How the COVID-19 pandemic and related school closures reduce physical activity among children and adolescents in the WHO European Region: a systematic review and meta-analysis.

BACKGROUND: Emerging research suggests that physical activity among children and adolescents decreased during the COVID-19 pandemic. However, a differentiated overview of European youth is lacking. In particular, no systematic analysis has been conducted to date on the impact of heterogeneous pandemic restrictions and school closures within European countries, and with regard to potentially vulnerable groups. METHODS: We searched seven databases and included studies for children and adolescents (≤ 19 years) of the WHO European Region that compared physical activity during the COVID-19 pandemic with a pre-pandemic baseline using validated measurement instruments. We used the Oxford Stringency Index and School Closure Index as indicators of restriction stringency. Screening for eligibility, data extraction, assessment of the study risk of bias (using the 'Risk of Bias in Non-randomized Studies - of Exposure' [ROBINS-E]) and certainty grading of evidence (using the GRADE approach), were all done in duplicate. Unpublished data was requested from study authors. Data were pooled in random effects models. An a priori protocol was published, reporting is carried out in accordance with the 'Preferred Reporting Items for Systematic Review and Meta-Analyses' (PRISMA) statement. RESULTS: Of 14,897 non-duplicate records, 26 publications (n = 15,038 pre-pandemic, n = 13,041 during pandemic) met full inclusion criteria. Comparison before and during the COVID-19 pandemic revealed a significant reduction in total physical activity (standardized mean difference [SMD], -0.57 [95%CI, -0.95; -0.20]) and moderate-to-vigorous physical activity (SMD, -0.43 [95% CI, -0.75; -0.10]), corresponding to a decrease of 12 min per day (a 20% reduction of the WHO recommendation). A decrease in sporting activity was also recorded. Subgroup analyses suggested that middle childhood (aged 8-12) and adolescents were particularly affected by the decline. School closures were associated with a reduction in physical activity. The certainty of evidence for all outcomes was low. CONCLUSIONS: A sharp decline in all forms of physical activity was recorded among European children and adolescents during the COVID-19 pandemic. This decline was higher during periods of school closure and mainly affected younger schoolchildren and adolescents. Immediate action by policy-makers and practitioners, as well as evidence-based public health strategies, are imperative in reversing this trend. TRIAL REGISTRATION: PROSPERO: CRD42023395871.

Physical activity and physical fitness among children and adolescents after the onset of the COVID-19 pandemic in the WHO European Region: a systematic review protocol.

INTRODUCTION: The implementation of COVID-19 pandemic-related restrictions resulted in limitations for physical activity (PA) opportunities, which may have initiated a longer-term behavioural change. The protocol describes the methodology for a planned systematic review that aims to summarise changes in PA and physical fitness (PF) in children and adolescents in the WHO European Region after the onset of the COVID-19 pandemic. METHODS AND ANALYSIS: The protocol adheres to the 'Preferred Reporting Items for Systematic Review and Meta-Analysis for Protocols' (PRISMA-P) statement. Using a peer-reviewed search strategy according to the evidence-based checklist 'Peer Review of Electronic Search Strategies' (PRESS), we will perform a systematic literature search in seven databases. Inclusion criteria are all primary studies that gathered data on children and adolescents ≤19 years living in the WHO European Region and made a comparison to pre-pandemic data. Primary outcomes are PA and PF. We will assess the risk of bias with the 'Risk of Bias Instrument for Non-Randomized Studies of Exposures' (ROBINS-E). The 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) approach will be used for the evaluation of the certainty of evidence. Also, subgroup analyses will be performed (eg, for gender, age, stringency of pandemic restrictions). ETHICS AND DISSEMINATION: Ethical approval is not required, as primary data will not be collected in this study. The results will be presented in a peer-reviewed publication and at congresses relevant to the research field. PROSPERO REGISTRATION NUMBER: CRD42023395871.

Anxiety increased among children and adolescents during pandemic-related school closures in Europe: a systematic review and meta-analysis.

BACKGROUND: Considering the heterogenous evidence, a systematic review of the change in anxiety in European children and adolescents associated with the COVID-19 pandemic is lacking. We therefore assessed the change compared with pre-pandemic baselines stratified by gender and age as well as evaluated the impact of country-specific restriction policies. METHODS: A registration on the 'International Prospective Register of Systematic Reviews' (PROSPERO) occurred and an a priori protocol was published. We searched six databases (PubMed, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, Web of Science, WHO COVID-19) using a peer-reviewed search string with citation tracking and grey literature screening. Primary outcomes were: (1) general anxiety symptoms; and (2) clinically relevant anxiety rates. We used the Oxford COVID-19 Stringency Index as an indicator of pandemic-related restrictions. Screening of title/abstract and full text as well as assessing risk of bias (using the 'Risk of Bias in Non-randomized Studies of Exposure' [ROBINS-E]) and certainty of evidence (using the 'Grading of Recommendations Assessment, Development and Evaluation' [GRADE]) was done in duplicate. We pooled data using a random effects model. Reporting is in accordance with the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) statement. RESULTS: Of 7,422 non-duplicate records, 18 studies with data from 752,532 pre-pandemic and 763,582 pandemic participants met full inclusion criteria. For general anxiety symptoms the total change effect estimate yielded a standardised mean difference (SMD) of 0.34 (95% confidence interval [CI], 0.17-0.51) and for clinically relevant anxiety rates we observed an odds ratio of 1.08 (95%-CI, 0.98-1.19). Increase in general anxiety symptoms was highest in the 11-15 years age group. Effect estimates were higher when pandemic-related restrictions were more stringent (Oxford Stringency Index > 60: SMD, 0.52 [95%-CI, 0.30-0.73]) and when school closures (School Closure Index ≥ 2: SMD, 0.44 [95%-CI, 0.23-0.65]) occurred. CONCLUSION: General anxiety symptoms among children and adolescents in Europe increased in a pre/during comparison of the COVID-19 pandemic; particularly for males aged 11-15 years. In periods of stringent pandemic-related restrictions and/or school closures a considerable increase in general anxiety symptoms could be documented. PROSPERO registration: CRD42022303714.

Anxiety among children and adolescents during the COVID-19 pandemic in Europe: a systematic review protocol.

BACKGROUND: A growing number of studies point to a high mental health burden among children and adolescents during the COVID-19 pandemic, particularly concerning anxiety. However, the study quality and effect direction are heterogeneous in the existing primary studies with a lacking overview for the European continent. Therefore, this systematic review aims to critically synthesise the evidence regarding the impact of the COVID-19 pandemic on anxiety among children and adolescents in Europe compared to a pre-pandemic baseline. METHODS: A systematic literature search will be performed in six databases (MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, Web of Science, and WHO COVID-19 database) with a peer reviewed search strategy according to the evidence-based checklist Peer Review of Electronic Search Strategies (PRESS). Inclusion criteria are children and adolescents ≤ 19 years living in Europe and data report during the COVID-19 pandemic with an appropriate pre-pandemic baseline. Primary outcomes are general anxiety symptoms and clinically relevant anxiety rates. Risk of bias will be assessed using the 'Risk of Bias in Non-randomised Studies of Exposure' (ROBINS-E). Data extraction will systematically include information on study design, population characteristics, COVID-19 determinants, pre-pandemic baseline, diagnostic instruments and outcome. The certainty of evidence for each outcome will be evaluated by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach adapted to the use of non-randomised studies. All process steps will be performed independently by two reviewers; any discrepancies will be discussed and, if necessary, resolved by a third author. Also, subgroup analysis, sensitivity analysis, publication bias analysis, and meta-regression analysis, if applicable, will be performed. The systematic review was registered in the Prospective Register of Systematic Reviews (PROSPERO) and the protocol was prepared in accordance to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. DISCUSSION: This systematic review will address the lack of a critical and comprehensive summary of findings on the COVID-19 pandemic impact on anxiety among children and adolescents in Europe. In addition, it aims to identify pandemic-policy differences, such as the effect of school-closures, and identify particularly vulnerable risk groups. SYSTEMATIC REVIEW REGISTRATION: CRD42022303714 (PROSPERO).

Increase of depression among children and adolescents after the onset of the COVID-19 pandemic in Europe: a systematic review and meta-analysis.

BACKGROUND: Research points to a high depression burden among youth during the COVID-19 pandemic; however, a lack of systematic evidence exists. We determine the change in depression symptoms among children and adolescents during COVID-19 compared to pre-pandemic baselines. By using country differences in pandemic-related restrictions and school closures in Europe as quasi-experimental design, we evaluate policy impacts on depression. METHODS: In this systematic review and meta-analysis, following the PRISMA statement, we searched six databases (MEDLINE, EMBASE, PsycINFO, Cochrane Central, Web of Science, WHO COVID-19) using a peer-reviewed search string up until March 18, 2022 with citation tracking and grey literature searches. No limitations regarding language and effect measures existed. We included studies that compared (1) general depression symptoms or (2) clinically relevant depression rates in children and adolescents (≤ 19 years) before and during the COVID-19 pandemic in Europe. The validated Oxford Stringency Index was used as indicator for pandemic-related restrictions. Screening for eligibility, extracting data from published reports and from unpublished data requested directly from study authors, assessing the study risk of bias and grading certainty of evidence using the GRADE approach, were all done in duplicate. Data were pooled in a random-effects model. PROSPERO: CRD42022303714. RESULTS: Of 7,422 nonduplicate records, 22 studies with data from 868,634 participants pre-pandemic and 807,480 during pandemic, met full inclusion criteria. For the comparison of depression symptoms before and during the COVID-19 pandemic, moderate certainty of evidence was observed for general depression symptoms (standardized mean difference, 0.21 [95%CI, 0.12-0.30]; I2 = 94%) and low certainty of evidence for clinically relevant depression rates (odds ratio, 1.36 [95%CI, 1.05-1.76]; I2 = 95%) for total population. Increase in general depression symptoms was higher for male adolescents, whereas increase in clinically relevant depression rates was higher for females. Effect estimates were significantly higher when pandemic-related restrictions were more stringent or school closure occurred. CONCLUSION: An increase in depression symptoms occurred in a pre-pandemic vs. during-pandemic comparison within the COVID-19 pandemic, whereby pandemic-related restrictions (such as school closures) resulted in a considerable effect increase. Ensuring adequate supply of mental health recovery services and long-term monitoring is of high public health relevance.

Maternal pregnancy weight or gestational weight gain and offspring's blood pressure: A systematic review.

AIMS: An increasing number of studies suggest that maternal weight parameters in pregnancy are associated with offspring's blood pressure (BP). The aim of this systematic review - following the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement - was to assess and judge the evidence for an association between maternal pregnancy weight/body mass index (BMI) or gestational weight gain (GWG) with offspring's BP in later life. DATA SYNTHESIS: MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science were searched without limits. Risk of bias was assessed using the "US National Heart, Lung and Blood Institute"-tool, and an evidence grade was allocated following the "World Cancer Research Fund" criteria. Of 7,124 publications retrieved, 16 studies (all cohort studies) were included in the systematic review. Overall data from 52,606 participants (0 years [newborns] to 32 years) were enclosed. Association between maternal pregnancy BMI and offspring's BP were analyzed in 2 (both "good-quality" rated) studies, without consistent results. GWG and offspring's BP was analyzed in 14 studies (2 "good-quality", 9 "fair-quality", 3 "poor-quality" rated). Of these, 3 "fair-quality" studies described significant positive results for systolic BP and significant results, but partly with varying directions of effect estimates for diastolic BP. Mean arterial pressure (MAP) was analyzed in 1 "poor-quality" congress paper. Overall, based on the small number of "good-quality"-rated studies and the inconsistency of effect direction, no firm conclusion can be drawn. CONCLUSION: Evidence for an association of maternal pregnancy weight determinants with offspring's BP was overall graded as "limited - no conclusion".

Early life factors and their relevance for markers of cardiometabolic risk in early adulthood.

BACKGROUND AND AIMS: Early life exposures could be pertinent risk factors of cardiometabolic diseases in adulthood. We assessed the prospective associations of early life factors with markers of cardiometabolic risk among healthy German adults. METHODS AND RESULTS: We examined 348 term-born DONALD Study participants with measurement of fasting blood at the age of 18-24 years to assess metabolic indices: fatty liver index (FLI), hepatic steatosis index (HSI), pro-inflammatory score and insulin sensitivity (HOMA2-%S). Early life factors (maternal weight in early pregnancy, maternal early pregnancy BMI, gestational weight gain (GWG), maternal age, birth weight and full breastfeeding (>17 weeks)) were assessed at enrolment of the offspring into the study. Multivariable linear regression models were used to analyze associations between early life factors and markers of cardiometabolic risk in early adulthood with adjustment for potential confounders. A higher early pregnancy BMI was related to notably higher levels of offspring FLI, HSI, pro-inflammatory score and a lower HOMA2-%S (all p < 0.0001). Similarly, a higher gestational weight gain was associated with a higher FLI (p = 0.044), HSI (p = 0.016), pro-inflammatory score (p = 0.032) and a lower HOMA2-%S among females (p = 0.034). Full breastfeeding was associated with a lower adult FLI (p = 0.037). A casual mediation analysis showed that these associations were mediated by offspring adult waist circumference (WC). CONCLUSION: This study suggests that early pregnancy BMI, gestational weight gain, and full breastfeeding are relevant for offspring markers of cardiometabolic risk which seems to be mediated by body composition in young adulthood.

Maternal prepregnancy BMI or weight and offspring's blood pressure: Systematic review.

Emerging evidence suggests that maternal prepregnancy body mass index or weight (MPBW) may be associated with offspring's blood pressure (BP). Therefore, we conducted a systematic review-following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement-to assess and judge the evidence for an association between MPBW with offspring's later BP. Five data bases were searched without limits. Risk of bias was assessed using the "Tool to Assess Risk of Bias in Cohort Studies," and an evidence grade was allocated following the World Cancer Research Fund criteria. Of 2,011 publications retrieved, 16 studies (all cohort studies) were included in the systematic review; thereof, 5 studies (31%) were rated as good-quality studies. Overall, data from 63,959 participants were enclosed. Systolic BP was analysed in 15 (5 good quality), diastolic BP in 12 (3 good quality), and mean arterial pressure in 3 (no good quality) studies. Five good-quality studies of MPBW with offspring's systolic BP as the outcome and 1 good-quality study with offspring's diastolic BP as the outcome observed a significant association. However, after adding offspring's anthropometry variables to the statistical model, the effect attenuated in 4 studies with systolic BP to nonsignificance, the study with diastolic BP remained significant. No good-quality studies were found with respect to offspring's later mean arterial pressure. In conclusion, this systematic review found suggestive, but still limited, evidence for an association between MPBW with offspring's later BP. The available data suggest that the effect might be mainly mediated via offspring's anthropometry.

Access to Difficult-to-reach Population Subgroups: A Family Midwife Based Home Visiting Service for Implementing Nutrition-related Preventive Activities - A Mixed Methods Explorative Study.

Health and social inequality are tightly linked and still pose an important public health problem. However, vulnerable and disadvantaged populations are difficult to reach for health-related interventions. Given the long-lasting effects of an adverse, particular nutrition-related, intrauterine and neonatal environment on health development (perinatal programming), an early and easy access is essential for sustainable interventions. The goal of this explorative study was therefore to elucidate whether an existing access of family midwives (FMs) to families in need of support could be an option to implement effective public health and nutrition interventions. To that end three research objectives were formulated: (1) to determine whether a discernible impact of home visits by FMs can be described; (2) to identify subgroups among these families in need of more specific interventions; (3) to determine how relevant nutrition-related topics are for both FMs and the supported families. For addressing these objectives a mixed methods design was used: Routine documentation data from 295 families visited by a family midwife (FM) were analyzed (secondary analysis), and structured expert interviews with FMs were conducted and analyzed. Study reporting followed the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) statement. Based on the FMs reports, a significant improvement (p < 0.001) regarding psycho-social variables could be determined after the home visits. Single mothers, however, seemed to benefit less from the FMs service compared to their counterparts (p = 0.015). Nutritional counseling was demanded by 89% of the families during the home visits. In addition, nutrition-related topics were reported in the interviews to be of high interest to both families and the FMs. Based on the obtained results it is concluded that FMs home visits offer a promising access to vulnerable and disadvantaged families for implementing nutrition-related preventive activities.

Breastfeeding and its prospective association with components of the GH-IGF-Axis, insulin resistance and body adiposity measures in young adulthood--insights from linear and quantile regression analysis.

BACKGROUND: Breastfeeding may lower chronic disease risk by long-term effects on hormonal status and adiposity, but the relations remain uncertain. OBJECTIVE: To prospectively investigate the association of breastfeeding with the growth hormone- (GH) insulin-like growth factor- (IGF) axis, insulin sensitivity, body composition and body fat distribution in younger adulthood (18-37 years). DESIGN: Data from 233 (54% female) participants of a German cohort, the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study, with prospective data on infant feeding were analyzed. Multivariable linear as well as quantile regression were performed with full breastfeeding (not: ≤ 2, short: 3-17, long: >17 weeks) as exposure and adult IGF-I, IGF binding proteins (IGFBP) -1, -2, -3, homeostasis model assessment of insulin resistance (HOMA-IR), fat mass index, fat-free mass index, and waist circumference as outcomes. RESULTS: After adjustment for early life and socio-economic factors, women who had been breastfed longer displayed higher adult IGFBP-2 (p(trend) = 0.02) and lower values of HOMA-IR (p(trend) = 0.004). Furthermore, in women breastfeeding duration was associated with a lower mean fat mass index (p(trend) = 0.01), fat-free mass index (p(trend) = 0.02) and waist circumference (p(trend) = 0.004) in young adulthood. However, there was no relation to IGF-I, IGFBP-1 and IGFBP-3 (all p(trend) > 0.05). Associations for IGFBP-2 and fat mass index were more pronounced at higher, for waist circumference at very low or high percentiles of the distribution. In men, there was no consistent relation of breastfeeding with any outcome. CONCLUSIONS: Our data suggest that breastfeeding may have long-term, favorable effects on extremes of adiposity and insulin metabolism in women, but not in men. In both sexes, breastfeeding does not seem to induce programming of the GH-IGF-axis.

Isoform-specific regulation of Akt signaling by the endosomal protein WDFY2.

Recent work has led to the identification of novel endocytic compartments with functional roles in both protein trafficking and growth factor signal transduction. The phosphatidylinositol 3-phosphate binding, FYVE domain-containing protein WDFY2 is localized to a distinct subset of early endosomes, which are localized close to the plasma membrane. Here, we find that the serine/threonine kinase Akt interacts with these endosomes in an isoform-specific manner. Using quantitative fluorescence microscopy we demonstrate specific co-localization of WDFY2 with endogenous Akt2, but not Akt1. Moreover, depletion of WDFY2 leads to impaired phosphorylation of Akt in response to insulin due to isoform specific reduction of Akt2, but not Akt1, protein levels, and to a marked reduction in the insulin-stimulated phosphorylation of numerous Akt substrates. This is accompanied by an impairment in insulin-stimulated glucose transport and, after prolonged silencing, a reduction in the level of expression of adipogenic genes. We propose that WDFY2-enriched endosomes serve as a scaffold that enables specificity of insulin signaling through Akt2.

Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.

Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.

Beta-cell PDE3B regulates Ca2+-stimulated exocytosis of insulin.

cAMP signaling is important for the regulation of insulin secretion in pancreatic beta-cells. The level of intracellular cAMP is controlled through its production by adenylyl cyclases and its breakdown by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE3B is involved in the regulation of nutrient-stimulated insulin secretion. Here, aiming at getting deeper functional insights, we have examined the role of PDE3B in the two phases of insulin secretion as well as its localization in the beta-cell. Depolarization-induced insulin secretion was assessed and in models where PDE3B was overexpressed [islets from transgenic RIP-PDE3B/7 mice and adenovirally (AdPDE3B) infected INS-1 (832/13) cells], the first phase of insulin secretion, occurring in response to stimulation with high K(+) for 5 min, was significantly reduced ( approximately 25% compared to controls). In contrast, in islets from PDE3B(-/-) mice the response to high K(+) was increased. Further, stimulation of isolated beta-cells from RIP-PDE3B/7 islets, using successive trains of voltage-clamped depolarizations, resulted in reduced Ca(2+)-triggered first phase exocytotic response as well as reduced granule mobilization-dependent second phase, compared to wild-type beta-cells. Using sub-cellular fractionation, confocal microscopy and transmission electron microscopy of isolated mouse islets and INS-1 (832/13) cells, we show that endogenous and overexpressed PDE3B is localized to insulin granules and plasma membrane. We conclude that PDE3B, through hydrolysis of cAMP in pools regulated by Ca(2+), plays a regulatory role in depolarization-induced insulin secretion and that the enzyme is associated with the exocytotic machinery in beta-cells.

Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B.

Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether beta-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a beta-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyper-glycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located alpha-cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of beta-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.