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Philipp Moog, Klaus Thuermel Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Abstract: A 54-year-old patient presented to his general practitioner because of strong muscle pain in both thighs. Inflammatory parameters (CRP 16.3 mg/dL) and white blood cells (15 g/L) were elevated. The patient reported a weight loss of 10 kg in 4 weeks. There was no fever or any other specific symptoms. Urine dipstick examination and computed tomography of the chest were unremarkable. Because of increasing symptoms, the patient was referred to our department. Magnetic resonance tomography showed diffuse inflammatory changes of the muscles of both thighs. Neurological examination and electrophysiology revealed axonal sensorimotor neuropathy and ground-glass opacities of both lungs had occurred. Serum creatinine increased to 229 µmol/L within a few days, with proteinuria of 3.3 g/g creatinine. Kidney biopsy showed diffuse pauci-immune proliferative glomerulonephritis. Proteinase 3-specific antineutrophil cytoplasmic antibodies were markedly increased. Birmingham Vasculitis Activity Score was 35. Within 2 days, serum creatinine further increased to 495 µmol/L. Plasma exchange, high-dose glucocorticosteroids, and hemodialysis were started. The patient received cyclophosphamide 1 g twice and rituximab 375 mg/m2 four times according to the RITUXVAS protocol. Despite ongoing therapy, hemodialysis could not be withdrawn and had to be continued over 3 weeks until diuresis normalized. Glucocorticosteroids were tapered to 20 mg after 2 months, and serum creatinine was 133 µmol/L. However, nephritic urinary sediment reappeared. Another dose of 1 g cyclophosphamide was given, and glucocorticosteroids were raised for another 4 weeks. After 6 months, the daily prednisolone dose was able to be tapered to 5 mg. Serum creatinine was 124 µmol/L, proteinuria further decreased to 382 mg/g creatinine, and the Birmingham Vasculitis Activity Score was 0. Maintenance therapy with rituximab 375 mg/m2 every 6 months was started. At the last visit after 8 months, the patient was still in remission, with only minor persistent dysesthesia of the left foot and a persistent serum creatinine of 133 µmol/L. Keywords: ANCA, GPA, granulomatosis with polyangiitis, MPA, microscopic polyangiitis, management

BackgroundChildhood maltreatment is associated with adverse health outcomes and this risk can be transmitted to the next generation. We aimed to investigate the association between exposure to maternal childhood maltreatment and common childhood physical and mental health problems, neurodevelopmental disorders, and related comorbidity patterns in offspring.MethodsWe conducted a retrospective cohort study using data from the Environmental influences on Child Health Outcomes (ECHO) Program, which was launched to investigate the influence of early life exposures on child health and development in 69 cohorts across the USA. Eligible mother-child dyads were those with available data on maternal childhood maltreatment exposure and at least one child health outcome measure (autism spectrum disorder, attention-deficit hyperactivity disorder [ADHD], internalising problems, obesity, allergy, and asthma diagnoses). Maternal history of childhood maltreatment was obtained retrospectively from the Adverse Childhood Experiences or Life Stressor Checklist questionnaires. We derived the prevalence of the specified child health outcome measures in offspring across childhood and adolescence by harmonising caregiver reports and other relevant sources (such as medical records) across cohorts. Child internalising symptoms were assessed using the Child Behavior Checklist. Associations between maternal childhood maltreatment and childhood health outcomes were measured using a series of mixed-effects logistic regression models. Covariates included child sex (male or female), race, and ethnicity; maternal and paternal age; maternal education; combined annual household income; maternal diagnosis of depression, asthma, ADHD, allergy, or autism spectrum disorder; and maternal obesity. Two latent class analyses were conducted: to characterise patterns of comorbidity of child health outcomes; and to characterise patterns of co-occurrence of childhood maltreatment subtypes. We then investigated the association between latent class membership and maternal childhood maltreatment and child health outcomes, respectively.FindingsOur sample included 4337 mother-child dyads from 21 longitudinal cohorts (with data collection initiated between 1999 and 2016). Of 3954 mothers in the study, 1742 (44%) had experienced exposure to abuse or neglect during their childhood. After adjustment for confounding, mothers who experienced childhood maltreatment were more likely to have children with internalising problems in the clinical range (odds ratio [OR] 2·70 [95% CI 1·95-3·72], p

BackgroundPrenatal loss which occurs in approximately 20% of pregnancies represents a well-established risk factor for anxiety and affective disorders. In the current study, we examined whether a history of prenatal loss is associated with a subsequent pregnancy with maternal psychological state using ecological momentary assessment (EMA)-based measures of pregnancy-specific distress and mood in everyday life.MethodThis study was conducted in a cohort of N = 155 healthy pregnant women, of which N = 40 had a history of prenatal loss. An EMA protocol was used in early and late pregnancy to collect repeated measures of maternal stress and mood, on average eight times per day over a consecutive 4-day period. The association between a history of prenatal loss and psychological state was estimated using linear mixed models.ResultsCompared to women who had not experienced a prior prenatal loss, women with a history of prenatal loss reported higher levels of pregnancy-specific distress in early as well as late pregnancy and also were more nervous and tired. Furthermore, in the comparison group pregnancy-specific distress decreased and mood improved from early to late pregnancy, whereas these changes across pregnancy were not evident in women in the prenatal loss group.ConclusionOur findings suggest that prenatal loss in a prior pregnancy is associated with a subsequent pregnancy with significantly higher stress and impaired mood levels in everyday life across gestation. These findings have important implications for designing EMA-based ambulatory, personalized interventions to reduce stress during pregnancy in this high-risk group.

CRISPR-Cas9-generated zebrafish carrying a 12 base-pair deletion in stxbpb1b, a paralog sharing 79% amino acid sequence identity with human, exhibit spontaneous electrographic seizures during larval stages of development. Zebrafish stxbp1b mutants provide an efficient preclinical platform to test antiseizure therapeutics. The present study was designed to test antiseizure medications approved for clinical use and two recently identified repurposed drugs with antiseizure activity. Larval homozygous stxbp1b zebrafish (4 days postfertilization (dpf)) were agarose-embedded and monitored for electrographic seizure activity using a local field recording electrode placed in midbrain. Frequency of ictal-like events was evaluated at baseline and following 45 min of continuous drug exposure (1 mM, bath application). Analysis was performed on coded files by an experimenter blinded to drug treatment and genotype. Phenytoin (PHT), valproate (VPA), ethosuximide (ESX), levetiracetam (LEV), and diazepam (DZP) had no effect on the ictal-like event frequency in stxbp1b mutant zebrafish. Clemizole and trazodone decreased ictal-like event frequency in stxbp1b mutant zebrafish by 80% and 83%, respectively. These results suggest that repurposed drugs with serotonin receptor-binding affinities could be effective antiseizure treatments. Clemizole and trazodone were previously identified in a larval zebrafish model for Dravet syndrome. Based primarily on these preclinical zebrafish studies, compassionate-use and double-blind clinical trials with both drugs have progressed. The present study extends this approach to a preclinical zebrafish model representing STXBP1 (syntaxin-binding protein 1)-related disorders and suggests that future clinical studies may be warranted.

Because it has experienced a process of secularisation for more than three centuries, France can be considered as a laboratory of the relevance of faith in a society for which it is no longer the cultural matrix. By showing how the central question of secularisation is in fact that of the relationship between faith and culture, this article proposes to consider Catholic schools as places where a new way for the Catholic Church to support humanity in its growth, at a personal and community level, is being elaborated.

Understanding of the effects of in utero opioid exposure on neurodevelopment is a priority given the recent dramatic increase in opioid use among pregnant individuals. However, opioid abuse does not occur in isolation-pregnant individuals abusing opioids often have a significant history of adverse experiences in childhood, among other co-occurring factors. Understanding the specific pathways in which these frequently co-occurring factors may interact and cumulatively influence offspring brain development in utero represents a priority for future research in this area. We highlight maternal history of childhood adversity (CA) as one such co-occurring factor that is more prevalent among individuals using opioids during pregnancy and which is increasingly shown to affect offspring neurodevelopment through mechanisms beginning in utero. Despite the high incidence of CA history in pregnant individuals using opioids, we understand very little about the effects of comorbid prenatal opioid exposure and maternal CA history on fetal brain development. Here, we first provide an overview of current knowledge regarding effects of opioid exposure and maternal CA on offspring neurodevelopment that may occur during gestation. We then outline potential mechanistic pathways through which these factors might have interactive and cumulative influences on offspring neurodevelopment as a foundation for future research in this area.

Maternal psychosocial stress during pregnancy can impact the developing fetal brain and influence offspring mental health. In this context, animal studies have identified the hippocampus and amygdala as key brain regions of interest, however, evidence in humans is sparse. We, therefore, examined the associations between maternal prenatal psychosocial stress, newborn hippocampal and amygdala volumes, and child social-emotional development. In a sample of 86 mother-child dyads, maternal perceived stress was assessed serially in early, mid and late pregnancy. Following birth, newborn (aged 5-64 postnatal days, mean: 25.8 ± 12.9) hippocampal and amygdala volume was assessed using structural magnetic resonance imaging. Infant social-emotional developmental milestones were assessed at 6- and 12-months age using the Bayley-III. After adjusting for covariates, maternal perceived stress during pregnancy was inversely associated with newborn left hippocampal volume (β = -0.26, p = .019), but not with right hippocampal (β = -0.170, p = .121) or bilateral amygdala volumes (ps > .5). Furthermore, newborn left hippocampal volume was positively associated with infant social-emotional development across the first year of postnatal life (B = 0.01, p = .011). Maternal perceived stress was indirectly associated with infant social-emotional development via newborn left hippocampal volume (B = -0.34, 95% CIBC [-0.97, -0.01]), suggesting mediation. This study provides prospective evidence in humans linking maternal psychosocial stress in pregnancy with newborn hippocampal volume and subsequent infant social-emotional development across the first year of life. These findings highlight the importance of maternal psychosocial state during pregnancy as a target amenable to interventions to prevent or attenuate its potentially unfavorable neural and behavioral consequences in the offspring.

The aims of this study were to examine vocabulary scores of 5-year-old children who are deaf or hard of hearing (DHH), as well as the impact of early enrollment in specialized intervention on vocabulary outcomes. Receptive and expressive vocabulary scores were analyzed for 342 five-year-old children who are DHH enrolled in specialized listening and spoken language intervention programs. Regression analyses were utilized to examine the effects of age at enrollment on vocabulary outcomes. Overall, participants achieved scores within normal test limits on receptive and expressive measures of vocabulary. Children who enrolled in intervention prior to 28 months of age had better vocabulary skills at 5 years old. The findings support that children who are DHH can understand and produce vocabulary at skill levels commensurate with their typically hearing peers, regardless of severity of hearing loss. Results highlight the crucial impact of specialized programs on children's lexical readiness to participate in general education settings by kindergarten.

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

Purpose: The aims of this study were to explore expressive vocabulary growth rates of children who are deaf or hard of hearing (DHH) during critical periods of brain development (birth to 3 years) as well as the factors that influence the trajectories of vocabulary growth in these early years of development. Of primary interest was the effect of intervention frequency on expressive vocabulary growth. Method: Hierarchical linear modeling was used to investigate trajectories of expressive vocabulary growth using multiple measures of longitudinal vocabulary scores. A total of 417 assessments across 105 participants were analyzed to determine the average rate of lexical growth in a young population of children who are DHH receiving early intervention before age 3 years. Expected growth trajectories were constructed based on varying frequencies of intervention during critical periods of brain development. Results: Results indicated average growth rates of 5.21 new words expressed per week. Increased intervention hours prior to age 3 years was significantly associated with higher degrees of expressive vocabulary growth. Conclusion: The findings of this study suggest that greater intervention hours received before age 3 years are associated with higher degrees of expressive vocabulary growth for children who are DHH.