Prior exposure to alkylating agents negatively impacts testicular organoid formation in cells obtained from childhood cancer patients.

STUDY QUESTION: Can human pre- and peri-pubertal testicular cells obtained from childhood cancer patients, previously treated with chemotherapy, form testicular organoids (TOs)? SUMMARY ANSWER: Organoid formation from testicular tissue collected from childhood cancer patients positively correlates with SRY-Box transcription factor 9 (SOX9) expression in Sertoli cells, which in turn negatively correlates with previous exposure to alkylating chemotherapy. WHAT IS KNOWN ALREADY: Pre- and peri-pubertal boys exposed to highly gonadotoxic therapies can only safeguard their fertility potential through testicular tissue cryopreservation. Today, there is no established clinical tool to restore fertility using these testicular samples. Organoids hold promise in providing fundamental early insights in creating such platforms. However, the generation of TOs that closely resemble the innate testis, to enable a thorough monitoring of the necessary steps for germ cell differentiation and somatic functionalities, remains a challenge. STUDY DESIGN SIZE DURATION: We used a Matrigel-based three-layer gradient culture system to generate human TOs and to reveal whether chemotherapy exposure affects TO formation capacity and the functionality of pre- and peri-pubertal testicular somatic cells. Testicular cells of 11 boys (aged 7.7 ± 4.1 (mean ± SD) years) were assessed for TO formation in relation to previous chemotherapy exposure and SOX9 expression in histological sections of paraffin-embedded testicular tissue samples collected on the day of biopsy and compared with testicular tissue samples obtained from 28 consecutive patients (aged 6.9 ± 3.8 (mean ± SD) years). All 39 patients were part of the fertility preservation project NORDFERTIL; an additional 10 samples (from boys aged 5.5 ± 3.5 (mean ± SD) years, without an underlying pathology) in an internal biobank collection were used as controls. PARTICIPANTS/MATERIALS SETTING METHODS: We obtained 49 testicular tissue samples from boys aged 0.8-13.4 years. Fresh samples (n = 11) were dissociated into single-cell suspensions and applied to a three-layer gradient culture system for organoid formation. Histological sections of another 28 samples obtained as part of the fertility preservation project NORDFERTIL, and 10 samples from a sample collection of a pathology biobank were used to evaluate the effects of prior exposure to alkylating agents on testicular samples. Testicular organoid formation was defined based on morphological features, such as compartmentalized structures showing cord formation, and protein expression of testicular cell-specific markers for germ and somatic cells was evaluated via immunohistochemical staining. Hormone secretion was analysed by specific enzyme-linked immunosorbent assays for testosterone and anti-Müllerian hormone (AMH) production. MAIN RESULTS AND THE ROLE OF CHANCE: Our results revealed that 4 out of 11 prepubertal testicular samples formed TOs that showed compartmentalized cord-like structures surrounded by interstitial-like areas and increasing levels of both testosterone as well as AMH over a 7-day culture period. We observed that SOX9 expression was correlated positively with TO formation. Moreover, exposure to alkylating agents before biopsy was inversely correlated with SOX9 expression (P = 0.006). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: Due to the limited amount of material available, only 11 out of the 39 pre- and peri-pubertal testicular tissue samples could be used for the organoid formation experiments. The testicular tissue samples obtained from a sample collection of the internal biobank of Department of Pathology, Karolinska University Hospital were considered normal and included in the study if no testicular pathology was reported. However, detailed information regarding previous medical treatments and/or testicular volumes of the patients included in this biobank was not available. WIDER IMPLICATIONS OF THE FINDINGS: Our observations suggest that SOX9 expression may serve as a putative indicator of TO formation, indicating a critical role of Sertoli cells in promoting organoid formation, seminiferous tubule integrity, and testicular function in pre- and peri-pubertal testicular tissue. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from the Swedish Childhood Cancer Foundation (PR2019-0123; PR2022-0115; TJ2020-0023) (J.-B.S.), Finnish Cancer Society (K.J.), Finnish Foundation for Paediatric Research (K.J.), Swedish Research Council (2018-03094; 2021-02107) (J.-B.S.), and Birgitta and Carl-Axel Rydbeck's Research Grant for Paediatric Research (2020-00348; 2020-00335; 2021-00073; 2022-00317) (J.-B.S. and K.J.). Y.C. and Y.Y. received a scholarship from the Chinese Scholarship Council. J.P.A-L. was supported by a Starting Grant in Medicine and Health (2022-01467) from the Swedish Research Council. R.T.M. was supported by a UKRI Future Leaders Fellowship (MR/S017151/1). The MRC Centre for Reproductive Health was supported by an MRC Centre Grant (MR/N022556/1). The authors declare no competing interests.

Trends in overweight and obesity in Bergen, Norway, using data from routine child healthcare 2010-2022.

AIM: Trends in childhood overweight, obesity and severe obesity have been lacking in Norway. This study assessed pre-pandemic trends from 2010 to 2019 and evaluated differences in prevalence during the 2020-2022 pandemic years. METHODS: Routine height and weight measurements from child and school health centres were extracted retrospectively from children aged 2, 4, 6, 8 and 13 years. Overweight, obesity and severe obesity was classified according to the International Obesity Task Force cut-offs. Pre-pandemic trends were estimated using linear regression. The prevalence during the pandemic was compared to the 95% prediction interval of this model. RESULTS: We obtained 181 527 body mass index measurements on 78 024 children (51.0% boys). There was a decrease in the prevalence of overweight including obesity from 2010 to 2019 in boys and this was statistically significant at 4 and 13 years of age. We found no significant trends in girls during this period. During the pandemic, the prevalence of overweight including obesity exceeded the prediction intervals for boys aged 4, 6, and 8 years, and for 6-year-old girls. CONCLUSION: From 2010-2019, overweight including obesity plateaued in girls and decreased in boys but increased during the pandemic among prepubertal boys. Routine healthcare data is useful for estimating the prevalence of different weight status.

Decreased spermatogonial numbers in boys with severe haematological diseases.

This study examines spermatogonial numbers in testicular samples from 43 prepubertal patients undergoing haematopoietic stem cell transplantation (HSCT). High-dose chemotherapy and/or radiation during HSCT can impact spermatogenesis requiring fertility preservation. Results show that 49% of patients have decreased and 19% severely depleted spermatogonial pool prior to HSCT. Patients with Fanconi anaemia exhibit significantly reduced spermatogonial numbers. Patients with immunodeficiency or aplastic anaemia generally present within the normal range, while results in patients with myelodysplastic syndrome or myeloproliferative neoplasm vary. The study emphasizes the importance of assessing spermatogonial numbers in patients with severe haematological diseases for informed fertility preservation decisions.

[Insulin Resistance and Abnormalities in Blood Values of Icelandic Children Receiving Obesity Treatment].

INTRODUCTION: Worldwide, the rates of childhood obesity have risen dramatically in recent decades. Obesity may cause serious sequelae during childhood and throughout adulthood. Insulin resistance is prevalent metabolic abnormality in pediatric obesity. The Pediatric Obesity Clinic was established in 2011 at the Children's Medical Center, Landspítali University Hospital. This study aimed to observe metabolic abnormalities and insulin resistance in blood values of children receiving obesity treatment. METHODS: The study included all children (n = 180) who received obesity treatment at The Pediatric Obesity Clinic between 2016 and 2020 and had at least eight out of the nine following serum values analyzed while fasting: HbA1c, glucose, insulin, ALAT, total cholesterol, HDL-cholesterol, triglycerides, TSH and free T4. HOMA-IR value was calculated from insulin and glucose values. Decreased insulin sensitivity was defined as HOMA-IR > 3.42. RESULTS: 84% of the children had at least one abnormality in their tested blood values. 50% had abnormal insulin values and 44% had abnormal ALAT values. 78% had decreased insulin sensitivity, and their mean HOMA-IR was 7.3 (± 5.0), surpassing twice the normal value. CONCLUSION: A large majority of the children undergoing obesity treatment already exhibited signs of metabolic sequelae during their treatment. The prevalence of affected children has increased compared to a similar study conducted in 2013. Of particular concern is the growing number of children with decreased insulin sensitivity. Proper measures must be taken to combat this alarming trend.

Usage and Daily Attrition of a Smartphone-Based Health Behavior Intervention: Randomized Controlled Trial.

BACKGROUND: Although most adolescents have access to smartphones, few of them use mobile health (mHealth) apps for health improvement, highlighting the apparent lack of interest in mHealth apps among adolescents. Adolescent mHealth interventions have been burdened with high attrition rates. Research on these interventions among adolescents has frequently lacked detailed time-related attrition data alongside analysis of attrition reasons through usage. OBJECTIVE: The objective was to obtain daily attrition rates among adolescents in an mHealth intervention to gain a deeper understanding of attrition patterns, including the role of motivational support, such as altruistic rewards, through analysis of app usage data. METHODS: A randomized controlled trial was conducted with 304 adolescent participants (152 boys and 152 girls) aged 13-15 years. Based on 3 participating schools, participants were randomly assigned to control, treatment as usual (TAU), and intervention groups. Measures were obtained at baseline, continuously throughout the 42-day trial period (research groups), and at the trial end. The mHealth app is called SidekickHealth and is a social health game with the following 3 main categories: nutrition, mental health, and physical health. Primary measures were attrition based on time from launch, and the type, frequency, and time of health behavior exercise usage. Outcome differences were obtained through comparison tests, while regression models and survival analyses were used for attrition measures. RESULTS: Attrition differed significantly between the intervention and TAU groups (44.4% vs 94.3%; χ21=61.220; P<.001). The mean usage duration was 6.286 days in the TAU group and 24.975 days in the intervention group. In the intervention group, male participants were active significantly longer than female participants (29.155 vs 20.433 days; χ21=6.574; P<.001). Participants in the intervention group completed a larger number of health exercises in all trial weeks, and a significant decrease in usage was observed from the first to second week in the TAU group (t105=9.208; P<.001) but not in the intervention group. There was a significant increase in health exercises in the intervention group from the fifth to sixth week (t105=3.446; P<.001). Such a significant increase in usage was not evident in the TAU group. The research group was significantly related to attrition time (hazard ratio 0.308, 95% CI 0.222-0.420), as well as the numbers of mental health exercises (P<.001) and nutrition exercises (P<.001). CONCLUSIONS: Differences in attrition rates and usage between groups of adolescents were identified. Motivational support is a significant factor for lowering attrition in adolescent mHealth interventions. The results point to sensitivity periods in the completion of diverse health tasks, and emphasis on time-specific attrition, along with the type, frequency, and time of health behavior exercise usage, is likely a fruitful avenue for further research on mHealth interventions for adolescent populations, in which attrition rates remain excessive. TRIAL REGISTRATION: ClinicalTrials.gov NCT05912439; https://clinicaltrials.gov/study/NCT05912439.

Body Composition in Fussy-Eating Children, with and without Neurodevelopmental Disorders, and Their Parents, Following a Taste Education Intervention.

Fussy eaters may have an increased risk of becoming overweight or obese as adolescents, with fussy eating and weight status also correlating with neurodevelopmental disorders (NDs) such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Further, maternal and children's weight status relationships are well-established. In this study, we analyzed the body composition of parent-child dyads using bioelectrical impedance analysis (BIA). Fifty-one children aged 8-12 years, with an ND (n = 18) and without (n = 33), and their parents, participated in a 7-week food-based Taste Education intervention with 6-month follow-up. The paired t-test was used to compare differences in body composition based on children's ND status. In logistic regression analysis, odds of children being in the overweight/obese or overfat/obese categories increased by a factor of 9.1 and 10.6, respectively, when having NDs, adjusting for parents' BMI (body mass index) or fat percentage (FAT%). Children with NDs and their parents had significantly higher mean BMI-SDS (BMI standard deviation score) and FAT% at pre-intervention than children without NDs and their parents. Mean BMI-SDS and FAT% lowered significantly between time points for children with NDs and their parents but not for children without NDs or their parents. The findings underline the need for additional exploration into the relationships between children's and parents' body composition based on children's ND status.

Changes in Eating Behaviors Following Taste Education Intervention: Focusing on Children with and without Neurodevelopmental Disorders and Their Families: A Randomized Controlled Trial.

Fussy-eating children often display problematic behaviors around mealtimes, such as irritation, opposition, or may even throw tantrums. This may lead to reduced food variety and poor nutritional profiles, which may increase parents' worries about their children's diet, particularly when the children also have neurodevelopmental disorders (ND) such as Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactive Disorder (ADHD). To investigate the effect of Taste Education on problematic mealtime behaviors, 81 children aged 8-12 years, with ND (n = 33) and without (n = 48), and their parents, participated in a 7-week Taste Education intervention. Children were matched on age, sex, and ND, and allocated at random into Immediate-intervention and Delayed-intervention groups. Parents completed the Meals in Our Household Questionnaire (MiOH). To examine changes in MiOH-scores, repeated-measures analysis-of-variance with time-points were used, with condition as factors (Immediate intervention and Delayed intervention). Baseline measures were adjusted for, and a robust linear mixed-model was fitted. Results showed superior outcomes for Intervention compared to waiting on all measures of MiOH, with stable effects through six-month follow-up. Differences were non-significant between children with and without ND. The Taste Education program suggests a promising, simple, and non-intrusive way to reduce children's problematic mealtime behaviors in the long term.

Multiomics study of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.

[Graves' disease in children and adolescents in Iceland].

INTRODUCTION: Graves' disease is an autoimmune disease in which autoantibodies cause an increase in the production of thyroid hormones, and is the most common cause of thyrotoxicosis in children. Symptoms in children are often more obscure than in adults. The aim of the study is to assess the incidence of Graves' disease in children and adolescents in Iceland over the span of two decades (2001-2021), and furthermore to investigate if the incidence rate has increased, as well as to describe treatment options and disease recurrence. MATERIAL/METHODS: This retrospective descriptive study included all children diagnosed with Graves' disease in the years 2001-2021 in Iceland. Information was obtained from the Directorate of Health's drug database and from ICD-10 diagnoses at Landspítali - The National University Hospital. RESULTS: In total, 57 children and adolescents were diagnosed with Graves', the overall incidence rate was 3.5/100,000 person-years. Gender ratio was 1:2.7 (male : female) and the mean age at diagnosis was 13.6 for boys and 13.9 years for girls. Of those 12 individuals currently receiving drug therapy (21.8%), four patients have had disease relapse. Thirteen patients reached an euthyroid state with medication (23.7%), 25 received treatment with radioactive iodine (45.5%) and 5 underwent surgery (9.1%). Boys were more likely to relapse. Disease recurrence was 31.8%. CONCLUSION: The incidence of Graves' disease did not increase during the study period. The disease was more common in girls, although the gender ratio was lower than expected. Antithyroid drugs were the first choice in treatment and radioactive iodine was the most common permanent treatment option. Disease recurrence was common. A possible relationship between the duration of the original drug therapy and disease recurrence should be investigated.

Odds of fussy eating are greater among children with obesity and anxiety.

BACKGROUND: Fussy eating has been associated with autism spectrum disorder (ASD), attention-deficit/hyperactive disorder (ADHD), anxiety, and depression. Despite these disorders being prevalent in obesity treatment, no studies have been published on the association of fussy eating in children with obesity and these disorders. Understanding fussy eating in children with obesity and comorbid disorders is important as acceptance of healthy foods tends to be low, especially in children with sensory sensitivities. OBJECTIVES: Investigate the prevalence of fussy eating in a cross-sectional sample of children with obesity and ASD, ADHD, anxiety, and depression; and whether they were more likely to be fussy eaters, comparing those with and without these disorders. METHODS: One hundred and four children referred to family-based obesity treatment in Iceland 2011-2016, mean age 12.0 (SD = 3.0), mean body mass index standard deviation score 3.5 (SD = 0.9). Binary logistic regression was used to estimate the relationship between fussy eating and disorders, adjusting for medication use. RESULTS: A large minority (41.6%) were fussy eaters and 48.9% had at least one comorbid disorder. Over a third of children rejected bitter and sour tastes, and 1.9% and 7.9% rejected sweet and salty tastes, respectively. Compared with those without disorders, the odds of being a fussy eater were increased by a factor of 4.11 when having anxiety (95% confidence intervals) (1.02-16.58, p = 00.046), adjusting for medication use. The odds of being a fussy eater were not increased for other disorders; ASD, ADHD, or depression. CONCLUSIONS: In children attending obesity treatment, fussy eating was common. Clinical care models in pediatric obesity treatment should address fussy eating, especially in children with anxiety.

Randomized Trial for Weight Loss Using a Digital Therapeutic Application.

BACKGROUND: Smartphones present a near-ubiquitous channel through which structured lifestyle change can reduce risk or progression of the most common noncommunicable diseases. We explored whether a digital structured lifestyle program enhances weight loss. METHODS: We randomized overweight and obese participants attending a four-month lifestyle change program to either standard weekly coaching sessions (controls), or standard treatment supplemented with a digital therapeutic mobile application (intervention). Changes in body mass index after four months were the main outcome measure. Odds ratios of achieving 5% weight loss were estimated with unconditional logistic regression. RESULTS: Of 234 eligible persons, 146 (62%) agreed to participate, were block-randomized, showed up for the baseline measures, and constituted the intention-to-treat (ITT) sample (n = 95 intervention group, n = 51 control group). In the intervention group, 70 (74%) downloaded the mobile application and completed the program (intervention per-protocol). Significant weight loss and BMI reduction were observed for both the intention-to-treat intervention group (P < 0.05, P = 0.01) and the per-protocol intervention group (P < 0.0001, P < 0.0001). For the intervention per-protocol group, the odds ratio of achieving 5% weight loss, compared to not treated per-protocol, was 3.3 (95% CI 1.3-8.2), adjusting for age and weight at baseline.Attendance to weekly coaching sessions decreased by 18% during the program in the control group while it increased by 3% amongst the per-protocol group (P = 0.004). CONCLUSIONS: These preliminary findings support the benefit of a digital therapeutic to enhance weight reduction and attendance in a structured lifestyle change program. Larger trials of longer duration are needed to confirm these findings.

Growth Rate in Childhood and Adolescence and the Risk of Breast and Prostate Cancer: A Population-Based Study.

Growth rate is regulated by hormonal pathways that might affect early cancer development. We explored the association between rate of growth in height from ages 8 to 13 years (childhood) and from age 13 to attainment of adult height (adolescence), as measured at study entry, and the risk of breast or prostate cancer. Participants were 2,037 Icelanders born during 1915-1935, who took part in the Reykjavik Study, established in 1967. Height measurements were obtained from school records and at study entry. We used multivariable Cox regression models to calculate hazard ratios with 95% confidence intervals of breast and prostate cancer by rates of growth in tertiles. During a mean follow-up of 66 years (women) and 64 years (men), 117 women were diagnosed with breast cancer and 118 men with prostate cancer (45 with advanced disease). Women in the highest growth-rate tertile in adolescence had a higher risk of breast cancer (hazard ratio = 2.4, 95% confidence interval: 1.3, 4.3) compared with women in the lowest tertile. A suggestive inverse association was observed for highest adolescent growth rate in men and advanced prostate cancer: hazard ratio = 0.4, 95% confidence interval: 0.2, 1.0. Rapid growth, particularly in adolescence may affect cancer risk later in life.

Taste education - A food-based intervention in a school setting, focusing on children with and without neurodevelopmental disorders and their families. A randomized controlled trial.

Children with neurodevelopmental disorders (ND) such as Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactive Disorder (ADHD) have high levels of fussy eating. However, no school-based food interventions exist for children with ASD and ADHD. To investigate the effect of Taste Education, 81 children with ND (n = 33), and without (n = 48), aged 8-12 years, and their parents, participated in a 7-week food intervention. Children were matched on age, ND, and sex, and randomized into Immediate-intervention and Delayed-intervention groups. Parents completed the Children's Eating Behaviour Questionnaire (CEBQ), and a food-variety questionnaire. After adjusting for baseline measures, repeated-measures analysis-of-variance with time-points, and condition as factors (Immediate intervention and Delayed intervention) were used to examine changes in CEBQ-scores, with a robust linear mixed-model fitted. Changes in percentage of accepted foods were tested using a logistic-regression model adjusting for baseline acceptance. Results showed superior results for Intervention compared to waiting, on Food fussiness, but not Enjoyment of food, with stable effects through six-months follow-up. There were non-significant differences between children with and without ND. Results also showed increased odds of accepting vegetables by a factor of 1.6 (95% Confidence Interval [CI]: 1.33-1.93, p < .001); nuts and seeds by a factor of 1.4 (95% CI: 1.27-1.6, p < .001), but no significant association for fruit (OR 1.12, 95% CI: 0.92-1.34, p = .244). Trends were similar for children regardless of ND-status. The Taste Education program, shows promise, as a simple, non-invasive way to decrease fussy eating and increase food variety in the long-term.

Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland.

Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.

Mode of delivery was associated with transient changes in the metabolomic profile of neonates.

AIMS: To estimate potential differences in neonatal metabolomic profiles at birth and at the time of newborn screening by delivery mode. METHODS: A prospective study at Women's Clinic at Landspitali-The National University Hospital of Iceland. Women having normal vaginal birth or elective caesarean section from November 2013 to April 2014 were offered participation. Blood samples from mothers before birth and umbilical cord at birth were collected and amino acids and acylcarnitines measured by tandem mass spectrometry. Results from the Newborn screening programme in Iceland were collected. Amino acids and acylcarnitines from different samples were compared by delivery mode. RESULTS: Eighty three normal vaginal births and 32 elective caesarean sections were included. Mean differences at birth were higher for numerous amino acids, and some acylcarnitines in neonates born vaginally compared to elective caesarean section. Maternal blood samples and newborn screening results showed small differences that lost significance after correction for multiple testing. Many amino acids and some acylcarnitines were numerically higher in cord blood compared to maternal. Many amino acids and most acylcarnitines were numerically higher in newborn screening results compared to cord blood. CONCLUSION: We observed transient yet distinct differences in metabolomic profiles between neonates by delivery mode.

Spermatogonia Loss Correlates with LAMA 1 Expression in Human Prepubertal Testes Stored for Fertility Preservation.

Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.

Usage and Weekly Attrition in a Smartphone-Based Health Behavior Intervention for Adolescents: Pilot Randomized Controlled Trial.

BACKGROUND: The majority of adolescents own smartphones, although only 8% of them use health apps. Attrition rates from adolescent mobile health (mHealth) interventions for treating mental health problems such as anxiety and depression are an issue with a high degree of variation. Attrition in mHealth interventions targeting adolescent populations is frequently presented in a two-point fashion, from initiation of the intervention to the end of treatment, lacking more time-specific information on usage and times of attrition. Self-efficacy could provide an avenue to lower attrition rates, although a better understanding of the relationship between mental health factors and time-specific attrition rates is needed. OBJECTIVE: The aims of this study were to obtain time-specific attrition rates among adolescents in an mHealth intervention, and to describe the intervention's usage and feasibility in relation to adolescent self-efficacy levels, and emotional and physical health. METHODS: A single-center randomized controlled public school pilot trial was undertaken with 41 adolescents. Outcome measures were assessed at baseline and after 6 weeks, while in-app activity and attrition rates were continually assessed throughout the intervention period. The primary outcome was attrition based on time and type of in-app health behavior usage, and feasibility of the mHealth app. Secondary outcome measures were self-efficacy levels, depressive and anxiety symptoms, as well as standardized BMI and sleep. Analyses of group mean variances with adjusted α levels through Bonferroni corrections were used to assess main outcome effects. RESULTS: The attrition from initiation of the intervention to 6-week follow up was 35%. Attrition started in the third week of the intervention and was related to daily time of app usage (Rt=0.43, P<.001). The number of average weekly in-app health exercises completed decreased significantly from the first week of the intervention (mean 55.25, SD 10.96) to the next week (mean 13.63, SD 2.94). However, usage increased by 22% between week 2 and the last week of the intervention (mean 16.69, SD 8.37). Usability measures revealed satisfactory scores (mean 78.09, SD 9.82) without gender differences (P=.85). Self-reported daily physical activity increased by 19.61% in the intervention group but dropped by 26.21% among controls. Self-efficacy levels increased by 8.23% in the invention arm compared to a 3.03% decrease in the control group. CONCLUSIONS: This pilot study demonstrated the feasibility and usability of an mHealth intervention among adolescent participants. Indications were toward beneficial effects on physical and mental health that warrant further research. Focus on time-specific attrition measures alongside daily times of usage and ways to increase participants' self-efficacy levels appear to be a promising avenue for research on mHealth interventions for adolescent populations with the aim to ultimately lower attrition rates.

Does metabolomic profile differ with regard to birth weight?

BACKGROUND: Macrosomia and child obesity are growing health-care issues worldwide. The purpose of the study was to evaluate how extremely high or low birth weight affects metabolic markers evaluated in newborn screening. METHODS: The study was register-based and included full-term singletons born in Iceland from 2009 to 2012 with newborn screening samples taken 72-96 h after birth. Three groups based on birth weight were compared: low birth weight (<2500 g), appropriate-for-gestational age, and extreme macrosomia (≥5000 g). The comparison was adjusted for possible confounding factors. RESULTS: Compared to appropriate-for-gestational age neonates, both low birth weight and extreme macrosomia were associated with higher levels of glutamic acid. The amino acids alanine and threonine were increased in low birth weight neonates. Free carnitine and some medium- and long-chain acylcarnitines were higher in low birth weight infants. Hydroxybutyrylcarnitine was lower in low birth weight infants, but higher in extremely macrosomic neonates. Acetylcarnitine was higher in low birth weight and extremely macrosomic neonates. Succinylcarnitine was lower and hexadecenoylcarnitine higher in macrosomic newborns. CONCLUSION: Low birth weight and extremely macrosomic neonates show distinctive differences in their metabolomic profile compared to appropriate-for-gestational age newborns. The differences are not explained by gestational age. IMPACT: The key message of this article is that both low birth weight and extremely macrosomic newborns show dissimilar metabolomic profiles compared to appropriate-for-gestational age neonates. The article contributes to knowledge on what affects evaluation of results in newborn screening. The impact of this article is to provide information on metabolism at both ends of the birth weight range after accounting for confounding factors including gestational age.

Pubertal development and risk of premenstrual disorders in young adulthood.

STUDY QUESTION: Is pubertal timing associated with risk of premenstrual disorders (PMDs) in young adulthood? SUMMARY ANSWER: Late pubertal development is associated with decreased premenstrual symptom burden and risk of PMDs in young adulthood. WHAT IS KNOWN ALREADY: PMDs, including premenstrual syndrome and premenstrual dysphoric disorder, may begin during the teenage years. Few risk factors in early life have been identified for PMD development. STUDY DESIGN, SIZE, DURATION: A prospective cohort study of 6495 female participants during 1996-2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included participants from the Growing Up Today Study (GUTS). Pubertal development was indicated by the timing of menarche, breast and pubic hair growth. Self-reported age at menarche was longitudinally assessed at enrollment (in 1996/2004 for GUTS I/II) and onwards, and classified as early (age ≤ mean - SD, 11.64 years), normative and late menarche (age ≥ mean + SD, 13.95 years). Timing of pubic hair and breast growth were assessed multiple times during follow-up via Tanner scales, and classified into early, normative and late development according to mean ± SD. Using a validated questionnaire based on the Calendar of Premenstrual Experiences, we assessed premenstrual symptoms and identified probable cases of PMDs in 2013. We examined the associations of timing of pubertal development with premenstrual symptom score and disorders using multivariable linear and logistic regressions, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In 2013 (mean age = 26), 1001 (15.4%) individuals met criteria for a PMD. An inverse association was found between age at menarche and premenstrual symptom z-score (ß -0.05 per year, 95% CI -0.07 to -0.03) and risk of PMDs (odds ratio (OR) 0.93 per year, 95% CI 0.88 to 0.99). Compared to individuals with normative menarche, individuals with late menarche had a lower risk of PMDs (OR 0.73, 95% CI 0.59 to 0.91), while individuals with early menarche had comparable odds (OR 0.98, 95% CI 0.81 to 1.18). Moreover, early growth of pubic hair was associated with increased premenstrual symptoms (z-score ß 0.09 per year, 95% CI 0.02 to 0.17) and PMD risk (OR 1.28, 95% CI 1.04 to 1.56), independent of age at menarche. No associations were noted for breast development. LIMITATIONS, REASONS FOR CAUTION: One major limitation is some misclassification of menarche due to recall. We, however, showed robust association among participants who were premenarcheal at baseline. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that pubertal timing, particularly timing of menarche, is inversely associated with the risk of developing premenstrual symptoms in young adulthood, and that women with later menarche have significantly lower risk of PMDs. Information on PMDs should be provided to teenage girls and their parents. If these findings are confirmed in independent populations, prevention strategies and early detection programs may be considered for women with early pubertal development. STUDY FUNDING/COMPETING INTEREST(S): The work is supported by the National Institutes of Health and Swedish Research Council. TRIAL REGISTRATION NUMBER: N/A.