantation (KT). Therefore, a low human leukocyte antigen (HLA) mismatch (MM) load is favorable for KT outcomes. Hitherto, serological or low-resolution molecular HLA typing have been adapted in parallel. Here, we aimed to identify previously missed HLA mismatches and corresponding antibodies by high resolution HLA genotyping in a living-donor KT cohort., Methods: 103 donor/recipient pairs transplanted at the University of Leipzig Medical Center between 1998 and 2018 were re-typed using next generation sequencing (NGS) of the HLA loci -A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1, and -DPB1. Based on these data, we compiled HLA MM counts for each pair and comparatively evaluated genomic HLA-typing with pre-transplant obtained serological/low-resolution HLA (=one-field) typing results. NGS HLA typing (=two-field) data was further used for reclassification of de novo HLA antibodies as "donor-specific"., Results: By two-field HLA re-typing, we were able to identify additional MM in 64.1% (n=66) of cases for HLA loci -A, -B, -C, -DRB1 and -DQB1 that were not observed by one-field HLA typing. In patients with biopsy proven ABMR, two-field calculated MM count was significantly higher than by one-field HLA typing. For additional typed HLA loci -DRB345, -DQA1, -DPA1, and -DPB1 we observed 2, 26, 3, and 23 MM, respectively. In total, 37.3% (69/185) of de novo donor specific antibodies (DSA) formation was directed against these loci (DRB345 ➔ n=33, DQA1 ➔ n=33, DPA1 ➔ n=1, DPB1 ➔ n=10)., Conclusion: Our results indicate that two-field HLA typing is feasible and provides significantly more sensitive HLA MM recognition in living-donor KT. Furthermore, accurate HLA typing plays an important role in graft management as it can improve discrimination between donor and non-donor HLA directed cellular and humoral alloreactivity in the long range. The inclusion of additional HLA loci against which antibodies can be readily detected, HLA-DRB345, -DQA1, -DQB1, -DPA1, and -DPB1, will allow a more precise virtual crossmatch and better prediction of potential DSA. Furthermore, in living KT, two-field HLA typing could contribute to the selection of the immunologically most suitable donors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lehmann, Pehnke, Weimann, Bachmann, Dittrich, Petzold, Fürst, de Fallois, Landgraf, Henschler, Lindner, Halbritter, Doxiadis, Popp and Münch.)

Background: Mothers with borderline personality disorder (BPD) often show altered emotional availability toward their own child and heightened stress vulnerability. The aims of the present study were (1) to examine total cortisol output in saliva during mother-child interaction in mothers with BPD and their children and (2) to test whether maternal nonhostility as a subscale of emotional availability mediates the relationship between maternal BPD and child total cortisol output., Methods: We investigated 16 mothers with BPD and 30 healthy control mothers (HC) and 29 children of mothers with BPD and 33 children of HC mothers. Children were between 5 and 12 years old. Salivary cortisol was collected prior to and twice after an episode of a 21-min standardized play situation between mother and child. Nonhostility was rated using the emotional availability scales. Analyses of covariance were computed to test for group differences in total cortisol output (measured with area under the curve with respect to ground). Pearson's correlation was calculated to test the association between maternal and child total cortisol output. To test the second question, a mediation analysis according to Preacher and Hayes was conducted., Results: Mothers with BPD and their children had lower total cortisol output. Maternal and child total cortisol output was significantly correlated. Contrary to our hypothesis, maternal nonhostility did not mediate the relationship between BPD and child total cortisol output., Conclusion: Results imply that the hormonal stress activity of mothers with BPD and their children is altered, which may reflect modified stress regulation and stress vulnerability in mother and child and may impact on mother-child interaction. The finding of a positive association between mother's and child total cortisol output could indicate an intergenerational transmission of these alterations., (© 2022 S. Karger AG, Basel.)

Objective: The immediate impact of child maltreatment on health and developmental trajectories over time is unknown. Longitudinal studies starting in the direct aftermath of exposure with repeated follow-up are needed., Method: We assessed health and developmental outcomes in 6-month intervals over 2 years in 173 children, aged 3-5 years at study entry, including 86 children with exposure to emotional and physical abuse or neglect within 6 months and 87 nonmaltreated children. Assessments included clinician-administered, self- and parent-report measures of psychiatric and behavioral symptoms, development, and physical health. Linear mixed models and latent growth curve analyses were used to contrast trajectories between groups and to investigate the impact of maltreatment features on trajectories., Results: Maltreated children exhibited greater numbers of psychiatric diagnoses (b = 1.998, p < .001), externalizing (b = 13.29, p < .001) and internalizing (b = 11.70, p < .001) symptoms, impairments in cognitive (b = -11.586, p < .001), verbal (b = -10.687, p < .001), and motor development (b = -7.904, p = .006), and greater numbers of medical symptoms (b = 1.021, p < .001) compared to nonmaltreated children across all time-points. Lifetime maltreatment severity and/or age at earliest maltreatment exposure predicted adverse outcomes over time., Conclusion: The profound, immediate, and stable impact of maltreatment on health and developmental trajectories supports a biological embedding model and provides foundation to scrutinize the precise underlying mechanisms. Such knowledge will enable the development of early risk markers and mechanism-driven interventions that mitigate adverse trajectories in maltreated children., (© 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Prostaglandin D 2 receptor 2 (DP 2 ) antagonists inhibit prostaglandin D 2 -induced effects, including recruitment and activation of cells driving asthma pathogenesis. However, challenges identifying target population and end points persist., Research Question: What is the effect of the DP 2 antagonist GB001 on asthma worsening in patients with moderate to severe eosinophilic asthma?, Study Design and Methods: In this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/μL. Patients aged ≥ 18 years to < 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment., Results: A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg., Interpretation: Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03683576; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Platelets play a key role in the pathophysiology of coronary artery disease (CAD) and patients with enhanced platelet activation are at increased risk to develop adverse cardiovascular events. Beyond reliable cardiovascular risk factors such as dyslipoproteinaemia, significant changes of platelet lipids occur in patients with CAD. In this study, we investigate the platelet lipidome by untargeted liquid chromatography-mass spectrometry, highlighting significant changes between acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. Additionally, we classify the platelet lipidome, spotlighting specific glycerophospholipids as key players in ACS patients. Furthermore, we examine the impact of significantly altered lipids in ACS on platelet-dependent thrombus formation and aggregation., Methods and Results: In this consecutive study, we characterized the platelet lipidome in a CAD cohort (n = 139) and showed significant changes of lipids between patients with ACS and CCS. We found that among 928 lipids, 7 platelet glycerophospholipids were significantly up-regulated in ACS, whereas 25 lipids were down-regulated compared to CCS. The most prominent up-regulated lipid in ACS, PC18:0 (PC 10:0-8:0), promoted platelet activation and ex vivo platelet-dependent thrombus formation., Conclusions: Our results reveal that the platelet lipidome is altered in ACS and up-regulated lipids embody primarily glycerophospholipids. Alterations of the platelet lipidome, especially of medium chain lipids, may play a role in the pathophysiology of ACS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n DM  = 178,691, n noDM  = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM., (© 2022. The Author(s).)

Epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities. Cutaneous-skeletal hypophosphatemia syndrome (CSHS) constitutes a specific sub-entity in which elevated levels of fibroblast growth factor-23 cause hypophosphatemic rickets that are, to date, not amenable to causal therapy. Here, we report the first long-term follow-up of causal treatment with burosumab in a 3-year-old female patient with CSHS. 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels. Furthermore, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency. Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment. In summary, we, here, report about a successful treatment of hypophosphatemic rickets in CSHS with burosumab over the time course of 42 months. In our patient, burosumab showed convincing efficacy and safety profile, without any loss of effect or increase of dose., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Merz, Buerger, Ziegelasch, Zenker, Wieland, Lipek, Wallborn, Terliesner, Prenzel, Siekmeyer and Dittrich.)

Platelet ACKR3/CXCR7 surface expression is enhanced and influences prognosis in coronary artery disease (CAD) patients, who exhibit a distinct atherothrombotic platelet lipidome. Current investigation validates the potential of ACKR3/CXCR7 in regulating thromboinflammatory response through its impact on the platelet lipidome. CAD patients with enhanced platelet ACKR3/CXCR7 expression exhibited reduced aggregation. Pharmacological CXCR7 agonist (VUF11207) significantly reduced prothrombotic platelet response in blood from acute coronary syndrome patients ex vivo. CXCR7 agonist administration reduced thrombotic functions and thromboinflammatory plateletleukocyte interactions post-myocardial infarction and arterial injury in vivo. ACKR3/CXCR7 ligation did not affect surface availability of surface receptors, coagulation profile, bleeding time, plasma-dependent thrombin generation (thrombinoscopy), or clot formation (thromboelastography) but counteracted activation-induced phosphatidylserine exposure and procoagulant platelet-assisted thrombin generation. Targeted (micro-UHPLC-ESI-QTrap-MS/MS) and untargeted (UHPLCESI-QTOF-MS/MS) lipidomics analysis revealed that ACKR3/CXCR7 ligation favored generation of antithrombotic lipids (dihomo-γ-linolenic acid [DGLA], 12-hydroxyeicosatrienoic acid [12-HETrE]) over cyclooxygenase-1 (COX-1) or 12-lipoxygenase (12-LOX) metabolized prothrombotic and phospholipase-derived atherogenic lipids in healthy subjects and CAD patients, contrary to antiplatelet therapy. Through 12-HETrE, ACKR3/CXCR7 ligation coordinated with Gαs-coupled prostacyclin receptor to trigger cyclic adenosine monophosphate/protein kinase A-mediated platelet inhibition. ACKR3/CXCR7 ligation reduced generation of lipid agonists and lipid signaling intermediates, which affected calcium mobilization, intracellular signaling, and consequently platelet interaction with physiological matrices and thromboinflammatory secretome. This emphasized its functional dichotomy from prothrombotic CXCR4. Moreover, CXCR7 agonist regulated heparin-induced thrombocytopenia-sera/immunoglobulin G-triggered platelet and neutrophil activation, heparin-induced platelet aggregation, generation of thromboinflammatory lipids, platelet-neutrophil aggregate formation, and thromboinflammatory secretion ex vivo. Therefore, ACKR3/CXCR7 may offer a novel therapeutic strategy in acute/chronic thromboinflammation exaggerated cardiovascular pathologies and CAD., (© 2022 by The American Society of Hematology.)

Introduction: The cystatin C (CysC) serum level is a marker of glomerular filtration rate and depends on age, gender, and pubertal stage. We hypothesize that CysC might overall reflect energy homeostasis and be regulated by components of the endocrine system and metabolites in pubertal adolescents., Methods: Serum CysC levels and further possible effector parameters in 5355 fasting, morning venous blood samples from 2035 healthy participants of the LIFE Child cohort study (age 8 to 18 years) were analyzed. Recruitment started in 2011, with probands followed up once a year. Linear univariate and stepwise multivariate regression analyses were performed., Results: Annual growth rate, serum levels of thyroid hormones, parathyroid hormone, insulin-like growth factor 1, hemoglobin A1c (HbA1c), uric acid, and alkaline phosphatase show relevant and significant associations with CysC serum concentrations (p <0.001). Furthermore, male probands' CysC correlated with the body mass index and testosterone among other sexual hormones. Multivariate analyses revealed that uric acid and HbA1c are associated variables of CysC independent from gender (p <0.001). In males, alkaline phosphatase (p <0.001) is additionally significantly associated with CysC. Thyroid hormones show significant correlations only in multivariate analyses in females (p <0.001)., Conclusions: The described associations strongly suggest an impact of children's metabolism on CysC serum levels. These alterations need to be considered in kidney diagnostics using CysC in adolescents. Additionally, further studies are needed on CysC in children., (© 2021. The Author(s).)