Purpose

An inverse relationship between mental health problems and academic achievement is a well-known phenomenon in the scientific literature. However, how and when this association develops is not fully understood and there is a lack of longitudinal, population-based studies on young children. Early intervention is important if associations are to be found already during childhood. The aim of the present study was to investigate the development of the association between mental health and academic performance during different developmental periods of childhood and adolescence.

Methods

Data from a longitudinal birth cohort study of 1700 children were used. Child mental health was assessed through mother’s reports at age 3, and self-reports at age 12 and 20. Academic performance was assessed through teacher reports on educational results at age 12 and final grades from compulsory school (age 15–16) and upper secondary school (age 18–19). The association between mental health and academic performance was assessed through regression models.

Results

The results indicate that social selection mechanisms are present in all three periods studied. Behavioral and emotional problems at age 3 were associated with performing below grade at age 12. Similarly, mental health problems at age 12 were associated with lack of complete final grades from compulsory school and non-eligibility to higher education. Academic performance at ages 15 and 19 did not increase the risk for mental health problems at age 20.

Conclusion

Mental health problems in early childhood and adolescence increase the risk for poor academic performance, indicating the need for awareness and treatment to provide fair opportunities to education.

Background The influence of maternal temperament on child behavior, and whether maternal temperament impact boys and girls differently is not thoroughly studied. The aim was to investigate the impact of maternal temperament and character on child externalizing and internalizing problems at age 3. Methods A birth-cohort of 1723 mothers and their children were followed from birth to age 3. At the childs age of 3 months, the mothers filled out standardized instruments on their temperament and character using the Temperament and Character Inventory (TCI) and depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS). At the childs age of 3 years, the mothers reported on child behavior using the Child Behaviour Checklist (CBCL). Results Maternal temperamental trait novelty seeking was positively associated with externalizing problems in the total population and in girls. Harm avoidance was positively associated with externalizing problems in the total population and in boys, and with internalizing problems in the total population and boys and girls respectively. Maternal character traits of self-directedness and cooperativeness were negatively associated with both externalizing and internalizing problems in the total population and in boys and girls respectively. Conclusions Maternal character traits were more influential on child behavior than were temperamental traits, and thus the opportunities for intervention targeted at parental support are good. Maternal mental health and socioeconomic aspects also increased the risk for child behavior problems, indicating the need for recognition and support in clinical settings.

Objective: Mental illness is increasing among young people and likewise the request for health care services. At the same time, somatic comorbidity is common in children and adolescents with psychiatric disorders. There is a lack of studies on health care use in children and adolescents, and the hypothesis was that children and adolescents with psychiatric disorders use more primary-, and specialized somatic health care compared to children without psychiatric disorders. Methods: In this retrospective population-based register study, all individuals aged 3-17 years living in Vastra Gotaland region in Sweden in 2017 were included (n = 298,877). Linear and Poisson regression were used to compare health care use during 2016-2018 between children with and without psychiatric diagnoses, controlling for age and gender. The results were reported as unstandardised beta coefficient (beta) and adjusted prevalence ratio (aPR) respectively. Results: Having a psychiatric diagnosis was associated with more primary care visits (beta 2.35, 95% CI 2.30-2.40). This applied to most diagnoses investigated. Girls had more primary care visits than boys. Likewise, individuals with psychiatric diagnoses had more specialized somatic outpatient care (beta 1.70, 95% CI 1.67-1.73), both planned and unplanned (beta 1.23, 95% CI 1.21-1.25; beta 0.18, 95% CI 0.17-0.19). Somatic inpatient care was more common in those having a psychiatric diagnosis (aPR 1.65, 95% CI 1.58-1.72), with the diagnoses of psychosis and substance use exerting the greatest risk. Conclusions: Psychiatric diagnoses were associated with increased primary-, somatic outpatient- as well as somatic inpatient care. Increased awareness of comorbidity and easy access to relevant health care could be beneficial for patients and caregivers. The results call for a review of current health care systems with distinct division between medical disciplines and levels of health care.

PurposeEven though the mechanisms behind the development of depression and internalizing problems remains unknown, many different factors have been shown to increase the risk. Longitudinal studies enable the investigation of exposure during different developmental periods during childhood. This study aims to examine factors associated with depressive and internalizing problems at age 20 in terms of sociodemographic factors, previous mental health problems and stressful life events during childhood, adolescence, and early adulthood.MethodsA birth cohort of 1723 children were followed to age 20. At the 20-year follow-up, n = 731 (44%) participated. Standardized instruments were filled out at baseline and the 3-,12- and 20-year follow-ups.ResultsDepressive problems at age 20 were associated with female gender, experience of interpersonal life events reported at age 20, bullying victimization and reports on paternal mental health problems. Participants with depressive problems were also less likely to have experienced adolescence as happy and to report that their father had been a good father. Internalizing problems at age 20 were, in addition, associated with internalizing problems at age 12 and reports on maternal mental health problems. Internalizing problems were associated with a lower likelihood of experiencing adolescence as happy in the final model.ConclusionRecent events (i.e. interpersonal life events and bullying) seemed to be the most influential factors on the development of internalizing and depressive problems. Internalizing problems during childhood increased the risk for internalizing problems in early adulthood, emphasizing the importance of early intervention. Fewer factors were found to increase the risk for depressive problems compared to internalizing problems.

Background Unintentional injuries are a leading cause of morbidity and mortality in children of all ages. Prevention strategies require knowledge of risk factors, and behavior and psychiatric disorders have been suggested to influence the risk of injury during childhood. While externalizing disorders have been found to increase the risk for injuries, results are mixed regarding internalizing disorders, such as affective and anxiety conditions, and Autism Spectrum Disorders (ASD). There is a need for large scale studies relying on robust data sources. The aim of the present study was to examine the association between psychiatric disorders and injuries requiring medical attention, in a large population-based cohort of 350,000 children and adolescents in Sweden. Methods Data were obtained from the regional health care database Vega. Psychiatric diagnoses and injury diagnoses obtained during 2014-2018 for individuals aged 0-17 years in 2016 were extracted. Descriptive statistics were used to examine differences in 5-year injury prevalence between children with and without different psychiatric diagnoses. Logistic regression was used in age-stratified models to test the association between psychiatric diagnoses and injuries requiring medical attention. Results The results show an increased risk for concurrent injuries in general, but the patterns vary by age and psychiatric disorder. Externalizing disorders and anxiety conditions were associated with concurrent injuries, while individuals with ASD had a lower risk for most injuries included. Affective disorders were associated with an increased risk for wounds, concussion, complications and poisoning, while the risk for fractures was decreased. Self-inflicted injury was more common in all psychiatric conditions investigated during adolescence, except for ASD. Children and adolescents with many types of psychiatric disorders were also at increased risk for a concurrent maltreatment diagnosis. Conclusions A general pattern of increased risk for concurrent injuries in children and adolescents with most psychiatric diagnoses was found, but the associations vary by age and type of psychiatric disorder. The results add to the literature on risk factors for injuries in children and adolescents, supporting diagnosis specific patterns. Several psychiatric diagnoses were associated with a marked increase in injury risk, indicating a high burden of disease for affected individuals.

Introduction

There is a need for a fast, efficient and safe way to induce tolerance in patients with severe allergic rhinitis. Intralymphatic immune therapy has been shown to be effective.

Methods

Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abello), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analysed by flow cytometry and Luminex.

Results

The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment with one or two allergens. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased 3 years after treatment.

Conclusions

Intralymphatic immunotherapy with one or two allergens in patients with grass and birch pollen allergy was safe, effective and may be associated with bystander immune modulatory responses.

IntroductionThere is a need to evaluate the safety and efficacy of intralymphatic immunotherapy (ILIT) for inducing tolerance in patients with allergic rhinitis. MethodsThirty-seven patients with seasonal allergic symptoms to birch and grass pollen and skin prick test >3 mm and/or IgE to birch and timothy >0.35 kU/L were randomized to either ILIT, with three doses of 0.1 mL of birch pollen and 5-grass pollen allergen extracts on aluminium hydroxide (10,000 SQ-U/ml; ALK-Abello) or placebo using ultrasound-guided intralymphatic injections at monthly intervals. Daily combined symptom medical score and rhinoconjunctivitis total symptom score were recorded during the peak pollen seasons the year before and after treatment. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were recorded annually starting 2 years after treatment. Circulating proportions of T helper cell subsets and allergen-induced cytokine and chemokine production were analysed using flow cytometry and ELISA. ResultsThere were no differences between the groups related to daily combined symptom medical score the year before and after treatment. Two years after ILIT (after unblinding), the actively treated group reported significantly fewer symptoms, lower medication use and improved quality of life than did the placebo group. After the pollen seasons the year after ILIT, T regulatory cell frequencies and grass-induced IFN-gamma levels increased only in the actively treated group. ConclusionIn this randomized controlled trial, ILIT with birch and grass pollen extract was safe and accompanied by immunological changes. Further studies are required to confirm or refute the efficacy of the treatment.

BackgroundThe immunomodulatory capacity of breast milk may partially be mediated by microRNAs (miRNA), small RNA molecules that regulate gene expression on a post-transcriptional level and are hypothesized to be involved in modulation of immunological pathways. Here, we evaluate the expression of immune-related miRNAs in breast milk after pre- and postnatal supplementation with Limosilactobacillus reuteri and omega-3 (omega-3) polyunsaturated fatty acids (PUFAs), and the association to infant regulatory T cell (Treg) frequencies. MethodsOne-hundred and twenty women included in a double-blind, randomized, placebo-controlled allergy intervention trial received L. reuteri and/or omega-3 PUFAs daily from gestational week 20. Using Taqman qPCR, 24 miRNAs were analyzed from breast milk obtained at birth (colostrum) and after 3 months (mature milk) of lactation. The proportion of activated and resting Treg cells were analyzed in infant blood using flow cytometry at 6, 12, and 24 months. ResultsRelative expression changed significantly over the lactation period for most of the miRNAs; however, the expression was not significantly influenced by any of the supplements. Colostrum miR-181a-3p correlated with resting Treg cell frequencies at 6 months. Colostrum miR-148a-3p and let-7d-3p correlated with the frequencies of activated Treg cells at 24 months, as did mature milk miR-181a-3p and miR-181c-3p. ConclusionMaternal supplementation with L. reuteri and omega-3 PUFAs did not significantly affect the relative miRNA expression in breast milk. Interestingly, some of the miRNAs correlate with Treg subpopulations in the breastfed children, supporting the hypothesis that breast milk miRNAs could be important in infant immune regulation. Trial registrationClinicalTrials.gov-ID: NCT01542970.

Aims Albuminuria is strongly associated with risk of renal dysfunction, cardiovascular disease and mortality. However, clinical guidelines diverge, and evidence is sparse on what risk factor levels regarding blood pressure, blood lipids and BMI are needed to prevent albuminuria in adolescents and young adults with type 1 diabetes. Methods A total of 9347 children and adults with type 1 diabetes [mean age 15.3 years and mean diabetes duration 1.4 years at start of follow-up] from The Swedish National Diabetes Registry were followed from first registration until end of 2017. Levels for risk factors for a risk increase in nephropathy were evaluated, and the gradient of risk per 1 SD (standard deviation) was estimated to compare the impact of each risk factor. Results During the follow-up period, 8610 (92.1%) remained normoalbuminuric, 737 (7.9%) individuals developed micro- or macroalbuminuria at any time period of whom 132 (17.9% of 737) individuals developed macroalbuminuria. Blood pressure >= 140/80 mmHg was associated with increased risk of albuminuria (p <= 0.0001), as were triglycerides >= 1.0 mmol/L (p = 0.039), total cholesterol >= 5.0 mmol/L (p = 0.0003), HDL < 1.0 mmol/L (p = 0.013), LDL 3.5- < 4.0 mmol/L (p = 0.020), and BMI >= 30 kg/m(2) (p = 0.033). HbA1c was the strongest risk factor for any albuminuria estimated by the measure gradient of risk per 1 SD, followed by diastolic blood pressure, triglycerides, systolic blood pressure, cholesterol and LDL. In patients with HbA1c > 65 mmol/mol (> 8.1%), blood pressure > 140/70 mmHg was associated with increased risk of albuminuria. Conclusions Preventing renal complications in adolescents and young adults with type 1 diabetes need avoidance at relatively high levels of blood pressure, blood lipids and BMI, whereas very tight control is not associated with further risk reduction. For patients with long-term poor glycaemic control, stricter blood pressure control is advocated.

Aims: This study assessed hemoglobin A1c (HbA1c) across the lifespan in people with type 1 diabetes (T1D) in Germany/Austria, Sweden, and the United States between 2011 and 2017 to ascertain temporal and age-related trends. Methods: Data from the Diabetes-Patienten-Verlaufsdokumentation (DPV) (n = 25,651 in 2011, n = 29,442 in 2017); Swedish Pediatric Diabetes Quality Registry (SWEDIABKIDS)/National Diabetes Register (NDR), (n = 44,474 in 2011, n = 53,690 in 2017); and T1D Exchange (n = 16,198 in 2011, n = 17,087 in 2017) registries were analyzed by linear regression to compare mean HbA1c overall and by age group. Results: Controlling for age, sex, and T1D duration, HbA1c increased in the United States between 2011 and 2017, decreased in Sweden, and did not change in Germany/Austria. Controlling for sex and T1D duration, mean HbA1c decreased between 2011 and 2017 in all age cohorts in Sweden (P < 0.001). In the United States, HbA1c stayed the same for participants <6 years and 45 to <65 years and increased in all other age groups (P < 0.05). In Germany/Austria, HbA1c stayed the same for participants <6 to <13 years and 18 to <25 years; decreased for participants ages 13 to <18 years (P < 0.01); and increased for participants >= 25 years (P < 0.05). Conclusions: The comparison of international trends in HbA1c makes it possible to identify differences, explore underlying causes, and share quality improvement processes. National quality improvement initiatives are well accepted in Europe but have yet to be implemented systematically in the United States. However, disparities created by the lack of universal access to health care coverage, unequal access to diabetes technologies (e.g., continuous glucose monitoring) regardless of insurance status, and high out-of-pocket cost for the underinsured ultimately limit the potential of quality improvement initiatives.

It is the position of the International Network for Child and Family Centered Care (INCFCC) that COVID-19 restrictions pose tremendous challenges for the health care team in their efforts to provide child and family centered care (CFCC). COVID-19 restrictions impact on the familys right to be presernt with their ill child and to contribute to the caring process. A limited number of articles have discussed challenges about the successful delivery of CFCC during the COVID-19 pandemic. Based on current literature, the INCFCC stresses the need for continuous facilitation implementation of child and family centred care as, it is essential for childrens physical and psychological wellbeing. Furthermore we believe that the families presence and participation holds more benefits than risks to the health of children, their families, and the health care team. (C) 2021 Elsevier Inc. All rights reserved.

Semen-through its specific sperm and seminal plasma (SP) constituents-induces changes of gene expression in the internal genital tract of pigs, particularly in the functional sperm reservoir at the utero-tubal junction (UTJ). Although seminal effects are similarly elicited by artificial insemination (AI), major changes in gene expression are registered after natural mating, a fact suggesting the act of copulation induces per se changes in genes that AI does not affect. The present study explored which pathways were solely influenced by copulation, affecting the differential expression of genes (DEGs) of the pre/peri-ovulatory genital tract (cervix, distal uterus, proximal uterus and UTJ) of estrus sows, 24 h after various procedures were performed to compare natural mating with AI of semen (control 1), sperm-free SP harvested from the sperm-peak fraction (control 2), sperm-free SP harvested from the whole ejaculate (control 3) or saline-extender BTS (control 4), using a microarray chip (GeneChip(R)porcine gene 1.0 st array). Genes related to neuroendocrine responses (ADRA1,ADRA2,GABRB2,CACNB2), smooth muscle contractility (WNT7A), angiogenesis and vascular remodeling (poFUT1,NTN4) were, among others, overrepresented with distal and proximal uterine segments exhibiting the highest number of DEGs. The findings provide novel evidence that relevant transcriptomic changes in the porcine female reproductive tract occur in direct response to the specific act of copulation, being semen-independent.

Oxidative stress unbalance is a major factor causing impairment of sperm function and, ultimately, sperm death. In this study, we identified transcriptomic and proteomic markers for oxidative-related protectors from the generation of reactive oxygen species (ROS) in spermatozoa from breeding boars with documented high- or lowfertility. Particular attention was paid to glutathione peroxidases, and to transcripts related to DNA stabilization and compaction, as protamine and transition proteins. mRNA cargo analysis was performed using porcinespecific micro-arrays (GeneChip (R) miRNA 4.0 and GeneChip (R) Porcine Gene 1.0 ST) and qPCR validation. Differences between fertility-classed boars were ample among biomarkers; some upregulated only at protein level (catalase (CAT), superoxide dismutase 1 (SOD1) and glutathione proteins), or only at the mRNA level (ATOX1, Antioxidant Protein 1). In addition, protamines 2 and 3, essential for sperm DNA condensation and also transition proteins 1 and 2 (TNP1 and TNP2), required during histone-to-protamine replacement, were overexpressed in spermatozoa from high-fertile boars. This up-regulation seems concerted to reduce DNA accessibility to ROS attack, protecting the DNA. The upregulated intracellular phospholipid hydroperoxide glutathione peroxidase (GPx4), in high-fertile boars at mRNA level, can be considered a most relevant biomarker for fertility disclosure during sperm evaluation.

n/a

In the study presented here we identified transcriptomic markers for fertility in the cargo of pig ejaculated spermatozoa using porcine-specific micro-arrays (GeneChip((R)) miRNA 4.0 and GeneChip((R)) Porcine Gene 1.0 ST). We report (i) the relative abundance of the ssc-miR-1285, miR-16, miR-4332, miR-92a, miR-671-5p, miR-4334-5p, miR-425-5p, miR-191, miR-92b-5p and miR-15b miRNAs, and (ii) the presence of 347 up-regulated and 174 down-regulated RNA transcripts in high-fertility breeding boars, based on differences of farrowing rate (FS) and litter size (LS), relative to low-fertility boars in the (Artificial Insemination) AI program. An overrepresentation analysis of the protein class (PANTHER) identified significant fold-increases for C-C chemokine binding (GO:0019957): CCR7, which activates B- and T-lymphocytes, 8-fold increase), XCR1 and CXCR4 (with ubiquitin as a natural ligand, 1.24-fold increase), cytokine receptor activity (GO:0005126): IL23R receptor of the IL23 protein, associated to JAK2 and STAT3, 3.4-fold increase), the TGF-receptor (PC00035) genes ACVR1C and ACVR2B (12-fold increase). Moreover, two micro-RNAs (miR-221 and mir-621) were down- and up-regulated, respectively, in high-fertility males. In conclusion, boars with different fertility performance possess a wide variety of differentially expressed RNA present in spermatozoa that would be attractive targets as non-invasive molecular markers for predicting fertility.

The avian seminal fluid (SF) is a protein-rich fluid, derived from the testis, the rudimentary epididymis and, finally, from the cloacal gland. The SF interacts with spermatozoa and the inner cell lining of the female genital tract, to modulate sperm functions and female immune responsiveness. Its complex proteome might either be free or linked to extracellular vesicles (EVs) as it is the case in mammals, where EVs depict the tetraspanin CD9; and where those EVs derived from the epididymis (epididymosomes) also present the receptor CD44. In the present study, sperm-free SF from Red Jungle Fowl, White Leghorn and an advanced intercross (AIL, 12th generation) were studied using flow cytometry of the membrane marker tetraspanin CD9, Western blotting of the membrane receptor CD44 and electron microscopy in non-enriched (whole SF) or enriched fractions obtained by precipitation using a commercial kit (Total Exosome Precipitation Solution). Neither CD9- nor CD44 could be detected, and the ultrastructure confirmed the relative absence of EVs, raising the possibility that avian SF interacts differently with the female genitalia as compared to the seminal plasma of mammals.

BackgroundMating induces large changes in the female genital tract, warranting female homeostasis and immune preparation for pregnancy, including the preservation of crucial oxidative status among its pathways. Being highly susceptible to oxidative stress, sperm survival and preserved function depend on the seminal plasma, a protection that is removed during sperm handling but also after mating when spermatozoa enter the oviduct. Therefore, it is pertinent to consider that the female sperm reservoir takes up this protection, providing a suitable environment for sperm viability. These aspects have not been explored despite the increasing strategies in modulating the female status through diet control and nutritional supplementation. AimsTo test the hypothesis that mating modifies the expression of crucial oxidative-reductive transcripts across the entire pig female genital tract (cervix to infundibulum) and, particularly in the sperm reservoir at the utero-tubal junction, before ovulation, a period dominated by estrogen stimulation of ovarian as well as of seminal origin. MethodsThe differential expression of estrogen (ER) and progesterone (PR) receptors and of 59 oxidative-reductive transcripts were studied using a species-specific microarray platform, in specific segments of the peri-ovulatory sow reproductive tract in response to mating. ResultsMating induced changes along the entire tract, with a conspicuous downregulation of both ER and PR and an upregulation of superoxide dismutase 1 (SOD1), glutaredoxin (GLRX3), and peroxiredoxin 1 and 3 (PRDX1, PRDX3), among other NADH Dehydrogenase Ubiquinone Flavoproteins, in the distal uterus segment. These changes perhaps helped prevent oxidative stress in the area adjacent to the sperm reservoir at the utero-tubal junction. Concomitantly, there were a downregulation of catalase (CAT) and NADH dehydrogenase (ubiquinone) oxidoreductases 1 beta subcomplex, subunit 1 (NDUFB1) in the utero-tubal junction alongside an overall downregulation of CAT, SOD1, and PRDX3 in the ampullar and infundibulum segments. ConclusionsNatural mating is an inducer of changes in the expression of female genes commanding antioxidant enzymes relevant for sperm survival during sperm transport, under predominant estrogen influence through the bloodstream and semen. The findings could contribute to the design of new therapeutics for the female to improve oxidative-reductive balance.

Background/objectives This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity. Subjects/methods Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total of N = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8-11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income. Results Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts. Conclusions There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals.

The objective of this paper was to investigate if socioeconomic status (SES), measured by maternal education and household income, influenced the risk of developing autoimmune disease (Type 1 Diabetes, Celiac disease, Juvenile Idiopathic Arthritis, Crohns disease, Ulcerative colitis, and autoimmune thyroid disease), or age at diagnosis, and to analyse pathways between SES and autoimmune disease. We used data from the All Babies in Southeast Sweden (ABIS) study, a population-based prospective birth cohort, which included children born 1997-1999. Diagnoses of autoimmune disease was collected from the Swedish National Patient Register Dec 2020. In 16,365 individuals, low maternal education, but not household income, was associated with increased risk of Type 1 Diabetes; middle education RR 1.54, 95% CI 1.06, 2.23; P 0.02, low education RR 1.81, 95% CI 1.04, 3.18; P 0.04. Maternal education and household income was not associated with any other autoimmune disease and did not influence the age at diagnosis. Part of the increased risk of Type 1 Diabetes by lower maternal education was mediated by the indirect pathway of higher BMI and higher risk of Serious Life Events (SLE) at 5 years of age. The risk of developing Type 1 Diabetes associated to low maternal education might be reduced by decreasing BMI and SLE during childhood.

Objectives To investigate if socioeconomic status (SES) is predictive of cardiovascular risk factors among Swedish adolescents. Identify the most important SES variable for the development of each cardiovascular risk factor. Investigate at what age SES inequality in overweight and obesity occurs. Design Longitudinal follow-up of a prospective birth cohort. Setting All Babies in Southeast Sweden (ABIS) study includes data from children born between October 1997 and October 1999 in five counties of south east Sweden. Participants A regional ABIS-study subsample from three major cities of the region n=298 adolescents aged 16-18 years, and prospective data from the whole ABIS cohort for overweight and obesity status at the ages 2, 5, 8 and 12 years (n=2998-7925). Outcome measures Blood pressure above the hypertension limit, overweight/obesity according to the International Obesity Task Force definition, low high-density lipoproteins (HDL) or borderline-high low-density lipoproteins according to National Cholesterol Education Program expert panel on cholesterol levels in children. Results For three out of four cardiovascular risk outcomes (elevated blood pressure, low HDL and overweight/obesity), there were increased risk in one or more of the low SES groups (p<0.05). The best predictor was parental occupational class (Swedish socioeconomic classification index) for elevated blood pressure (area under the receiver operating characteristic (ROC) curve 0.623), maternal educational level for overweight (area under the ROC curve 0.641) and blue-collar city of residence for low HDL (area under the ROC curve 0.641). SES-related differences in overweight/obesity were found at age 2, 5 and 12 and for obesity at age 2, 5, 8 and 12 years (all p<0.05). Conclusions Even in a welfare state like Sweden, SES inequalities in cardiovascular risks are evident already in childhood and adolescence. Intervention programmes to reduce cardiovascular risk based on social inequality should start early in life.

Objectives To identify differences and similarities in HbA1c levels and patterns regarding age and gender in eight high-income countries. Subjects 66 071 children and adolescents below18 years of age with type 1 diabetes for at least 3 months and at least one HbA1c measurement during the study period. Methods Pediatric Diabetes Quality Registry data from Austria, Denmark, England, Germany, Norway, Sweden, the United States, and Wales were collected between 2013 and 2014. HbA1c, gender, age, and duration were used in the analysis. Results Distribution of gender and age groups was similar in the eight participating countries. The mean HbA1c varied from 60 to 73 mmol/mol (7.6%-8.8%) between the countries. The increase in HbA1c between the youngest (0-9 years) to the oldest (15-17 years) age group was close to 8 mmol/mol (0.7%) in all countries (P < .001). Females had a 1 mmol/mol (0.1%) higher mean HbA1c than boys (P < .001) in seven out of eight countries. Conclusions In spite of large differences in the mean HbA1c between countries, a remarkable similarity in the increase of HbA1c from childhood to adolescence was found.

This thesis focuses on glycemic control measured as HbA1c in type 1 diabetes (T1D) patients during childhood and especially during adolescence, both in a Swedish and an international context, and relates the glycemic control to the risk of complications in young adults.  

In studies I and II, the Swedish Pediatric Diabetes Quality Register (SWEDIABKIDS) and the Swedish National Diabetes Register (NDR) were used. More than 4000 young adults with T1D and data on HbA1c in NDR both in 2011 and 2012 as well as data on HbA1c in SWEDIABKIDS were used. The T1D patients with poor glycemic control during their teenage period had a risk for retinopathy several times higher than those with good glycemic control. The risk for micro- and macroalbuminuria was also higher in those with poor glycemic control and was most pronounced in the T1D patients with high HbA1c in both registers. Females had worse glycemic control than males during the teenage period and an increased risk of retinopathy as young adults.  

In studies III and IV, pediatric diabetes quality register data from, respectively, eight and seven Western high-income countries were collected in the year 2013. Data on about 60 000 T1D patients were analyzed according to mean HbA1c levels in the countries and related to actual age and T1D duration to determine if there were differences in glycemic control between the countries. There were large differences in mean HbA1c between the countries, both when related to age and T1D duration. Despite the differences in mean HbA1c, the increase in mean HbA1c with increasing age and T1D duration was very similar in all countries.  

The overall picture of these studies is that good glycemic control is very important to avoid complications of T1D as young adults, and it seems particularly important to maintain a good glycemic control during adolescence. Furthermore large differences in glycemic control in T1D patients in Western high-income countries were found. Despite the differences in glycemic control, the pattern of rising HbA1c with increasing age and duration of T1D was very similar in all countries. Females have worse glycemic control than males during their teenage period, both in Sweden and internationally, and they also have more retinopathy as young adults.   

This thesis shows that it is of the utmost importance to treat T1D patients intensively directly after diagnosis, to treat the young T1D patients intensely and to reduce the rise in HbA1c with increasing age and duration of T1D in order to avoid complications early in life. Diabetes quality registers give the opportunity to compare results and share experiences, both within and between countries, so treatment of T1D can be designed in the best possible way and thereby minimize T1D complications. 

Objective To investigate the association between a history of placental bed disorders and later dementia. Design Retrospective population-based cohort study. Setting Sweden. Sample All women giving birth in Sweden between 1973 and 1993 (1 128 709). Methods Women with and without placental bed disorders (hypertensive disorders of pregnancy including pre-eclampsia, fetal growth restriction, spontaneous preterm labour and birth, preterm premature rupture of membranes, abruptio placenta, late miscarriages) and other pregnancy complications were identified by means of the Swedish Medical Birth Register. International classification of disease was used. Data were linked to other National Registers. Participants were followed up until 2013. The Cox proportional hazards model was used to calculate hazard ratios for women with and without pregnancy complications and were adjusted for possible confounders. Main outcome measures Diagnosis of vascular dementia and non-vascular dementia. Results Adjusted for cardiovascular disease and socio-demographic factors, an increased risk of vascular dementia was shown in women with previous pregnancy-induced hypertension (Hazard ratio [HR] 1.88, 95% CI 1.32-2.69), pre-eclampsia (HR 1.63, 95% CI 1.23-2.16), spontaneous preterm labour and birth (HR 1.65, 95% CI 1.12-2.42) or preterm premature rupture of membranes (HR 1.60, 95% CI 1.08-2.37). No statistically significant increased risk was seen for other pregnancy complications or non-vascular dementia even though many of the point estimates indicated increased risks. Conclusions Women with placental bed disorders have a higher risk for vascular disease. Mechanisms behind the abnormal placentation remain elusive, although maternal constitutional factors, abnormal implantation as well as impaired angiogenesis have been suggested. Tweetable abstract Placental bed syndromes associated with vascular dementia even after adjusting for cardiovascular disease.

Background: Painful menstruation is common among girls. To optimize school nurses' work more knowledgeabout their experiences of supporting these girls is needed. The aim of this study was to describe school nurses'experiences of supporting girls with menstrual pain.Methods: Interviews were conducted with 15 school nurses in Sweden and analyzed using thematic analysis.Results: Three themes emerged: Taking menstrual pain seriously, Being a disseminator of knowledge, andExternal conditions for conducting professional work as a school nurse.Conclusion: School nurses felt competent in supporting girls with menstrual pain. However, they lacked struc-tural, written guidelines and routines for how to treat, support, follow-up and refer girls with menstrual pain.Practice implications: School education about menstruation and sexual health needs to be strengthened. Cooper-ation with other healthcare facilities and networks with other school nurses should be increased. Specific guide-lines on how to support girls with menstrual pain should be implemented.

An amendment to this paper has been published and can be accessed via the original article.

Background

To increase health and well-being in young children, it is important to acknowledge and promote the child’s sleep behaviour. However, there is a lack of brief, validated sleep screening instruments for children. The aims of the study were to (1) present a Swedish translation of the PISI, (2) examine the factor structure of the Swedish version of PISI, and test the reliability and validity of the PISI factor structure in a sample of healthy children in Sweden.

Methods

The English version of the PISI was translated into Swedish, translated back into English, and agreed upon before use. Parents of healthy 3- to 10-year-old children filled out the Swedish version of the PISI and the generic health-related quality of life instrument KIDSCREEN-27 two times. Exploratory and confirmatory factor analyses for baseline and test-retest, structural equation modelling, and correlations between the PISI and KIDSCREEN-27 were performed.

Results

In total, 160 parents filled out baseline questionnaires (test), whereof 100 parents (63%) filled out the follow-up questionnaires (retest). Confirmative factor analysis of the PISI found two correlated factors: sleep onset problems (SOP) and sleep maintenance problems (SMP). The PISI had substantial construct and test-retest reliability. The PISI factors were related to all KIDSCREEN-27 dimensions.

Conclusions

The Swedish version of the PISI is applicable for screening sleep problems and is a useful aid in dialogues with families about sleep.

Disruption of parental sleep in hospital, with frequent awakenings and poor sleep quality, limits the parents resources to meet the childs needs and maintain parental wellbeing. The aim of the study was to explore and describe how parents perceive their sleep when staying overnight with their sick child in hospital. A further aim was to explore and describe parents perception of what circumstances influence their sleep in the hospital. Twenty-two parents who were accommodated with their sick child (0-17 years) in paediatric wards in Norway and Sweden participated. Interviews were conducted during the hospital stay to elicit their perspectives. Phenomenography was used to analyse data. Two descriptive categories were found: (a) "Perceptions of sleep", with two sub-categories: "Sleep in the paediatric ward" and "Consequences of sleep loss"; and (b) "Circumstances influencing sleep in the paediatric ward" with three sub-categories: "The importance of the family", "Information and routines at the paediatric ward", and "Accommodation facilities". Parents sleep and needs must be acknowledged in paediatric wards. An individual plan of care for the upcoming night could be a valuable tool for both the parents and nurses. The childs medical needs must be met with respect to the parents willingness to take part in the childs care during the night, and the need for rest and sleep for both parent and child.

Purpose: Talking and grieving together may be advantageous for maintaining belief in a meaningful future and can help bereaved adolescents and their parents to cope better with the situation. The aim of this study was to explore communication, self-esteem and prolonged grief in adolescent-parent dyads, following the death of a parent to cancer. Method: This study has a descriptive and comparative design. Twenty family dyads consisting of parentally bereaved adolescents (12 & ndash;19 years) and their widowed parents completed the Parent and Adolescent Communication Scale, Rosenberg Self-Esteem Scale and Prolonged Grief-13, 1 & ndash;4 years following the death of a parent. Results: Twelve family dyads reported normal-high parent-adolescent communication, 11 dyads rated normal high self-esteem. Two adolescents and three parents scored above the cut-off for possible prolonged grief disorder (>= 35), none of these were in the same dyads. There was a difference (p < .05) between boys (mean 40.0) and girls (mean 41.9) with regard to open family communication, as assessed by parents. Girls reported lower self-esteem (mean 26.0) than boys (mean 34.1, p < .01). Conclusions: This study provides insights from parentally bereaved families which indicate that despite experiencing the often-traumatic life event of losing a parent or partner, most participants reported normal parent adolescent communication, normal self-esteem and few symptoms of prolonged grief. The potential usefulness of identifying families who may need professional support in family communication following the death of a parent is discussed.

The number of families conceived through sperm donation to single women is increasing. However, there is limited knowledge about health care professionals attitudes towards solo-mothers by choice, and there is some indication that professionals personal opinions influence their care of individuals who use alternate ways to build a family. The primary aim of the study was to investigate attitudes towards, and experiences of, families following sperm donation to single women among healthcare professionals working in primary child healthcare.

OBJECTIVE To evaluate HbA(1c) followed from diagnosis, as a predictor of severe microvascular complications (i.e., proliferative diabetic retinopathy [PDR] and nephropathy [macroalbuminuria]). RESEARCH DESIGN AND METHODS In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age from 1983 to 1987 in southeast Sweden were followed from diagnosis until 2019. Long-term weighted mean HbA(1c) (wHbA(1c)) was calculated by integrating the area under all HbA(1c) values. Complications were analyzed in relation to wHbA(1c) categorized into five levels. RESULTS After 32 years, 9% had no retinopathy, 64% non-PDR, and 27% PDR, and 83% had no microalbuminuria, 9% microalbuminuria, and 8% macroalbuminuria. Patients with near-normal wHbA(1c) did not develop PDR or macroalbuminuria. The lowest wHbA(1c) values associated with development of PDR and nephropathy (macroalbuminuria) were 7.3% (56 mmol/mol) and 8.1% (65 mmol/mol), respectively. The prevalence of PDR and macroalbuminuria increased with increasing wHbA(1c), being 74% and 44% in the highest category, wHbA(1c) >9.5% (>80 mmol/mol). In comparison with the follow-up done after 20-24 years duration, the prevalence of PDR had increased from 14 to 27% and macroalbuminuria from 4 to 8%, and both appeared at lower wHbA(1c) values. CONCLUSIONS wHbA(1c) followed from diagnosis is a very strong biomarker for PDR and nephropathy, the prevalence of both still increasing 32 years after diagnosis. To avoid PDR and macroalbuminuria in patients with type 1 diabetes, an HbA(1c) <7.0% (53 mmol/mol) and as normal as possible should be recommended when achievable without severe hypoglycemia and with good quality of life.

BackgroundMotor impairment is common after extremely preterm (EPT, <28 weeks gestational age (GA)) birth, with cerebral palsy (CP) affecting about 10% of children and non-CP movement difficulties (MD) up to 50%. This study investigated the sociodemographic, perinatal and neonatal risk factors for CP and non-CP MD.MethodsData come from a European population-based cohort of children born EPT in 2011-2012 in 11 countries. We used multinomial logistic regression to assess risk factors for CP and non-CP MD (Movement Assessment Battery for Children - 2nd edition <= 5th percentile) compared to no MD (>15th percentile) among 5-year-old children.ResultsCompared to children without MD (n = 366), young maternal age, male sex and bronchopulmonary dysplasia were similarly associated with CP (n = 100) and non-CP MD (n = 224) with relative risk ratios (RRR) ranging from 2.3 to 3.6. CP was strongly related to severe brain lesions (RRR >10), other neonatal morbidities, congenital anomalies and low Apgar score (RRR: 2.4-3.3), while non-CP MD was associated with primiparity, maternal education, small for GA (RRR: 1.6-2.6) and severe brain lesions, but at a much lower order of magnitude.ConclusionCP and non-CP MD have different risk factor profiles, with fewer clinical but more sociodemographic risk factors for non-CP MD.ImpactYoung maternal age, male sex and bronchopulmonary dysplasia similarly increased risks of both cerebral palsy and non-cerebral palsy movement difficulties.Cerebral palsy was strongly related to clinical risk factors including severe brain lesions and other neonatal morbidities, while non-cerebral palsy movement difficulties were more associated with sociodemographic risk factors.These results on the similarities and differences in risk profiles of children with cerebral palsy and non-cerebral palsy movement difficulties raise questions for etiological research and provide a basis for improving the identification of children who may benefit from follow-up and early intervention.

Aim To measure the association between cerebral palsy (CP) and non-CP-related movement difficulties and health-related quality of life (HRQoL) among 5-year-old children born extremely preterm (<28 weeks gestational age). Method We included 5-year-old children from a multi-country, population-based cohort of children born extremely preterm in 2011 to 2012 in 11 European countries (n = 1021). Children without CP were classified using the Movement Assessment Battery for Children, Second Edition as having significant movement difficulties (<= 5th centile of standardized norms) or being at risk of movement difficulties (6th-15th centile). Parents reported on a clinical CP diagnosis and HRQoL using the Pediatric Quality of Life Inventory. Associations were assessed using linear and quantile regressions. Results Compared to children without movement difficulties, children at risk of movement difficulties, with significant movement difficulties, and CP had lower adjusted HRQoL total scores (beta [95% confidence interval] = -5.0 [-7.7 to -2.3], -9.1 [-12.0 to -6.1], and - 26.1 [-31.0 to -21.2]). Quantile regression analyses showed similar decreases in HRQoL for all children with CP, whereas for children with non-CP-related movement difficulties, reductions in HRQoL were more pronounced at lower centiles. Interpretation CP and non-CP-related movement difficulties were associated with lower HRQoL, even for children with less severe difficulties. Heterogeneous associations for non-CP-related movement difficulties raise questions for research about mitigating and protective factors.

Objective The aim of the present study was to assess the impact of different maternal Body Mass Index (BMI) classes on the risk of postpartum endometritis, wound infection, and breast abscess after different modes of delivery. Secondly to estimate how the risk of postpartum infection varies with different maternal BMI groups after induction of labor and after obstetric anal sphincter injuries. Methods A population-based observational study including women who gave birth during eight years (N = 841,780). Data were collected from three Swedish Medical Health Registers, the Swedish Medical Birth Register, the Swedish National Patient Register, and the Swedish Prescribed Drug Register. Outcomes were defined by ICD-10 codes given within eight weeks postpartum. The reference population was uninfected women. Odds ratios were determined using Mantel-Haenszel technique. Year of delivery, maternal age, parity and smoking in early pregnancy were considered as confounders. Results There was a dose-dependent relationship between an increasing maternal BMI and a higher risk for postpartum infections. Women in obesity class II and III had an increased risk for endometritis after normal vaginal delivery aOR 1.45 (95% CI: 1.29-1.63) and for wound infections after cesarean section aOR 3.83 (95% CI: 3.39-4.32). There was no difference in how maternal BMI affected the association between cesarean section and wound infection, regardless of whether it was planned or emergent. Women in obesity class II and III had a lower risk of breast abscess compared with normal-weight women, aOR 0.47 (95% CI: 0.38-0.58). The risk of endometritis after labor induction decreased with increasing maternal BMI. The risk of wound infection among women with an obstetrical sphincter injury decreased with increasing BMI. Conclusion This study provides new knowledge about the impact of maternal BMI on the risk of postpartum infections after different modes of delivery. There was no difference in how BMI affected the association between cesarean section and wound infections, regardless of whether it was a planned cesarean section or an emergency cesarean section.

Background: Bullying is a type of aggressive behavior that occurs repeatedly and intentionally in school environments and where there is a power imbalance. The main objective of this study was to analyze the association that hormones and the psychosocial context jointly have with bullying behavior. Method: Participants were 302 11-year-old preadolescents from the Gipuzkoan cohort of the INMA Project. Bullying was assessed using the Olweus Bully/victim Questionnaire. Prenatal sexual hormones were assessed by calculating 2D:4D ratio and in order to measure prepubertal testosterone and cortisol levels saliva samples were collected within a week of each other. Additionally, various psychosocial factors were evaluated: executive function, family context, school environment and social context. To analyze our complex hypothesis, six metamodels were tested using structural equation modeling. Results: In relation to victims, results showed that victimization was related to worse school environment perception in boys, and higher stress and conflict in the family in girls. In the case of their involvement in bullying as a bully, lower salivary cortisol levels, worse school environment perception and lower peers and social support was related to being more frequently involved as a bully in boys, while having more family stress and conflict was related with being a bully in girls. Conclusions: This approach makes it possible not only to explore the different biological and psychosocial factors affect bullying behavior, but also to explore associations between the predictor variables.

Introduction The mortality rate of extremely low gestational age (ELGA) (born <gestational week 28+0) infants remains high, and severe infections and necrotising enterocolitis (NEC) are common causes of death. Preterm infants receiving human milk have lower incidence of sepsis and NEC than those fed a bovine milk-based preterm formula. Despite this, fully human milk fed ELGA infants most often have a significant intake of cows milk protein from bovine-based protein fortifier. The aim of this study is to evaluate whether the supplementation of human milk-based, as compared with bovine-based, nutrient fortifier reduces the prevalence of NEC, sepsis and mortality in ELGA infants exclusively fed with human milk. Methods and analysis A randomised-controlled multicentre trial comparing the effect of a human breast milk-based fortifier with a standard bovine protein-based fortifier in 222-322 ELGA infants fed human breast milk (mothers own milk and/or donor milk). The infants will be randomised to either fortifier before reaching 100 mU kg/day in oral feeds. The intervention, stratified by centre, will continue until the target postmenstrual week 34+0. The primary outcome is a composite of NEC, sepsis or death. Infants are characterised with comprehensive clinical and nutritional data collected prospectively from birth until hospital discharge. Stool, urine, blood and breast milk samples are collected for analyses in order to study underlying mechanisms. A follow-up focusing on neurological development and growth will be performed at 2 and 5.5 years of age. Health economic analyses will be made. Ethics and dissemination The study is conducted according to ICH/GCP guidelines and is approved by the regional ethical review board in Linkoping Sweden (Dnr 2018/193-31, Dnr 2018/384-32). Results will be presented at scientific meetings and published in peer-reviewed publications.

Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.

Context The European Increlex & REG; Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data on the use of recombinant human insulin-like growth factor-1 (rhIGF-1, mecasermin, Increlex) for the treatment of children/adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD).Objective This analysis of Eu-IGFD data aimed to identify the frequency and predictive factors for hypoglycemia adverse events (AEs) in children treated with rhIGF-1.Methods Data were collected from December 2008 to May 2021. Logistic regression was performed to identify predictive risk factors for treatment-induced hypoglycemia AEs. Odds ratios (ORs) are presented with 95% CIs for each factor.Results In total, 306 patients were enrolled in the registry; 84.6% were diagnosed with SPIGFD. Patients who experienced & GE; 1 hypoglycemia AE (n = 80) compared with those with no hypoglycemia AEs (n = 224) had a lower mean age at treatment start (8.7 years vs 9.8 years), a more frequent diagnosis of Laron syndrome (27.5% vs 10.3%), and a history of hypoglycemia (18.8% vs 4.5%). Prior history of hypoglycemia (OR 0.25; 95% CI: [0.11; 0.61]; P = .002) and Laron syndrome diagnosis (OR 0.36; 95% CI: [0.18; 0.72]; P = .004) predicted future hypoglycemia AEs. Total hypoglycemia AEs per patient per treatment year was 0.11 and total serious hypoglycemia AEs per patient per treatment year was 0.01.Conclusion Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this AE throughout treatment.

BackgroundPuberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex(R) Growth Forum Database (Eu-IGFD) Registry (NCT00903110). MethodsThe Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. ResultsThis analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3-13.0) cm/year in boys and 6.8 (1.3-9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. ConclusionChildren and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.

Objective: The European Increlex (R) Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex (R)) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design: Ongoing, open-label, observational registry (NCT00903110). Methods: Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naive/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain >= 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results: Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions: In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naive and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD(65) only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.

The seminal plasma (SP) modulates the female reproductive immune environment after mating, and microRNAs (miRNAs) could participate in the process. Considering that the boar ejaculate is built by fractions differing in SP-composition, this study evaluated whether exposure of mucosal explants of the sow internal genital tract (uterus, utero-tubal junction and isthmus) to different SP-fractions changed the profile of explant-secreted miRNAs. Mucosal explants retrieved from oestrus sows (n = 3) were in vitro exposed to: Medium 199 (M199, Control) or M199 supplemented (1:40 v/v) with SP from the sperm-rich fraction (SRF), the post-SRF or the entire recomposed ejaculate, for 16 h. After, the explants were cultured in M199 for 24 h to finally collect the media for miRNA analyses using GeneChip miRNA 4.0 Array (Affymetrix). Fifteen differentially expressed (False Discovery Rate (FDR) < 0.05 and Fold-change ≥ 2) miRNAs (11 down- versus 4 up-regulated) were identified (the most in the media of uterine explants incubated with SP from post-SRF). Bioinformatics analysis identified that predicted target genes of dysregulated miRNAs, mainly miR-34b, miR-205, miR-4776-3p and miR-574-5p, were involved in functions and pathways related to immune response. In conclusion, SP is able to elicit changes in the miRNAs profile secreted by female genital tract, ultimately depending SP-composition.

The study evaluated the relation between the oxidative stress index (OSI) in porcine seminal plasma (n = 76) with sperm resilience and in vivo fertility (farrowing rate and litter size of 3137 inseminated sows) of liquid-stored artificial insemination (AI) semen doses. The OSI was assessed as the ratio of advanced oxidation protein products to Trolox-equivalent antioxidant capacity, both measured using an automated analyzer. Sperm motility (computer-assisted sperm analyzer) and viability (flow cytometry) were evaluated in semen AI-doses at 0 and 72 h of storage at 17 degrees C. Sperm resilience was defined as the difference between storage intervals. Semen AI-doses were hierarchically clustered as having high, medium and low seminal OSI (p &lt; 0.001) with those of low displaying higher resilience (p &lt; 0.01). Boars were hierarchically clustered into two groups (p &lt; 0.001) as having either positive or negative farrowing rate and litter size deviation; the negative one showing higher seminal OSI (p &lt; 0.05). In sum, seminal OSI was negatively related to sperm motility and the in vivo fertility of liquid-stored boar semen AI-doses, with the receiver operating characteristic curve presenting seminal OSI as a good predictive biomarker of in vivo fertility of AI-boars (area under the curve: 0.815, p &lt; 0.05).

Seminal plasma contains many morphologically hetero-geneous extracellular vesicles (sEVs). These are sequentially released by cells of the testis, epididymis, and accessory sex glands and involved in male and fe-male reproductive processes. This study aimed to define in depth sEV subsets isolated by ultrafiltration and size exclusion chromatography, decode their proteomic profiles using liquid chromatography-tandem mass spectrometry, and quantify identified proteins using sequential window acquisition of all theoretical mass spectra. The sEV subsets were defined as large (L-EVs) or small (S-EVs) by their protein concentration, morphology, size distribution, and EV-specific protein markers and purity. Liquid chromatography-tandem mass spectrometry identified a total of 1034 proteins, 737 of them quantified by SWATH in S-EVs, L-EVs, and non-EVs-enriched samples (18-20 size exclusion chromatography-eluted fractions). The differential expression analysis revealed 197 differentially abundant proteins between both EV subsets, S-EVs and L-EVs, and 37 and 199 between S-EVs and L-EVs versus non-EVs-enriched samples, respectively. The gene ontology enrichment analysis of differentially abundant proteins suggested, based on the type of protein detected, that S-EVs could be mainly released through an apocrine blebbing pathway and be involved in modulating the im-mune environment of the female reproductive tract as well as during sperm-oocyte interaction. In contrast, L-EVs could be released by fusion of multivesicular bodies with the plasma membrane becoming involved in sperm physiological processes, such as capacitation and avoidance of oxidative stress. In conclusion, this study provides a procedure capable of isolating subsets of EVs from pig seminal plasma with a high degree of purity and shows differences in the proteomic profile between EV subsets, indicating different sources and biological functions for the sEVs.

Seminal plasma (SP) antioxidants are considered biomarkers of sperm function and fertility for AI-boars. The current protocol for their measurement implies the SP was harvested immediately after ejaculation and prompt stored at -80 degrees C until analysis. Such protocol may be impractical for AI-centers. This study evaluated how SP levels of antioxidants were influenced by delays in (1) SP-harvesting (0 [control], 2 or 24 h at 17 degrees C after ejaculate collection), in (2) SP-freezing (0 [control] or 24 hat 17 degrees C after SP-harvesting) or (3) the temperature of storage (-80 degrees C [control] or - 20 degrees C). The SP-antioxidants evaluated were: glutathione peroxidase [GPx], superoxide dismutase [SOD], paraoxonase-1 [PON-1], trolox equivalent antioxidant capacity [TEAC] and oxidative stress index [OSI]. A total of 120 aliquots from 10 entire ejaculates were handled in three trials. They were centrifuged (1500 g, 10 min) for harvesting SP and antioxidants were measured with an Automatic Chemistry Analyzer. A 24 h-delay in harvesting the SP led to an increase (p 0.001) in TEAC and SOD SP-levels, and a decrease (p 0.05) of OSI and PON-1. Similarly, a 24 h-delay to freeze the SP increased (p 0.01) TEAC values and decreased (p 0.01) PON-1 and GPx activity levels. Finally, storing the SP at -20 degrees C decreased (p 0.001) SP-levels of TEAC, PON-1 and GPx, and increased (p 0.01) OSI values. Strong positive relationships (p 0.001) were found between antioxidant SP-levels in processed samples and their respective controls. In sum, handling and SP storage influence antioxidant measurements in AI-boars. Reliable levels of SP-antioxidants can only be warranted if a strict protocol for harvesting and SP storage is followed.

There is great cultural diversity across Europe. This is reflected in the organisation of child and adolescent mental health (CAMH) services and the training of the respective professionals in different countries in Europe. Patients and their parents will want a high quality, knowledgeable, and skillful service from child and adolescent psychiatrists (CAPs) wherever they see them in Europe. A European comparison of training programs allows all stakeholders in different European countries to assess the diversity and to initiate discussions as to the introduction of improvements within national training programs. Major issues to be addressed in comparing child and adolescent psychiatric training programs across Europe include: (1) formal organisation and content of training programs and the relationship to adult psychiatry and paediatrics; (2) flexibility of training, given different trainee interests and that many trainees will have young families; (3) quality of governance of training systems; (4) access to research; and (5) networking. The Child and Adolescent Psychiatry-Study of Training in Europe (CAP-State) is a survey of training for child and adolescent psychiatrists (CAPs) across European countries. It aims to revisit and extend the survey carried out in 2006 by Karabekiroglu and colleagues. The current article is embedded in a special issue of European Child + Adolescent Psychiatry attempting to for the first time address training in CAP at the European and global levels. Structured information was sought from each of 38 European and neighboring countries (subsequently loosely referred to as Europe) and obtained from 31. The information was provided by a senior trainee or recently qualified specialist and their information was checked and supplemented by information from a senior child and adolescent psychiatry trainer. Results showed that there is a very wide range of provision of training in child and adolescent psychiatry in different countries in Europe. There remains very substantial diversity in training across Europe and in the degree to which it is subject to national oversight and governance. Some possible reasons for this variation are discussed and some recommendations made.

The original article has been corrected.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggres-sive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methyl-ation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improv-ing prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respec-tively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Impor-tantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2-silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous ret-roviruses (HERVs), which was further enhanced by the addition of phys-iological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2-silenced T-ALL.

Background  

Menopause is a physiological event, but is associated with bothersome symptoms as well as physical changes that affect women’s health. About 75 % of women experience vasomotor symptoms (hot flushes and night sweats) related to menopause that often reduce quality of life. The vasomotor symptoms may be attributed to dysfunctional temperature regulation centrally in the hypothalamus and peripherally in the skin’s circulation. The most effective treatment for vasomotor symptoms is menopausal hormone therapy, but not all women are able to, or want to, use it.  

In addition to the impact on quality of life, studies have associated vasomotor symptoms and menopause with macrovascular endothelial dysfunction. Previous studies on the association of these factors with the skin’s microcirculatory function are small and few. Observational studies have associated physical activity and exercise with less vasomotor symptoms, but the evidence from intervention trials is of low quality and the results are ambiguous. Physical activity has established general health effects, and could potentially decrease vasomotor symptoms by effects on endogenous opioids centrally, and by more efficient thermoregulation peripherally.  

The aim of this thesis was to investigate the effect of resistance training on vasomotor symptoms and health-related quality of life in postmenopausal women, and to explore the women’s experiences of the training to find barriers and facilitators. We also aimed to investigate whether the skin’s microcirculatory function differed between women regarding menopausal status, vasomotor symptoms, menopausal hormone therapy, and physical activity.  

Material and methods  

The first study was an open randomized controlled trial including 65 postmenopausal women with moderate to severe vasomotor symptoms and low physical activity levels. We randomized the women to 15 weeks of resistance training (intervention) or unchanged physical activity (control). The participants registered vasomotor symptoms daily in a diary, and answered health-related quality of life questionnaires at baseline and at 15 weeks. The first 15 women to finish the intervention were recruited to a qualitative study. The women’s experiences of the resistance training intervention were explored in individual interviews after the intervention period, and all were followed-up with telephone interviews after one year. The third study was cross-sectional, including 1148 women from Linköping, 50-64 years old, who participated in the Swedish CArdioPulmonary bioImage Study (SCAPIS). These women answered a questionnaire about menopausal status, vasomotor symptoms and menopausal hormone therapy use, and wore accelerometers for seven days to assess physical activity. The skin’s microcirculation was assessed at rest and during post-occlusive reactive hyperemia.  

Results  

Moderate to severe vasomotor symptoms per 24 hours decreased significantly more in the group of women randomized to resistance training compared with the control group (mean difference -2.7, 95% CI -4.2 to -1.3). The resistance training group improved in domains of menopause-specific health-related quality of life compared with the control group but there was little impact on generic health-related quality of life. In the qualitative study we found that the vasomotor symptoms acted as a “trigger” for the women to become motivated to exercise. Their motivation then evolved from being driven by hopes of symptom relief into being driven by a wish for general well-being, which was still a driving force after one year. Microvascular function did not differ between postmenopausal and premenopausal women, or between women with or without vasomotor symptoms or menopausal hormone therapy. Women with higher levels of objectively measured and self-reported physical activity had a better reactivity of the skin’s microcirculation. The differences remained significant after adjusting for BMI, smoking, hypertension, diabetes, and education.   

Conclusions  

Resistance training could be effective for decreasing vasomotor symptoms and improving some aspects of health-related quality of life in motivated postmenopausal women. The vasomotor symptoms themselves spurred motivation to exercise, indicating they present an opportunity to increase physical activity. When a woman seeks medical advice for vasomotor symptoms, this could be a chance for health care professionals to help her initiate or increase exercise. Women who performed more physical activity and exercise had better skin microvascular function, but no association with VMS was found. Future studies are needed to investigate what type and dose of exercise is the most effective to reduce vasomotor symptoms and whether there is a way to predict for whom exercise will or will not be an effective intervention.