Publications by authors named "Wieland Kiess"

458 Publications

Associations between changes in behavioral difficulties and levels of problematic smartphone use in adolescents over a 1-year period.

Eur Child Adolesc Psychiatry 2021 Sep 21. Epub 2021 Sep 21.

LIFE Leipzig Research Center for Civilization Diseases, Leipzig University, Philipp-Rosenthal-Strasse 27, 04103, Leipzig, Germany.

Objectives: The present longitudinal study investigates associations between changes in externalizing and internalizing behavioral difficulties and changes in problematic smartphone usage within the same 1-year period in healthy adolescents.

Methods: The project is part of the LIFE Child cohort study conducted in Leipzig, Germany. Ten- to 16-year-old adolescents (n = 363) provided information on behavioral difficulties [Strengths and Difficulties Questionnaire (SDQ)], the duration of daily smartphone use, and symptoms of smartphone addiction [Smartphone Addiction Proneness Scale (SAPS)] at two consecutive study visits, t1 and t2 (1 year after t1). In the first of two analysis phases, we applied linear regression analyses to assess cross-sectional associations between externalizing and internalizing behavioral difficulties and the duration of smartphone use and symptoms of smartphone addiction (at t1 and t2). In the second, we assessed associations between the changes measured in these variables over the period of a year. All associations were adjusted for age, sex, and soci-economic status.

Results: Children who reported prolonged periods of smartphone use or more symptoms of smartphone addiction exhibited significantly higher levels of externalizing and internalizing behavioral difficulties at t1 and t2. Further, children who increased their usage or developed addiction symptoms between t1 and t2 also developed more externalizing behavioral difficulties. We found the same tendencies in regard to internalizing behavioral difficulties, although the associations did not reach statistical significance.

Conclusions: The present findings suggest that externalizing behavioral difficulties and problematic smartphone use are mutually dependent in the long term.
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http://dx.doi.org/10.1007/s00787-021-01874-8DOI Listing
September 2021

Calcitonin and complementary biomarkers in the diagnosis of hereditary medullary thyroid carcinoma in children and adolescents.

J Pediatr Endocrinol Metab 2021 Sep 21. Epub 2021 Sep 21.

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany.

Objectives: Medullary thyroid carcinoma (MTC) is a rare malignancy that is effectively curable by surgery. Unlike in adults, hereditary MTC has a predominant role in children. A fast and safe diagnosis is important to assure the good prognosis for the patients. A major cornerstone is the assessment of biomarkers, but the interpretation must respect their pre-, post- and analytical features. Especially calcitonin (Ctn) is a challenging biomarker in daily laboratory diagnostics. However, Ctn is of particular relevance for the diagnostic in MTC. The American Thyroid Association recommends thyroidectomy if the upper reference range of Ctn is exceeded. Interestingly, age-dependent reference ranges for children and adolescents have become available only recently for Ctn assays. With this review, we aim to highlight the importance of a timely diagnosis of MTC in children and adolescents.

Content: Recent developments in pediatric biochemical diagnostics of MTC were summarized. This includes guidance on interpretation of , Ctn, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 19-9, and chromogranin A.

Summary: Currently, Ctn is the most investigated biomarker in the diagnosis of MTC in children and adolescents. Other biomarkers as PCT suggest complementary evidence about pediatric MTC but their interpretation based largely on adult's data. A successful treatment of MTC requires, besides results of biomarkers, information about medical history, RET gene analysis and recent guideline knowledge.

Outlook: More research is required to validate complementary biomarkers of Ctn in children. Additionally, the effect of different confounder on pediatric Ctn levels has to be further clarified.
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http://dx.doi.org/10.1515/jpem-2021-0163DOI Listing
September 2021

Maternal depressive symptoms and stress during pregnancy as predictors of gestational age at birth and standardized body mass index from birth up to 2 years of age.

BMC Pregnancy Childbirth 2021 Sep 18;21(1):635. Epub 2021 Sep 18.

Integrated Research and Treatment Center AdiposityDiseases, Behavioral Medicine Research Unit, Department of Psychosomatic Medicine and Psychotherapy, Leipzig University Medical Center, Semmelweisstrasse 10, 04103, Leipzig, Germany.

Background: While depressive symptoms and stress during pregnancy are known to affect gestational age and weight at birth, evidence on their impact on child anthropometric development in the long term remains limited, showing inconsistent effects. Importantly, previous research indicated a substantially stronger impact of categorically rather than dimensionally assessed mental health problems on birth outcomes and child development.

Methods: The Patient Health Questionnaire was used to assess depressive symptoms and stress during the 2nd trimester of pregnancy dimensionally and categorically, with scores ≥10 indicating clinical significance. Gestational age at birth and BMI-SDS from birth up to 2 years of age were examined as dependent variables. Structural equation modeling was used to examine the prediction of birth outcomes and child anthropometry by mental health problems while controlling for multiple maternal and child characteristics in 322 mother-child dyads.

Results: Dimensionally assessed mental health problems did not significantly predict birth outcomes. While categorical depressive symptoms significantly predicted a higher child BMI-SDS, categorical stress significantly predicted a lower gestational age at birth. Neither categorical nor dimensional mental health problems significantly predicted child BMI-SDS at 6, 12, and 24 months postpartum.

Conclusions: Depressive symptoms and stress during pregnancy seem to differentially affect birth outcomes, and only if clinically relevant. The results implicate the importance to timely treat pregnant women that are greatly affected by mental health problems to potentially reduce adverse birth outcomes.
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http://dx.doi.org/10.1186/s12884-021-04111-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449913PMC
September 2021

Well-being and COVID-19-related worries of German children and adolescents: A longitudinal study from pre-COVID to the end of lockdown in Spring 2020.

JCPP Adv 2021 Apr 17;1(1):e12004. Epub 2021 Mar 17.

LIFE Child Leipzig University Hospital for Children and Adolescents Leipzig University Leipzig Germany.

Background: There is concern that pandemic measures put a strain on the health and well-being of children. We investigated the effects of the COVID-19 pandemic, the lockdown, and social distancing on the well-being, media use, and emotions of children and adolescents between 9 and 18 years.

Methods: We used linear and proportional odds logistic regression correcting for age, sex, and socioeconomic status (SES) and to compare media use, peers/social support, physical, and psychological well-being between 2019 (pre-COVID baseline) and two time points shortly after the start of the lockdown (last week of March and April 2020, respectively) in 391 9-19-year-old healthy children and adolescents of the LIFE Child cohort. COVID-19-related feelings and their relationship to age, sex, and SES were assessed at two time points during lockdown.

Results: We found significantly lower scores in physical and psychological well-being during lockdown compared to baseline. The effect was significantly stronger in children with medium/low SES. Perceived social support scores were also significantly lower during the lockdown. The percentage of children who had no contact with their peers (in-person or online) increased from 3% pre-COVID to 14% and 13% in April and March 2020, respectively. About 80% of the children missed in-person contacts with friends. Most of the children worried more about the health of their families than their own. Sixty percent worried about the international situation at least moderately, whereas only 20% were afraid of COVID-19 itself. The percentage of children who believed it would never be as before COVID-19 rose from 7.4% at the beginning lockdown end of March to 16.2% a month later. In contrast, all other COVID-19-related worries, showed a (nonsignificant) decline during the same period.

Conclusion: Our study supports the notion that pandemic measures have to be balanced against adverse public health effects. Especially vulnerable groups have to be protected.
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http://dx.doi.org/10.1111/jcv2.12004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250267PMC
April 2021

Changes in diet from pregnancy to one year after birth: a longitudinal study.

BMC Pregnancy Childbirth 2021 Sep 4;21(1):600. Epub 2021 Sep 4.

LIFE Leipzig Research Center for Civilization Diseases, Leipzig University, Philipp-Rosenthal-Strasse 27, 04103, Leipzig, Germany.

Background: Pregnancy and the first year after giving birth are marked by physiological and psychological changes. While it is well known that energy requirements change during this time, the question of how a woman's diet actually changes from pregnancy until 1 year postpartum has been left virtually unexplored. The present study employs a longitudinal design to investigate these changes.

Methods: Data were collected within the framework of the LIFE Child study (Leipzig, Germany). The diet composition and culture of eating of 110 women were assessed at 3 time points: in the 24th week of pregnancy, 3 months after giving birth (breastfeeding period), and 12 months after giving birth (after weaning). We assessed differences in nutritional health (Nutritional Health Score, NHS) and the consumption of different food items at each of these time points. We also investigated associations between nutritional health and age, socio-economic status (SES), BMI before pregnancy, and previous births at all three time points.

Results: The analyses revealed high correlations in the NHS values between the three time points (rho = .55, rho = .60). On average, nutritional health was lower in the breastfeeding period than during pregnancy. In more detail, women reported less healthy levels of treats and white bread consumption and a higher frequency of snacking in the breastfeeding period than during pregnancy. In contrast, overall nutritional health did not differ significantly between pregnancy and the time after weaning. Increased age was associated with a healthier diet during pregnancy, and a high SES was associated with healthier diet after weaning. Furthermore, the increase in nutritional health from the breastfeeding period to the time after weaning was significantly stronger in women with a higher BMI. We observed no significant associations between dietary nutritional health and previous births.

Conclusions: The present findings suggest that higher energy requirements in the breastfeeding period are met by consuming high-calorie and unhealthy food products rather than healthy and nutrient-rich food. Young mothers should be supported in taking care of their own nutritional health during the challenging time of breastfeeding and caring for a newborn child.
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http://dx.doi.org/10.1186/s12884-021-04038-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418026PMC
September 2021

Endocrine-disrupting chemicals.

Best Pract Res Clin Endocrinol Metab 2021 Aug 17:101566. Epub 2021 Aug 17.

Department of Pediatrics and Adolescent Medicine, Vienna Bone and Growth Center, Medical University of Vienna, A 1090, Vienna, Austria.

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http://dx.doi.org/10.1016/j.beem.2021.101566DOI Listing
August 2021

Expression of the adipocyte progenitor markers MSCA1 and CD36 is associated with adipose tissue function in children.

J Clin Endocrinol Metab 2021 Aug 27. Epub 2021 Aug 27.

University of Leipzig, Medical Faculty, University Hospital for Children and Adolescents, Center for Pediatric Research Leipzig (CPL), 04103 Leipzig, Germany.

Context: MSCA1 (mesenchymal stem cell antigen 1) and CD36 (cluster of differentiation 36) have been described as novel adipocyte progenitor markers in adults with a potential relevance for obesity and adipocyte progenitor function.

Objective: With the early manifestation of obesity in children and formation of adipose tissue (AT) dysfunction, children provide the opportunity to characterize the function of MSCA1 and CD36 during physiological AT accumulation and with obesity and related disease.

Methods: We investigated MSCA1 and CD36 expression in adipocytes and stroma vascular fraction (SVF) cells from 133 children of the Leipzig AT Childhood cohort with regard to AT accumulation and biology. In a subsample we analyzed how MSCA1 and CD36 expression is related to adipose progenitor capacities in vitro, i.e. proliferation, differentiation and mitochondrial function.

Results: Both, MSCA1 and CD36 are differentially expressed in adipocytes and SVF cells of children. MSCA1 expression is positively correlated to obesity-associated AT dysfunction, i.e. adipocyte hypertrophy and serum hs-CRP, and high SVF MSCA1 expression is associated with increased mitochondrial respiration in vitro. CD36 expression is not associated with AT dysfunction but SVF CD36 expression is downregulated in children with overweight and obesity and shows a positive association with the differentiation capacity of SVF cells ex vivo and in vitro.

Conclusion: In conclusion, both MSCA1 and CD36 are associated with obesity-related alterations in AT of children. In particular, CD36 expression predicts adipogenic potential of SVF cells, indicating a potential role in the regulation of adipocyte hyperplasia and hypertrophy with obesity development in children.
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http://dx.doi.org/10.1210/clinem/dgab630DOI Listing
August 2021

Cystatin C relates to metabolism in healthy, pubertal adolescents.

Pediatr Nephrol 2021 Aug 25. Epub 2021 Aug 25.

Hospital for Children and Adolescents, University of Leipzig, Liebigstraße 27b, 04103, Leipzig, Germany.

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.
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http://dx.doi.org/10.1007/s00467-021-05209-2DOI Listing
August 2021

Dynamic alterations in linear growth and endocrine parameters in children with obesity and height reference values.

EClinicalMedicine 2021 Jul 23;37:100977. Epub 2021 Jun 23.

University of Leipzig, Medical Faculty, University Hospital for Children and Adolescents, Center for Pediatric Research, Liebigstr.19, Leipzig 04103, Germany.

Background: Obesity can affect linear growth of children but there is uncertainty regarding the dynamics and potential causes.

Methods: In the population-based LIFE Child and the obesity-enriched Leipzig Obesity Childhood cohorts (8,629 children, 37,493 measurements), recruited from 1999 to 2018 in Germany, we compared height, growth, and endocrine parameters between normal-weight and children with obesity (0-20 years). Derived from the independent German CrescNet registry (12,703 children) we generated height reference values specific for children with obesity (data collected from 1999 to 2020).

Findings: Children with obesity were significantly taller than normal-weight peers, differing at maximum by 7·6 cm (1·4 height, standard deviation scores or SDS) at age 6-8 years. Already at birth, children with obesity were slightly taller and thereafter had increased growth velocities by up to 1·2 cm/year. This growth acceleration was unrelated to parental height, but was accompanied by increased levels of insulin-like growth factor-1 (IGF-1), insulin and leptin. During puberty, children with obesity showed a catch-down in height SDS. The reduction in pubertal growth velocity by up to 25% coincided with a decrease in levels of IGF-1 (by 17%) and testosterone (by 62%) in boys and estradiol (by 37%) in girls. We confirmed these alterations in growth in the independent CrescNet cohort and furthermore provide height reference values for children with obesity for open access.

Interpretation: Dynamics of linear growth are altered distinctively in different developmental phases in children with obesity. Early emergence before other profound comorbidities implies predisposition, environmental, and/or endocrine factors affecting growth in early life. Height reference values for children with obesity may enhance the precision of clinical health surveillance.

Funding: German Research Foundation, German Diabetes Association, EU, ESF, ERDF, State of Saxony, ESPE, Hexal, Novo Nordisk, Pfizer Pharma.
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http://dx.doi.org/10.1016/j.eclinm.2021.100977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343253PMC
July 2021

Handling Errors in the Use of Inhalation Devices: Inhalation Technique Skills and Knowledge in Pediatric Nurses.

J Nurs Care Qual 2021 Jul 27. Epub 2021 Jul 27.

Clinical Pharmacy, Institute of Pharmacy, Medical Faculty, Leipzig University and Drug Safety Center, Leipzig University and University Hospital, Leipzig, Germany (Drs Neininger and T. Bertsche and Mss Kaune and Musiol); University Hospital for Children and Adolescents, Center for Pediatric Research, Leipzig, Germany (Drs Kiess, A. Bertsche, and Prenzel); and Neuropediatrics, University Hospital for Children and Adolescents, Rostock, Germany (Dr A. Bertsche).

Background: Children suffering from bronchial diseases need assistance from nurses in the use of inhalation devices.

Purpose: We aimed to assess nurses' skills and knowledge concerning drug administration with inhalation devices in hospitalized pediatric patients.

Methods: An expert panel defined medication errors in drug administration with inhalation devices in children. We monitored 241 inhalation procedures to investigate nurses' inhalation technique skills. Twenty-nine nurses completed a questionnaire to assess nurses' knowledge.

Results: Skills: In 93 of 241 (39%) inhalation procedures, the mask/mouthpiece did not fit airtight. In none of the 11 inhalations administering a glucocorticoid, the patient's mouth was thoroughly cleaned afterward. Knowledge: Ten of 29 nurses (34%) thought a distance between mask and the patient's face was acceptable. Only 16 of 29 (55%) knew that it is necessary to thoroughly clean the patient's mouth after the inhalation of budesonide.

Conclusions: We found that education on inhalation procedures including practical training is required to increase patient safety.
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http://dx.doi.org/10.1097/NCQ.0000000000000587DOI Listing
July 2021

Effect of physical activity and BMI SDS on bone metabolism in children and adolescents.

Bone 2021 Jul 24;153:116131. Epub 2021 Jul 24.

Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany. Electronic address:

Objective: Children with obesity are known to have reduced bone density and are at a higher risk for fractures. This may be caused by decreased physical activity or a metabolic phenomenon. In this study, we evaluated associations of physical activity with bone metabolism in children and adolescents with and without obesity.

Methods: Results from 574 visits of 397 subjects, 191 girls and 206 boys aged five to 18 years (mean: 11.7 ± 2.8) representing 180 children with (mean BMI SDS 2.5 ± 0.4) and 217 without obesity (mean BMI SDS 0.2 ± 1.0) from the LIFE Child study, a population-based cohort of children/adolescents with normal weight and with obesity were analyzed for the impact of their daily physical activity (MET/day, SenseWear Accelerometer) on serum SDS levels for bone formation (alkaline phosphatase, osteocalcin, procollagen type I N propeptide [P1NP]), bone resorption (beta-crosslaps), and calcium homeostasis (parathormone, OH-25-vitamin D) by a linear regression model adjusted for gender- and age-based differences.

Results: For male subjects, BMI SDS significantly influenced the association of physical activity to PTH, vitamin D, and beta-crosslaps SDS levels. A higher physical activity was accompanied by increased PTH but decreased vitamin D SDS levels in children with normal weight. In males with obesity, all levels remained unaltered. In females, BMI SDS significantly impacted the association of physical activity to PTH, vitamin D, P1NP, beta-crosslaps, and osteocalcin SDS levels. In females with obesity, higher physical activity was related to higher SDS levels of vitamin D, P1NP, and beta-crosslaps. In contrast, in normal weight females, only PTH SDS was higher.

Conclusions: The effect of daily physical activity on bone metabolic markers and calciotropic hormones depends significantly on gender and BMI SDS. However, higher levels of physical activity were associated with increased bone turnover for female subjects with obesity only. Thus, motivating especially girls with obesity to be physically active may help improve their bone health.
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http://dx.doi.org/10.1016/j.bone.2021.116131DOI Listing
July 2021

PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging.

J Biol Chem 2021 Aug 14;297(2):100968. Epub 2021 Jul 14.

University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham, UK.

The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
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http://dx.doi.org/10.1016/j.jbc.2021.100968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350019PMC
August 2021

Associations of prenatal exposure to phthalates and one phthalate substitute with anthropometric measures in early life: Results from the German LIFE Child cohort study.

Best Pract Res Clin Endocrinol Metab 2021 May 20:101532. Epub 2021 May 20.

Leipzig Research Center for Civilization Diseases (LIFE), LIFE Child, Leipzig University, Faculty of Medicine, Philipp-Rosenthal-Straße 27, D-04103, Leipzig, Germany; Hospital for Children and Adolescents, Center for Pediatric Research, Leipzig University, Liebigstraße 20a, D-04103, Leipzig, Germany.

Exposure to phthalates is widespread and especially early life stages represent a critical window of exposure. In the present study, we investigated the effect of prenatal exposure to phthalates on birth outcomes and weight development in early life. In 130 mother-child pairs, we estimated the association of concentrations of 13 phthalates in spot-urine samples collected during pregnancy and birth outcomes and weight gain in the first two years of life using robust linear regression. High molecular weight phthalates were inversely associated with birth weight in girls but not in boys. Thus, prenatal exposure to phthalates may affect birth weight in a sex-specific manner.
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http://dx.doi.org/10.1016/j.beem.2021.101532DOI Listing
May 2021

Composition and Culture of Eating (CoCu) pregnancy: a new short questionnaire to evaluate diet composition and culture of eating during pregnancy.

Public Health Nutr 2021 Jun 28:1-9. Epub 2021 Jun 28.

Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), Leipzig University, Liebigstrasse 20a, 04103Leipzig, Germany.

Objective: The project aimed to validate a short questionnaire (CoCu pregnancy - Composition and Culture of Eating during pregnancy) and to investigate associations with age and socio-economic status (SES).

Design: The questionnaire was developed according to the validated CoCu for children and adolescents containing a diet composition (fourteen items) and a culture of eating part (six items). A Nutritional Health Score (NHS) was calculated based on diet composition (-120 and +120, with higher scores indicating healthier diets). The validity was assessed by comparing answers in CoCu pregnancy with a FFQ. In a subsample (n 97), we assessed the percentage of having chosen the same (or adjacent) response categories in the 24th and 36th week of pregnancy (wp).

Setting: Data were collected within the LIFE Child study in Leipzig, Germany.

Participants: We evaluated 430 questionnaires of pregnant women (24th wp).

Results: The results indicated a healthy diet in the present sample (NHS at 24th wp = 49·74 (95 % CI 47·27, 52·22)). The analyses revealed significant positive correlations between CoCu and FFQ (rho ranging from 0·32 to 0·61). For each food item, >90 % of women had chosen the same (50-60 %) or adjacent response categories in the 24th and 36th wp. The analysis revealed associations of the NHS with age (β = 0·11, P = 0·027), SES (β = 0·21, P < 0·001), snacking (β = -0·24, P < 0·001) and media use (β = -0·18, P < 0·001).

Conclusions: The questionnaire represents a useful tool for surveying the diets during pregnancy for research and clinical practice.
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http://dx.doi.org/10.1017/S1368980021002445DOI Listing
June 2021

Elevated transaminases potentiate the risk for emerging dysglycemia in children with overweight and obesity.

Pediatr Obes 2021 Jun 21:e12822. Epub 2021 Jun 21.

University of Leipzig, Medical Faculty, University Hospital for Children and Adolescents, Center for Pediatric Research, Leipzig, Germany.

Background: There is evidence that nonalcoholic fatty liver disease (NAFLD) increases the risk for dysglycemia in children in cross-sectional studies. However, the extent to which NAFLD may confer the risk for dysglycemia in longitudinal studies remains uncertain.

Objectives: We investigated whether elevated levels of alanine aminotransferase (ALT) as a proxy for NAFLD can serve as a predictor for future dysglycemia among children.

Methods: We performed survival analysis up to 11 years of follow-up on longitudinal data of 510 children with overweight and obesity from the Leipzig Childhood Cohort.

Results: Children with overweight/obesity and elevated ALT values had a more than 2-fold increased risk (hazard ratio 2.59, 95% confidence interval 1.49 to 4.50; P < 0.01) for future dysglycemia independent of age, sex and BMI-SDS.

Conclusions: Elevated transaminases are an early predictor for glycemic deterioration. Hence, NAFLD should further be addressed as a risk factor and therapeutic target for the early prevention of type 2 diabetes.
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http://dx.doi.org/10.1111/ijpo.12822DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Motor skills in relation to body-mass index, physical activity, TV-watching, and socioeconomic status in German four-to-17-year-old children.

PLoS One 2021 17;16(5):e0251738. Epub 2021 May 17.

Department of Women and Child Health, University Hospital for Children and Adolescents and Center for Pediatric Research, Leipzig University, Leipzig, Saxony, Germany.

Background: The present study describes motor skills in a large sample of German children and adolescents and investigates associations with age, gender, body-mass index, physical activity, television time, and socioeconomic status.

Methods: 2,106 children (1076 boys, 1030 girls) aged 4 to 17 years performed five different motor tests for strength (pushups, standing long jump), coordination (backward balancing, jumping side-to-side) and flexibility (forward bend) within the framework of the LIFE Child study (Leipzig, Germany). Anthropometric parameters were assessed through standardized measurement. Data on physical activity, television time, and socioeconomic status were collected via questionnaires. Linear regression analyses were applied to assess relations.

Results: Strength and coordination performance were higher in older than in younger children. While boys showed a higher performance in strengths tests than girls, girls performed better in flexibility and coordination during precision tasks (backward balancing). In terms of coordination under time constraint (jumping side-to-side), both genders produced similar results. Lower body-mass index, higher physical activity, and higher socioeconomic status were significantly related to better motor skills. Longer television times were significantly associated with lower performance in long jump.

Conclusions: The present findings are similar to data collected at the beginning of the century, indicating that motor skills have hardly changed in recent years. The findings furthermore suggest that children from lower social strata, children with higher body weight, and children who move little have a higher risk of developing insufficient motor skills and should therefore be given special support.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251738PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128247PMC
May 2021

Psychological well-being of early and continuously treated phenylketonuria patients.

JIMD Rep 2021 May 21;59(1):69-80. Epub 2021 Feb 21.

Hospital for Children and Adolescents, Center for Pediatric Research Leipzig (CPL), Department of Women and Child Health, University Hospital, University of Leipzig Leipzig Germany.

Background: Despite enormous advances in therapy, phenylketonuria (PKU) remains an incurable, inherited metabolic disease requiring life-long treatment with potential to negatively impact quality of life and psychological well-being. Therefore, the aim of this study was to screen early diagnosed and continuously treated children with PKU on psychological strengths and behavioral difficulties.

Methods: Evaluation of psychological strengths and behavioral difficulties in 49 patients with PKU (23f, 2-17 years) by Strengths and Difficulties Questionnaire (SDQ; self-report 11-17 years and parent-report 2-17 years). Comparison to age, sex and BMI-matched healthy controls (n = 98; 46f).

Results: In patients with PKU and healthy controls median SDQ Total Difficulties Score and median scores of subscales were within the normal range in parent- and self-report, irrespective of sex and age group (children 2-10 years, adolescents 11-17 years). No influence of long-term metabolic control in PKU on SDQ could be revealed. The 2- to 10-year-old boys with PKU showed significantly higher scores in Prosocial Behavior compared to their healthy peers ( = .032). Likewise, adolescent boys with PKU showed fewer Conduct Problems (parent-report, = .006). Adolescent girls with PKU rated themselves more often as abnormal in the subscale Emotional Problems compared to their healthy peers ( = .041). This subscale was also responsible for a significantly different Total SDQ Difficulties Score between patients and their parents' report ( = .008).

Discussion: SDQ represents a suitable instrument within the care for patients with PKU. Specific aspects, however, require separate consideration and evaluation with respect to this chronic disease. Special attention should be paid on adolescent PKU girls who seem to be at risk to develop emotional problem.
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http://dx.doi.org/10.1002/jmd2.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100406PMC
May 2021

Impact of short stature on quality of life: A systematic literature review.

Growth Horm IGF Res 2021 Apr-Jun;57-58:101392. Epub 2021 Apr 30.

UCL Great Ormond Street Institute of Child Health, London, UK.

Objective: We sought to obtain a better understanding of the burden of short stature using a systematic literature review.

Methods: Studies of the burden of short stature, of any cause in adults and children, were searched using Embase, MEDLINE and Cochrane databases in April 2020, capturing publications from 2008 onwards. Case series and populations with adult-onset growth hormone deficiency (GHD) were excluded.

Results: Of 1684 publications identified, 41 studies (33 in children, 8 in adults) were included. All studies assessed human burden. Most study populations in children included short stature due to GHD, idiopathic short stature (ISS) and short stature after being born small for gestational age (SGA). In these populations, four studies showed that quality of life (QoL) in children with short stature was significantly worse than in children with normal stature. A significant association between QoL and short stature was observed in children with chronic kidney disease (CKD) (3 studies), achondroplasia (1 study) and transfusion-dependent β-thalassaemia (1 study), and in samples with mixed causes of short stature (3 studies). Three studies (one in GHD/ISS/SGA and two in CKD) found no significant association between short stature and QoL, and several studies did not report statistical significance. Approximately half of adult studies showed that QoL was reduced with short stature, and the other half showed no association. Two studies, one in adults with Prader-Willi syndrome and one in children with GHD, suggested a potential association between short stature and poorer cognitive outcomes. Three studies demonstrated an increased caregiver burden in parents of children with short stature.

Conclusions: Evidence suggests that, compared with those with normal stature, children and adults with short stature of any cause may experience poorer QoL. Further research could extend our understanding of the human burden in this field.
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http://dx.doi.org/10.1016/j.ghir.2021.101392DOI Listing
April 2021

Ocular biometry in children and adolescents from 4 to 17 years: a cross-sectional study in central Germany.

Ophthalmic Physiol Opt 2021 05;41(3):496-511

Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), Leipzig University, Leipzig, Germany.

Purpose: To evaluate ocular biometry in a large paediatric population as a function of age and sex in children of European descent.

Methods: Children were examined as part of the LIFE Child Study (Leipzig Research Centre for Civilization Disease), a population-based study in Leipzig, Germany. Altogether, 1907 children, aged from 4 to 17 years, were examined with the Lenstar LS 900. Data from the right eye was analysed for axial length, central corneal thickness, flat and steep corneal radii, aqueous depth, lens thickness and vitreous depth. Wavefront-based autorefraction was employed for analysis.

Results: Axial length increased in girls from 21.6 mm (4 years) up to 23.4 mm (17 years); this increase (0.174 mm per year) was statistically significant up to age 14 (23.3 mm). Axial length increased in boys from 22.2 mm (4 years) up to 23.9 mm (17 years); this increase (0.178 mm per year) was statistically significant up to age 10 (23.3 mm). No change was observed for central corneal thickness (average: girls 550 µm; boys 554 µm). Corneal curvature in girls was somewhat flatter at age 4 (7.70 mm) compared to age 10 (7.78 mm), whereas it was constant in boys (7.89 mm). Aqueous depth at age 4 was 2.73 mm for girls and 2.86 mm for boys, with the same rate of increase per year (girls: 0.046 mm; boys: 0.047 mm) from age 4 to 10. At age 17, aqueous depth was 3.06 mm in girls and 3.20 mm in boys. Lens thickness was reduced from age 4 (3.75 mm) to age 10 (3.47 mm) in girls and from age 4 (3.73 mm) to age 10 (3.44 mm) in boys, with the same rate of decrease per year of 0.046 and 0.047 mm, respectively. At age 17, lens thickness was 3.52 mm in girls and 3.50 mm in boys. Vitreous depth at age 4 was 14.51 mm for girls and 15.08 mm for boys; with 0.156 mm (girls) or 0.140 mm (boys) increase per year until age 14 (girls: 16.08 mm; boys: 16.48 mm). At age 17, vitreous depth was 16.29 mm in girls and 16.62 mm in boys.

Conclusions: Eye growth (axial length) in girls showed a lag of about four years compared to boys. Aqueous depth increase matches the lens thickness decrease from ages 4 to 10 years in girls and boys. Lens thickness minimum is reached at 11 years in girls and at 12 years in boys. All dimensions of the optical ocular components are closely correlated with axial length. These data may serve as normative values for the assessment of eye growth in central European children and will provide a basis for monitoring refractive error development.
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http://dx.doi.org/10.1111/opo.12814DOI Listing
May 2021

And yet Again: Having Breakfast Is Positively Associated with Lower BMI and Healthier General Eating Behavior in Schoolchildren.

Nutrients 2021 Apr 18;13(4). Epub 2021 Apr 18.

LIFE Child, Hospital for Children and Adolescents, Medical Faculty, Leipzig University, Ph-Rosenthal-Str. 27, 04103 Leipzig, Germany.

Given the high prevalence of childhood overweight, school-based programs aiming at nutritional behavior may be a good starting point for community-based interventions. Therefore, we investigated associations between school-related meal patterns and weight status in 1215 schoolchildren. Anthropometry was performed on-site in schools. Children reported their meal habits, and parents provided family-related information via questionnaires. Associations between nutritional behavior and weight status were estimated using hierarchical linear and logistic regression. Analyses were adjusted for age, socio-economic status, school type, migration background, and parental weight status. Having breakfast was associated with a lower BMI-SDS ( = -0.51, = 0.004) and a lower risk of being overweight (ORj = 0.30, = 0.009), while having two breakfasts resulting in stronger associations (BMI-SDS: = -0.66, < 0.001; risk of overweight: OR = 0.22, = 0.001). Likewise, children who regularly skipped breakfast on school days showed stronger associations (BMI-SDS: = 0.49, < 0.001; risk of overweight: OR = 3.29, < 0.001) than children who skipped breakfast only occasionally (BMI-SDS: = 0.43, < 0.001; risk of overweight: OR = 2.72, = 0.032). The associations persisted after controlling for parental SES and weight status. Therefore, our data confirm the school setting as a suitable starting point for community-based interventions and may underline the necessity of national programs providing free breakfast and lunch to children.
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http://dx.doi.org/10.3390/nu13041351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072724PMC
April 2021

Pediatric Reference Intervals for Thyrotropin, Free Triiodothyronine, and Free Thyroxine and the Relevance of Body Mass Index and Puberty in Measurement Interpretation.

Thyroid 2021 08 21;31(8):1192-1202. Epub 2021 Jun 21.

Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (ILM) Leipzig University, Leipzig, Germany.

The present study aimed to establish age- and sex-specific reference intervals for serum concentrations of thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) in healthy children and adolescents. Additionally, we investigated the association of TSH, fT3, and fT4 with putative influencing factors, such as sex, body mass index (BMI), and puberty. A total of 9404 blood serum samples from 3140 children and adolescents without thyroid affecting diseases were included in determining TSH, fT3, and fT4 levels and age- and sex-specific reference ranges. To investigate the association of TSH, fT3, and fT4 with age, sex, weight status, and the role of puberty-based changes, the hormone levels and BMI values were converted to standard deviation scores (SDS). In general, TSH, fT3, and fT4 were found to be age- and sex-dependent. Puberty was accompanied by decreased TSH, decreased fT3 with a temporary peak in males, and a temporary nadir of fT4 in Tanner stage 3 for both sexes. BMI-SDS was positively associated with TSH-SDS ( = 0.081,  < 0.001); the effect was more pronounced in overweight subjects ( = 0.142,  < 0.01) and insignificantly negative in underweight subjects ( = -0.047,  > 0.05). BMI-SDS was positively associated with fT3-SDS ( = 0.066,  < 0.001) and negatively associated with fT4-SDS ( = -0.135,  < 0.001), with the effect insignificantly less negative in overweight children ( = -0.055,  > 0.05). Age- and sex-specific reference intervals are important for the interpretation of measurements of TSH, fT3, and fT4 in children and adolescents. Influencing factors such as BMI and puberty should be taken into consideration when using measurements of TSH and thyroid hormones in the diagnosis, treatment, and monitoring of thyroid diseases. Clinical Trial Registration number: NCT02550236.
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http://dx.doi.org/10.1089/thy.2020.0780DOI Listing
August 2021

Covid19 pandemic and pediatric endocrinology and metabolism-Are we through with it?

J Pediatr Endocrinol Metab 2021 04 28;34(5):535-537. Epub 2021 Apr 28.

Department of Women & Child Health, Center of Paediatric Research, Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany.

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http://dx.doi.org/10.1515/jpem-2021-2133DOI Listing
April 2021

Atopic diseases in children and adolescents are associated with behavioural difficulties.

BMC Pediatr 2021 04 23;21(1):197. Epub 2021 Apr 23.

Department of Women and Children's Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), Leipzig University, Liebigstrasse 20a, 04103, Leipzig, Germany.

Background: Atopic diseases and behavioural difficulties in children have both been on the rise in recent decades. This study seeks to assess associations between atopic diseases and behavioural difficulties, examining the differences considering child age and how behavioural difficulties were reported (via self-report or parent-report).

Methods: Data on behavioural difficulties, assessed through the Strengths and Difficulties Questionnaire (SDQ), and on atopic diseases, assessed through the participant's medical history, were available for 2701 study participants aged 3 to 18 years. Associations between atopic diseases and behavioural difficulties were evaluated using linear regression analyses. We split the study sample into two groups. I: 3-to 10-year-olds/parent-reported SDQ (n = 1764), II: 11- to 18-year-olds/parent-reported SDQ (n = 937) and self-reported SDQ (n = 915). All analyses were adjusted for age, gender, and socioeconomic status.

Results: In younger children, atopic dermatitis was strongly associated with higher total difficulties scores, more emotional problems and conduct problems, and more symptoms of hyperactivity/inattention. Parents reported higher total difficulties scores, more emotional problems, and more peer-relationship problems for adolescents with bronchial asthma and other allergies, whereas the adolescents themselves reported more peer relationship problems.

Conclusion: In younger children, atopic dermatitis is associated with internalizing and externalizing problems. In adolescents, bronchial asthma and other allergies are associated with a greater level of internalizing problems only. The findings further suggest that parents of adolescents are more likely to perceive associations between atopic diseases and behavioural difficulties than the adolescents themselves.
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http://dx.doi.org/10.1186/s12887-021-02663-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063387PMC
April 2021

Slim Evidence to Suggest Preschoolers Are Emerging from the Obesity Epidemic.

J Pediatr 2021 Sep 16;236:292-296. Epub 2021 Apr 16.

Liggins Institute, University of Auckland, Auckland, New Zealand; A Better Start-National Science Challenge, University of Auckland, Auckland, New Zealand. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2021.04.015DOI Listing
September 2021

COVID-19 pandemic and families' utilization of well-child clinics and pediatric practices attendance in Germany.

BMC Res Notes 2021 Apr 16;14(1):140. Epub 2021 Apr 16.

Leipzig University Hospital for Children and Adolescents, LIFE Child, Leipzig University, Ph.-Rosenthal-Str. 27, 04103, Leipzig, Germany.

Objective: The COVID-19 pandemic and the measures implemented to stop the pandemic had a broad impact on our daily lives. Besides work and social life, health care is affected on many levels. In particular, there is concern that attendance in health care programs will drop or hospital admissions will be delayed due to COVID-19-related anxieties, especially in children. Therefore, we compared the number of weekly visits to 78 German pediatric institutions between 2019 and 2020.

Results: We found no significant differences during the first 10 weeks of the year. However, and importantly, from April, the weekly number of visits was more than 35% lower in 2020 than in 2019 (p = 0.005). In conclusion, the COVID-19 pandemic seems to relate to families´ utilization of outpatient well-child clinics and pediatric practice attendance in Germany.
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http://dx.doi.org/10.1186/s13104-021-05562-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050987PMC
April 2021

Comparison of cardiovascular risk factors between children and adolescents with classes III and IV obesity: findings from the APV cohort.

Int J Obes (Lond) 2021 05 7;45(5):1061-1073. Epub 2021 Apr 7.

German Center for Diabetes Research, Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.

Objective: Obesity is associated with many cardiovascular risk factors (CVRF) in childhood. There is an ongoing discussion whether there is a linear relationship between degree of overweight and deterioration of CVRFs justifying body mass index (BMI) cut-offs for treatment decisions.

Methods: We studied the impact of BMI-SDS on blood pressure, lipids, and glucose metabolism in 76,660 children (aged 5-25 years) subdivided in five groups: overweight (BMI-SDS 1.3 to <1.8), obesity class I (BMI-SDS 1.8 to <2.3), class II (BMI-SDS 2.3-2.8), class III (BMI-SDS > 2.8-3.3), and class IV (BMI-SDS > 3.3). Analyses were stratified by age and sex.

Results: We found a relationship between BMI-SDS and blood pressure, triglycerides, HDL cholesterol, liver enzymes, and the triglycerides-HDL-cholesterol ratio at any age and sex. Many of these associations lost significance when comparing children with obesity classes III and IV: In females < 14 years and males < 12 years triglycerides and glucose parameters did not differ significantly between classes IV and III obesity. Prevalence of dyslipidemia was significantly higher in class IV compared to class III obesity only in females ≥ 14 years and males ≥ 12 years but not in younger children. In girls < 14 years and in boys of any age, the prevalences of type 2 diabetes mellitus did not differ between classes III and IV obesity.

Conclusions: Since a BMI above the highest BMI cut-off was not associated consistently with dyslipidemia and disturbed glucose metabolism in every age group both in boys and girls, measurements of CVRFs instead of BMI cut-off seem preferable to guide different treatment approaches in obesity such as medications or bariatric surgery.
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http://dx.doi.org/10.1038/s41366-021-00773-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081660PMC
May 2021

Persistent organic pollutants in pregnant women potentially affect child development and thyroid hormone status.

Pediatr Res 2021 Apr 6. Epub 2021 Apr 6.

Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), Leipzig University, Leipzig, Germany.

Background: Potentially harmful effects of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) on prenatal development and the endocrine system have been controversially discussed.

Methods: Working with a German cohort of 324 pregnant women, we assessed POP levels and used robust linear regression models to determine potential associations between maternal POP concentrations and pre- and postnatal development in the children, as well as the thyroid hormone status of the mother and child.

Results: Maternal p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and most measured PCBs positively correlated with postnatal weight gain. We detected no correlation between newborn birth weight and head circumference, respectively, and maternal PCB and p,p'-DDE serum levels, while body length at birth was negatively associated with the maternal serum concentration of PCB 183. Maternal p,p'-DDE and nearly all PCB serum levels showed a negative correlation with maternal free triiodothyronine (FT3). p,p'-DDE and PCB 74 and 118 were negatively associated with maternal thyroid-stimulating hormone levels. In addition, we identified significant associations between maternal POP levels and thyroid hormone parameters of the child.

Conclusions: These results indicate that POP exposure likely affects different aspects of pre- and postnatal development and impacts the thyroid hormone status of both mother and child.

Impact: Pregnant women in a German cohort display a substantial accumulation of POPs. Body mass index and age influence maternal serum POP levels. Maternal POP levels show correlations with the child's length at birth and weight gain, and FT3 levels in the mother and child. Our data provide additional evidence for the potentially harmful influence of POPs. Our data indicate that POPs influence pre- and postnatal development.
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http://dx.doi.org/10.1038/s41390-021-01488-5DOI Listing
April 2021

Longitudinal analysis of axial length growth in a German cohort of healthy children and adolescents.

Ophthalmic Physiol Opt 2021 05 1;41(3):532-540. Epub 2021 Apr 1.

Leipzig Research Center for Civilization Diseases (LIFE), Leipzig University, Leipzig, Germany.

Purpose: To generate continuous growth curves for axial length (AL) in German children. We hypothesise that percentile curves of AL can be used as a predictive measure of myopia.

Methods: In this longitudinal and cross-sectional LIFE Child Study, children's non-cycloplegic refraction data was collected using the Zeiss i.Profiler plus while AL was measured using the Haag-Streit Lenstar. Reference growth curves were estimated as a continuous non-parametric function of age.

Results: Data from 4511 visits of 1965 participants (1021 boys and 944 girls) between 3 and 18 years of age were analysed. For all ages and percentiles, the estimated AL was higher in boys than girls. AL differences between boys and girls were most pronounced in the 98 percentile at 3 years of age, being 0.93 mm longer eyes in boys. This difference decreased to 0.21 mm at 18 years of age. While the lower percentiles of AL reach their final value around age 13, the 50 percentile was still increasing by 0.05 mm per year until the end of the observation period. While, in general, children with longer eyes are more likely to develop myopia, this relationship is weaker between the ages of 5 and 8.

Conclusion: The LIFE Child Study data provides European AL data. In both Germany and China, AL has comparable growth rates when the baseline ALs are compared as percentiles. Thus, percentile curves of AL can be used as a predictive measure for the likelihood of developing as well as the progression of myopia.
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http://dx.doi.org/10.1111/opo.12817DOI Listing
May 2021
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