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Abstract Preterm infants with oxygen supplementation are at high risk for bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Inflammation with macrophage activation is central to the pathogenesis of BPD. CXCL10, a chemotactic and pro-inflammatory chemokine, is elevated in the lungs of infants evolving BPD and in hyperoxia-based BPD in mice. Here, we tested if CXCL10 deficiency preserves lung growth after neonatal hyperoxia by preventing macrophage activation. To this end, we exposed Cxcl10 knockout (Cxcl10 −/−) and wild-type mice to an experimental model of hyperoxia (85% O2)-induced neonatal lung injury and subsequent regeneration. In addition, cultured primary human macrophages and murine macrophages (J744A.1) were treated with CXCL10 and/or CXCR3 antagonist. Our transcriptomic analysis identified CXCL10 as a central hub in the inflammatory network of neonatal mouse lungs after hyperoxia. Quantitative histomorphometric analysis revealed that Cxcl10 −/− mice are in part protected from reduced alveolar. These findings were related to the preserved spatial distribution of elastic fibers, reduced collagen deposition, and protection from macrophage recruitment/infiltration to the lungs in Cxcl10 −/− mice during acute injury and regeneration. Complimentary, studies with cultured human and murine macrophages showed that hyperoxia induces Cxcl10 expression that in turn triggers M1-like activation and migration of macrophages through CXCR3. Finally, we demonstrated a temporal increase of macrophage-related CXCL10 in the lungs of infants with BPD. In conclusion, our data demonstrate macrophage-derived CXCL10 in experimental and clinical BPD that drives macrophage chemotaxis through CXCR3, causing pro-fibrotic lung remodeling and arrest of alveolarization. Thus, targeting the CXCL10-CXCR3 axis could offer a new therapeutic avenue for BPD.

IntroductionThe SARS-CoV-2 pandemic has significantly impacted children and adolescents, leading to mental health challenges. Knowledge on their resources and difficulties is crucial and there is a need for valid instruments to assess their psychosocial condition especially in this exceptional situation. We assessed psychopathological symptoms using the SDQ during the pandemic, comparing to pre-pandemic data. Our study aims to understand adolescents’ strengths and difficulties amidst COVID-19, evaluating the SDQ’s utility in crisis settings.MethodsWithin the German school-based surveillance study (“B-Fast”), we assessed behavioral strengths and difficulties in 664 adolescents aged 11–17 years during the peak of the German COVID-19 pandemic using the validated Strengths and Difficulties Questionnaire (SDQ) for both external and self-assessed data collection. Data were collected between November 2020 and April 2021. We compared self-assessed SDQ-scores to pre-pandemic data from a comparable sample and examined adolescent classification as “normal” or “borderline/abnormal” based on both external and self-assessed SDQ subscale scores using established cut-off values. Additionally, we conducted sex and rater-based score comparisons.ResultsIn our study, we observed a significant worsening of “Emotional Symptoms” compared to pre-pandemic levels, while “Conduct Problems” and “Prosocial Behavior” showed improvement. Variations in classification to “normal” and “abnormal” emerged when applying German versus British cut-off values. Females scored higher on “Emotional Symptoms” while males scored higher on “Hyperactivity Symptoms.” Correlations between external and self-assessed SDQ ratings ranged from 0.43 (p

Abstract The multitude of obesogenic diets used in rodent studies can hardly be overviewed. Since standardization is missing and assuming that individual compositions provoke individual effects, the choice of quality, quantity and combination of diet ingredients seems to be crucial for the outcome and interpretation of obesity studies. Therefore, the present study was conducted to compare the individual effects of three commonly used obesogenic diets, mainly differing in sugar and fat content. Besides basic phenotypic and metabolic characterization, one main aspect was a comparative liver proteome analysis. As expected, the obtained results picture differentiated consequences mainly depending on fat source and/or fat- and sugar quantity. By confirming the general presumption that the choice of nutritional composition is a pivotal factor, the present findings demonstrate that a conscious selection is indispensable for obtaining reliable and sound results in obesity research. In conclusion, we strongly recommend a careful selection of the appropriate diet in advance of a new experiment, taking into account the specific research question.

Intrauterine growth restriction (IUGR) and being small for gestational age (SGA) are two distinct conditions with different implications for short- and long-term child development. SGA is present if the estimated fetal or birth weight is below the tenth percentile. IUGR can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnion, lack of growth in the interval, estimated weight below the third percentile) and can also be present in fetuses and neonates with weights above the tenth percentile. There is a need to differentiate between IUGR and SGA whenever possible, as IUGR in particular is associated with greater perinatal morbidity, prematurity and mortality, as well as an increased risk for diseases in later life. Recognizing fetuses and newborns being “at risk” in order to monitor them accordingly and deliver them in good time, as well as to provide adequate follow up care to ameliorate adverse sequelae is still challenging. This review article discusses approaches to differentiate IUGR from SGA and further increase diagnostic accuracy. Since adverse prenatal influences increase but individually optimized further child development decreases the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood. Moreover, we present current concepts of pathophysiology, with a focus on oxidative stress and consecutive inflammatory and metabolic changes as key molecular mechanisms of adverse sequelae, and look at future scientific opportunities and challenges. Most importantly, awareness needs to be raised that pre- and postnatal care of IUGR neonates should be regarded as a continuum.

This study shows that maternal and perinatal obesity cause bronchial and vascular smooth muscle cell proliferation through an IL-6-FoxO1 axis, and favor thereby the emergence of bronchial obstruction and pulmonary hypertension later in life.

Dewald et al. combine a non-invasive sampling approach (Lolli-Test) with an RT qPCR-pool testing strategy to screen for SARS-CoV-2 infections in children and use the method for surveillance and infection control in > 4000 school and daycare settings.

Objective: Asprosin is a recently discovered hormone associated with obesity and diabetes mellitus. Little is known about asprosin’s role during pregnancy, but a contribution of asprosin to pregnancy complications resulting from maternal obesity and gestational diabetes mellitus (GDM) is conceivable. We assessed the potential effects of obesity, GDM and other clinical parameters on maternal and fetal umbilical plasma asprosin concentrations and placental asprosin expression. Design: The Cologne-Placenta Cohort Study comprises 247 female patients, from whom blood and placentas were collected at the University Hospital Cologne. Methods: We studied the maternal and fetal umbilical plasma and placentas of pregnant women with an elective, primary section. Sandwich ELISA measurements of maternal and fetal umbilical plasma and immunohistochemical stainings of placental tissue were performed to determine the asprosin levels. Also, the relation between asprosin levels and clinical blood parameters was studied. Results: There was a strong correlation between the maternal and fetal plasma asprosin levels and both increased with GDM in normal-weight and obese women. Asprosin immunoreactivity was measured in cultivated placental cells and placental tissue. BMI and GDM were not but pre-pregnancy exercise and smoking were correlated with maternal and/or fetal asprosin levels. Placental asprosin levels were associated with maternal but not with fetal plasma asprosin levels and with BMI but not with GDM. Placental asprosin was related to maternal insulin levels and increased upon insulin treatment in GDM patients. Conclusions: Asprosin could potentially act as a biomarker and contribute to the clinical manifestation of pregnancy complications associated with maternal obesity.

Abstract The C-terminal pro-fibrillin-1 propeptide asprosin is described as white adipose tissue derived hormone that stimulates rapid hepatic glucose release and activates hunger-promoting hypothalamic neurons. Numerous studies proposed correlations of asprosin levels with clinical parameters. However, the enormous variability of reported serum and plasma asprosin levels illustrates the need for sensitive and reliable detection methods in clinical samples. Here we report on newly developed biochemical methods for asprosin concentration and detection in several body fluids including serum, plasma, saliva, breast milk, and urine. Since we found that glycosylation impacts human asprosin detection we analyzed its glycosylation profile. Employing a new sandwich ELISA revealed that serum and saliva asprosin correlate strongly, depend on biological sex, and feeding status. To investigate the contribution of connective tissue-derived asprosin to serum levels we screened two cohorts with described cartilage turnover. Serum asprosin correlated with COMP, a marker for cartilage degradation upon running exercise and after total hip replacement surgery. This together with our finding that asprosin is produced by primary human chondrocytes and expressed in human cartilage suggests a contribution of cartilage to serum asprosin. Furthermore, we determined asprosin levels in breast milk, and urine, for the first time, and propose saliva asprosin as an accessible clinical marker for future studies.

Introduction: Obesity in women is often associated with hyperandrogenism, but the role of adipose tissue (AT) in androgen synthesis remains unclear. Therefore, we studied whether AT could be a source of androgens promoting hyperandrogenism. Methods: Subcutaneous and visceral (visc) AT was collected from lean and obese women. Androgen levels were evaluated in serum, AT, and cell-culture supernatant. Gene and protein expression of steroidogenic enzymes were determined. Results: Obese subjects had elevated serum androgen levels, which reduced after weight loss. Androgens were measurable in AT and in cell-culture supernatants of adipocytes. Steroids were higher in AT from obese women, with the highest difference for testosterone in visc AT (+7.9-fold, p = 0.032). Steroidogenic enzymes were expressed in human AT with depot-specific differences. Obese women showed a significantly higher expression of genes of the backdoor pathway and of CYP19 in visc AT. Conclusion: The whole steroidogenic machinery of the classical and backdoor pathways of steroidogenesis, and the capacity for androgen biosynthesis, were found in both AT depots and cultured adipocytes. Therefore, we hypothesize that AT is a de novo site of androgen production and the backdoor pathway of steroidogenesis might be a new pathomechanism for hyperandrogenism in women with obesity.

Background School-level infection control measures in Germany during the early Coronavirus Disease 2019 (COVID-19) pandemic differed across the 16 federal states and lacked a dependable evidence base, with available evidence limited to regional data restricted to short phases of the pandemic. This study aimed to assess the (a) infection risks in students and staff; (b) transmission risks and routes in schools; (c) effects of school-level infection control measures on school and population infection dynamics; and (d) contribution of contacts in schools to population cases. Methods and findings For this retrospective observational study, we used German federal state (NUTS-2) and county (NUTS-3) data from public health and education agencies from March 2020 to April 2022. We assessed (a) infection risk as cumulative risk and crude risk ratios and (b) secondary attack rates (SARs) with 95% confidence interval (CI). We used (c) multiple regression analysis for the effects of infection control measures such as reduced attendance, mask mandates, and vaccination coverage as absolute reduction in case incidence per 100,000 inhabitants per 14 days and in percentage relative to the population, and (d) infection dynamic modelling to determine the percentage contribution of school contacts to population cases. We included (a) nationwide NUTS-2 data from calendar weeks (W) 46-50/2020 and W08/2021-W15/2022 with 3,521,964 cases in students and 329,283 in teachers; (b) NUTS-3 data from W09-25/2021 with 85,788 student and 9,427 teacher cases; and (c) detailed data from 5 NUTS-3 regions from W09/2020 to W27/2021 with 12,814 cases (39% male, 37% female; median age 14, range 5 to 63), 43,238 contacts and 4,165 secondary cases for students (for teachers, 14,801 [22% male, 50% female; median age 39, range 16 to 75], 5,893 and 472). Infection risk (a) for students and teachers was higher than the population risk in all phases of normal presence class and highest in the early 2022 omicron wave with 30.6% (95% CI 30.5% to 32.6%) of students and 32.7% (95% CI 32.6% to 32.8%) of teachers infected in Germany. SARs (b) for students and staff were below 5% in schools throughout the study period, while SARs in households more than doubled from 13.8% (95% CI 10.6% to 17.6%) W21-39/2020 to 28.7% (95% CI 27% to 30.4%) in W08-23/2021 for students and 10.9% (95% CI 7% to 16.5%) to 32.7% (95% CI 28.2% to 37.6%) for staff. Most contacts were reported for schools, yet most secondary cases originated in households. In schools, staff predominantly infected staff. Mandatory surgical mask wearing during class in all schools was associated with a reduction in the case incidence of students and teachers (c), by 56/100,000 persons per 14 days (students: 95% CI 47.7 to 63.4; teachers: 95% CI 39.6 to 71.6; p < 0.001) and by 29.8% (95% CI 25% to 35%, p < 0.001) and 24.3% (95% CI 13% to 36%, p < 0.001) relative to the population, respectively, as were reduced attendance and higher vaccination coverage. The contribution of contacts in schools to population cases (d) was 2% to 20%, lowest during school closures/vacation and peaked during normal presence class intervals, with the overall peak early during the omicron wave. Limitations include underdetection, misclassification of contacts, interviewer/interviewee dependence of contact-tracing, and lack of individual-level confounding factors in aggregate data regression analysis. Conclusion In this study, we observed that open schools under hygiene measures and testing strategies contributed up to 20% of population infections during the omicron wave early 2022, and as little as 2% during vacations/school closures; about a third of students and teachers were infected during the omicron wave in early 2022 in Germany. Mandatory mask wearing during class in all school types and reduced attendance models were associated with a reduced infection risk in schools. Torben Heinsohn and co-authors investigate infection and transmission risks of COVID-19 in schools, school-level infection control measures, and their contribution to population infections in Germany. Author summary Why was this study done? Infection control policy for schools in Germany is sovereignty of the 16 federal states. A lack of evidence for measures in schools resulted in varying approaches to school infection control, in particular, masking and reduced attendance measures during the first year of the pandemic and beyond. Data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in schools was limited to small regions and short time periods. What did the researchers do and find? We gathered data collected by national and regional government agencies on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) school infections and transmission, covering March 2020 to April 2022 and in total 3,534,778 cases in students and 340,429 in staff or teachers. The risk of getting infected was higher for students and teachers than the general population when schools were open with all students present. Strict masking and reducing student numbers were associated with a reduction in this risk. Students and teachers are more likely to pass on their infection in the household than the school. Their contacts in school were responsible for up to 20% of infections in the population during the early 2022 omicron wave and as little as 2% during school closures and vacations. What do these findings mean? When hygiene measures to reduce infections in schools are necessary including masking policies for students and teachers in all schools during class and reducing student numbers should be considered. Contribution of school contacts to overall transmission in the population is highly variable, ranging from 20% during the omicron wave with open schools to 2% during closures/vacations. Limitations include underreporting of cases, misclassification of school contacts, inaccuracies in contact tracing, and lack of data on individual person factors in grouped data analysis.

The benefits of maternal physical activity during pregnancy are well documented, but long-term effects on the child have been less studied. Therefore, we conducted a pilot follow-up study of a lifestyle intervention during pregnancy that aimed to investigate whether exercise (endurance and strength training) during pregnancy affects motor performance and body composition of children up to 9 years of age, as well as possible influencing factors like brain-derived neurotrophic factor (BDNF) and lifestyle. Eleven mother−child pairs from the intervention and eight mother−child pairs from the control group were included. From birth up to 9 years of age, no differences in body mass index (BMI) or body mass index standard deviation scores (BMI-SDS) were found between the groups. Lifestyle intervention was one of the influencing factors for children’s cardiorespiratory endurance capacity and coordination. Moreover, maternal BDNF in the last trimester was significantly associated with running performance, which may be due to better neuronal development. This is the first study evaluating the effects of a lifestyle intervention during pregnancy on the motor performance 9 years after birth. Children’s participation in exercise programs over the past 9 years was not continuously recorded and therefore not included in the analysis. Even a cautious interpretation of these results indicates that a healthy lifestyle during pregnancy is essential in promoting child health. Larger studies and randomized control trials are necessary to confirm our results, especially those pertaining to the role of BDNF.

Abstract Being born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p

Abstract Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450–1098) ml/m in Null/null, 403 (260–538) ml/m in Null/mis, 230 (169–357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150–267) ml/m in CKD stage 1, 472 (266–880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female rats, we investigated 1) how an elevated dietary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular protein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intrauterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncompromised pregnancy. On postnatal (P) days P2–P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and proteomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus mitigating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proinflammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.

Abstract Intrauterine growth restriction (IUGR) and low birth weigth (LBW) are risk factors for neonatal chronic lung disease. However, maternal and fetal genetic factors and the molecular mechanisms remain unclear. We investigated the relationship between LBW and lung function with Mendelian randomisation analyses and studied angiogenesis in a low protein diet rat model of IUGR. Our data indicate a possible association between LBW and reduced FEV1 (p = 5.69E−18, MR-PRESSO) and FVC (6.02E-22, MR-PRESSO). Complimentary, we demonstrated two-phased perinatal programming after IUGR. The intrauterine phase (embryonic day 21) is earmarked by a reduction of endothelial cell markers (e.g. CD31) as well as mRNA expression of angiogenic factors (e.g., Vegfa, Flt1, Klf4). Protein analysis identified an activation of anti-angiogenic mTOR effectors. In the postnatal phase, lung capillaries (

Objectives To summarise multivariable predictive models for 30-day unplanned hospital readmissions (UHRs) in paediatrics, describe their performance and completeness in reporting, and determine their potential for application in practice.Design Systematic review.Data source CINAHL, Embase and PubMed up to 7 October 2021.Eligibility criteria English or German language studies aiming to develop or validate a multivariable predictive model for 30-day paediatric UHRs related to all-cause, surgical conditions or general medical conditions were included.Data extraction and synthesis Study characteristics, risk factors significant for predicting readmissions and information about performance measures (eg, c-statistic) were extracted. Reporting quality was addressed by the ‘Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis’ (TRIPOD) adherence form. The study quality was assessed by applying six domains of potential biases. Due to expected heterogeneity among the studies, the data were qualitatively synthesised.Results Based on 28 studies, 37 predictive models were identified, which could potentially be used for determining individual 30-day UHR risk in paediatrics. The number of study participants ranged from 190 children to 1.4 million encounters. The two most common significant risk factors were comorbidity and (postoperative) length of stay. 23 models showed a c-statistic above 0.7 and are primarily applicable at discharge. The median TRIPOD adherence of the models was 59% (P25–P75, 55%–69%), ranging from a minimum of 33% to a maximum of 81%. Overall, the quality of many studies was moderate to low in all six domains.Conclusion Predictive models may be useful in identifying paediatric patients at increased risk of readmission. To support the application of predictive models, more attention should be placed on completeness in reporting, particularly for those items that may be relevant for implementation in practice.

Lifestyle during pregnancy impacts the health of the mother and child. However, the extent to which physical activity affects maternal biomarkers and factors that might influence birth weight remains unclear. We analysed data from two lifestyle interventions in which the effects of an exercise programme (2x/week, 60–90 min) on the course of pregnancy with regard to adipokines and offspring were evaluated. A total of 70 women participated in this study (45, intervention group; 25, control group). Anthropometric data and maternal fasting serum leptin and resistin levels were measured at three time points (approximately 14th (T1), 24th (T2), and 36th (T3) weeks of gestation). Neonatal/child data were retrieved from screening examinations. Independent of the intervention, we found a positive correlation between the fat mass at T1 and both leptin and resistin levels at all time points. Leptin level was significantly higher in the control group at T3; however, no differences between the groups were found for resistin. The birth weight was influenced by the birth length, fat mass at T1/T3, and resistin level at T2. The BMI-SDS at one year of age was influenced by maternal fat-free mass at T3 and resistin at T1/T2. Even if these results can only be interpreted cautiously, lifestyle interventions during pregnancy are important in promoting maternal and child health. Further randomised controlled trials and translational studies are warranted to clarify the underlying mechanisms.

Background: The extent to which children and adolescents contribute to SARS-CoV-2 transmission remains not fully understood. Novel high-capacity testing methods may provide real-time epidemiological data in educational settings helping to establish a rational approach to prevent and minimize SARS-CoV-2 transmission. We investigated whether pooling of samples for SARS-CoV-2 detection by RT-qPCR is a sensitive and feasible high-capacity diagnostic strategy for surveillance of SARS-CoV-2 infections in schools. Methods: In this study, students and school staff of 14 educational facilities in Germany were tested sequentially between November 9 and December 23, 2020, two or three times per week for at least three consecutive weeks. Participants were randomized for evaluation of two different age adjusted swab sampling methods (oropharyngeal swabs or buccal swabs compared to saliva swabs using a ‘lolli method’). Swabs were collected and pooled for SARS-CoV-2 RT-qPCR. Individuals of positive pooled tests were retested by RT-qPCR the same or the following day. Positive individuals were quarantined while the SARS-CoV-2 negative individuals remained in class with continued pooled RT-qPCR surveillance. The study is registered with the German Clinical Trials register (registration number: DRKS00023911). Findings: 5,537 individuals were eligible and 3970 participants were enroled and included in the analysis. In students, a total of 21,978 swabs were taken and combined in 2218 pooled RT-qPCR tests. We detected 41 positive pooled tests (1·8%) leading to 36 SARS-CoV-2 cases among students which could be identified by individual re-testing. The cumulative 3-week incidence for primary schools was 564/100,000 (6/1064, additionally 1 infection detected in week 4) and 1249/100,000 (29/2322) for secondary schools. In secondary schools, there was no difference in the number of SARS-CoV-2 positive students identified from pooled oropharyngeal swabs compared to those identified from pooled saliva samples (lolli method) (14 vs. 15 cases; 1·3% vs. 1·3%; OR 1.1; 95%-CI 0·5–2·5). A single secondary school accounted for 17 of 36 cases (47%) indicating a high burden of asymptomatic prevalent SARS-CoV-2 cases in the respective school and community. Interpretation: In educational settings, SARS-CoV-2 screening by RT-qPCR-based pooled testing with easily obtainable saliva samples is a feasible method to detect incident cases and observe transmission dynamics. Funding: Federal Ministry of education and research (BMBF; Project B-FAST in “NaFoUniMedCovid19”; registration number: 01KX2021).

Abstract Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower’s sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a “template” defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown–models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity.

Background: Early infant weight development influences metabolic regulation later in life. For the prevention of obesity and metabolic diseases, it is important to understand the underlying mechanisms in detail. Objectives: This study aims to examine the effects of maternal anthropometric, sociodemographic, and lifestyle factors on maternal and cord blood leptin levels at birth and on the development of body mass index (BMI) standard deviation scores (SDS) in offspring up to 1 year of age. Methods: Seventy-six mother-child pairs were enrolled in this follow-up analysis in a cross-sectional design. Standardized questionnaires were used to collect information regarding maternal anthropometrics, lifestyle habits, and sociodemographic conditions, and newborn weight, or, rather, BMI-SDS, development during the first year of life. Results: Cord blood leptin (β = –0.222, p = 0.074), maternal leptin (β = 0.414, p = 0.001), and female sex of the offspring (β = 0.385, p = 0.003) explained 29.0% of the variance in BMI-SDS changes in the first year of life. Cord blood leptin was influenced by newborn sex (male; β = –0.220, p = 0.025) and maternal moderate-intensity physical activity in the third trimester (β = 0.265, p = 0.007, corr. R2 = 9.2%); maternal leptin was influenced by maternal prepregnancy BMI (β = 0.602, p < 0.001) and weight gain during pregnancy (β = 0.247, p = 0.004, corr. R2 = 35.5%). Conclusions: Higher maternal and lower cord blood leptin levels are associated with a higher BMI-SDS increase during the first year of life. Maternal leptin is influenced by maternal BMI and weight gain during pregnancy, and cord blood leptin is influenced by maternal physical activity; therefore, it can be suggested that an active and healthy maternal lifestyle may play a pivotal and beneficial role in the offspring’s weight development.

Lung development is not completed at birth, but expands beyond infancy, rendering the lung highly susceptible to injury. Exposure to various influences during a critical window of organ growth can interfere with the finely-tuned process of development and induce pathological processes with aberrant alveolarization and long-term structural and functional sequelae. This concept of developmental origins of chronic disease has been coined as perinatal programming. Some adverse perinatal factors, including prematurity along with respiratory support, are well-recognized to induce bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease that is characterized by arrest of alveolar and microvascular formation as well as lung matrix remodeling. While the pathogenesis of various experimental models focus on oxygen toxicity, mechanical ventilation and inflammation, the role of nutrition before and after birth remain poorly investigated. There is accumulating clinical and experimental evidence that intrauterine growth restriction (IUGR) as a consequence of limited nutritive supply due to placental insufficiency or maternal malnutrition is a major risk factor for BPD and impaired lung function later in life. In contrast, a surplus of nutrition with perinatal maternal obesity, accelerated postnatal weight gain and early childhood obesity is associated with wheezing and adverse clinical course of chronic lung diseases, such as asthma. While the link between perinatal nutrition and lung health has been described, the underlying mechanisms remain poorly understood. There are initial data showing that inflammatory and nutrient sensing processes are involved in programming of alveolarization, pulmonary angiogenesis, and composition of extracellular matrix. Here, we provide a comprehensive overview of the current knowledge regarding the impact of perinatal metabolism and nutrition on the lung and beyond the cardiopulmonary system as well as possible mechanisms determining the individual susceptibility to CLD early in life. We aim to emphasize the importance of unraveling the mechanisms of perinatal metabolic programming to develop novel preventive and therapeutic avenues.

Sedentary behaviour has a negative impact on children’s physical and mental health. However, limited data are available on language development. Therefore, this pilot study aimed to analyse the associations between language development and possible predictors such as motor skills and leisure time behaviour in preschool-aged children. Methods: In this cross-sectional analysis, motor skills and speech development status were assessed in 49 healthy preschool children. Physical activity and screen time were assessed via a parental questionnaire. Results: On average, physical activity was 8.2 ± 6.5 h/week; mean screen time was 154.2 ± 136.2 min/week. A positive relationship between the results in the item ‘One-leg stand’ and ‘Phonological working memory for nonwords’ (β-coefficient −0.513; p < 0.001) resp. ‘Formation of morphological rules’ (β-coefficient −0.626; p = 0.004) was shown within backward stepwise regression. ‘Lateral jumping’, resp. ‘Sit and Reach’ were positively associated with ‘Understanding sentences’ (β-coefficient 0.519; p = 0.001 resp. β-coefficient 0.735; p = 0.002). ‘Physical inactivity’ correlated negatively with all language development subtests (each p < 0.05). Media consumption had a negative predictive effect on the subdomain ‘Understanding Sentences’ (β-coefficient −0.530, p = 0.003). Conclusions: An inactive lifestyle correlated negatively with selected subtests of language development in early childhood. These results should be verified in larger groups and longitudinally but support the need for early health promotion.

Cell cilia: Protein crucial for function identified A protein involved in building and maintaining thin protrusions from cell surfaces called cilia is implicated in “ciliopathies”, diseases in which ciliary function is disrupted. These include polycystic kidney disease and disorders collectively known as ciliary dyskinesias. “Primary cilia” perform sensory functions, detecting external chemical and physical signals and initiating responses within cells. In addition, “motile cilia” beat rhythmically to move fluids surrounding cells. Researchers in Germany and the Netherlands, led by Bernhard Schermer and Max C. Liebau at the University of Cologne, studied a protein called Ruvbl1, known to interact with DNA and other proteins. The researchers found it is crucial for the functioning of both types of cilia. Deleting the gene for Ruvbl1 in mice caused kidney failure and a build-up of fluid in the brain known as hydrocephalus. The research could help understand and ultimately treat ciliopathies.

Prematurely born infants often require supplemental oxygen that impairs lung growth and results in arrest of alveolarization and bronchopulmonary dysplasia (BPD). The growth hormone (GH)- and insulin-like growth factor (IGF)1 systems regulate cell homeostasis and organ development. Since IGF1 is decreased in preterm infants, we investigated the GH- and IGF1 signaling (1) in newborn mice with acute and prolonged exposure to hyperoxia as well as after recovery in room air; and (2) in cultured murine lung epithelial cells (MLE-12) and primary neonatal lung fibroblasts (pLFs) after treatment with GH, IGF1, and IGF1-receptor (IGF1-R) inhibitor or silencing of GH-receptor (Ghr) and Igf1r using the siRNA technique. We found that (1) early postnatal hyperoxia caused an arrest of alveolarization that persisted until adulthood. Both short-term and prolonged hyperoxia reduced GH-receptor expression and STAT5 signaling, whereas Igf1 mRNA and pAKT signaling were increased. These findings were related to a loss of epithelial cell markers (SFTPC, AQP5) and proliferation of myofibroblasts (αSMA+ cells). After recovery, GH-R-expression and STAT5 signaling were activated, Igf1r mRNA reduced, and SFTPC protein significantly increased. Cell culture studies showed that IGF1 induced expression of mesenchymal (e.g., Col1a1, Col4a4) and alveolar epithelial cell type I (Hopx, Igfbp2) markers, whereas inhibition of IGF1 increased SFTPC and reduced AQP5 in MLE-12. GH increased Il6 mRNA and reduced proliferation of pLFs, whereas IGF1 exhibited the opposite effect. In summary, our data demonstrate an opposite regulation of GH- and IGF1- signaling during short-term/prolonged hyperoxia-induced lung injury and recovery, affecting alveolar epithelial cell differentiation, inflammatory activation of fibroblasts, and a possible uncoupling of the GH-IGF1 axis in lungs after hyperoxia.

PurposeMaternal obesity has emerged as an important risk factor for the development of metabolic disorders in the offspring. The hypothalamus as the center of energy homeostasis regulation is known to function based on complex neuronal networks that evolve during fetal and early postnatal development and maintain their plasticity into adulthood. Development of hypothalamic feeding networks and their functional plasticity can be modulated by various metabolic cues, especially in early stages of development. Here, we aimed at determining the underlying molecular mechanisms that contribute to disturbed hypothalamic network formation in offspring of obese mouse dams.MethodsFemale mice were fed either a control diet (CO) or a high-fat diet (HFD) after weaning until mating and during pregnancy and gestation. Male offspring was sacrificed at postnatal day (P) 21. The hypothalamus was subjected to gene array analysis, quantitative PCR and western blot analysis.ResultsP21 HFD offspring displayed increased body weight, circulating insulin levels, and strongly increased activation of the hypothalamic insulin signaling cascade with a concomitant increase in ionized calcium binding adapter molecule 1 (IBA1) expression. At the same time, the global gene expression profile in CO and HFD offspring differed significantly. More specifically, manifest influences on several key pathways of hypothalamic neurogenesis, axogenesis, and regulation of synaptic transmission and plasticity were detectable. Target gene expression analysis revealed significantly decreased mRNA expression of several neurotrophic factors and co-factors and their receptors, accompanied by decreased activation of their respective intracellular signal transduction.ConclusionTaken together, these results suggest a potential role for disturbed neurotrophin signaling and thus impaired neurogenesis, axogenesis, and synaptic plasticity in the pathogenesis of the offspring’s hypothalamic feeding network dysfunction due to maternal obesity.

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.

Introduction: Autosomal recessive polycystic kidney disease (ARPKD) is a severe hepatorenal disorder of childhood. Early renal disease in ARPKD may require renal replacement therapy and is associated with failure to thrive resulting in a need for nasogastric tube feeding or gastrostomy. In ARPKD patients, the benefit of a gastrostomy in nutrition and growth needs to be weighed against the potential risk of complications of congenital hepatic fibrosis (CHF) and portal hypertension like variceal bleeding. CHF in ARPKD has thus been considered as a relative contraindication for gastrostomy insertion. Yet, data on gastrostomies in pediatric patients with ARPKD is lacking.Methods: We conducted a web-based survey study among pediatric nephrologists, pediatric hepatologists and pediatric gastroenterologists on their opinions on and experiences with gastrostomy insertion in ARPKD patients.Results: 196 participants from 39 countries shared their opinion. 45% of participants support gastrostomy insertion in all ARPKD patients, but portal hypertension is considered to be a contraindication by a subgroup of participants. Patient-specific data was provided for 38 patients indicating complications of gastrostomy that were in principal comparable to non-ARPKD patients. Bleeding episodes were reported in 3/38 patients (7.9%). Two patients developed additional severe complications. Gastrostomy was retrospectively considered as the right decision for the patient in 35/38 (92.1%) of the cases.Conclusions: This report on the results of an online survey gives first insights into the clinical practice of gastrostomy insertion in ARPKD patients. For the majority of participating physicians benefits of gastrostomy insertion retrospectively outweigh complications and risks. More data will be required to lay the foundation for clinical recommendations.

Chronic kidney disease affects more than 10% of the population. Programming studies have examined the interrelationship between environmental factors in early life and differences in morbidity and mortality between individuals. A number of important principles has been identified, namely permanent structural modifications of organs and cells, long-lasting adjustments of endocrine regulatory circuits, as well as altered gene transcription. Risk factors include intrauterine deficiencies by disturbed placental function or maternal malnutrition, prematurity, intrauterine and postnatal stress, intrauterine and postnatal overnutrition, as well as dietary dysbalances in postnatal life. This mini-review discusses critical developmental periods and long-term sequelae of renal programming in humans and presents studies examining the underlying mechanisms as well as interventional approaches to “re-program” renal susceptibility toward disease. Clinical manifestations of programmed kidney disease include arterial hypertension, proteinuria, aggravation of inflammatory glomerular disease, and loss of kidney function. Nephron number, regulation of the renin–angiotensin–aldosterone system, renal sodium transport, vasomotor and endothelial function, myogenic response, and tubuloglomerular feedback have been identified as being vulnerable to environmental factors. Oxidative stress levels, metabolic pathways, including insulin, leptin, steroids, and arachidonic acid, DNA methylation, and histone configuration may be significantly altered by adverse environmental conditions. Studies on re-programming interventions focused on dietary or anti-oxidative approaches so far. Further studies that broaden our understanding of renal programming mechanisms are needed to ultimately develop preventive strategies. Targeted re-programming interventions in animal models focusing on known mechanisms will contribute to new concepts which finally will have to be translated to human application. Early nutritional concepts with specific modifications in macro- or micronutrients are among the most promising approaches to improve future renal health.

Nutrient deprivation during early development has been associated with the predisposition to metabolic disorders in adulthood. Considering its interaction with metabolism, appetite and behavior, the endocannabinoid (eCB) system represents a promising target of developmental programming.By cross-fostering and variation of litter size, early postnatal nutrition of CB6F1-hybrid mice was controlled during the lactation period (3, 6, or 10 pups/mother). After weaning and redistribution at P21, all pups received standard chow ad libitum. Gene expression analyses (liver, visceral fat, hypothalamus) were performed at P50, eCB concentrations were determined in liver and visceral fat. Locomotor activity and social behavior were analyzed by means of computer-assisted videotracking.Body growth was permanently altered, with differences for length, weight, body mass index and fat mass persisting beyond P100 (all 3>6>10,p6>10 (DAGLα p6>10 (FAAH p