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Background: Gastroschisis prevalence has increased for decades with corresponding increases in the need for immediate and follow-up care. Such care can be complicated by presence of co-occurring malformations. This study explores prevalence of gastroschisis and co-occurring malformations among a 28-year cohort of Danish live-born infants., Methods: This retrospective cohort study used data from 1,695,992 infants born in Denmark during 1994-2021 and registered in the neonatal screening program. Infants were identified from the Danish Civil Registration System and Danish National Patient Register accessed through the Danish Biobank Register. Data on co-occurring malformations were ascertained to classify infants as syndromic or non-syndromic (either isolated or with co-occurring major malformations) and on selected infant and parental characteristics. Poisson regression models were used to estimate prevalence and corresponding 95% confidence intervals (CIs)., Results: Prevalence (per 10,000 live births) of gastroschisis was 1.64 (CI: 1.45-1.84). Temporal trend analyses showed a statistically significant annual increase of 2.8% (CI: 1.4-3.3). Infants with gastroschisis most often presented as isolated (77.7%; CI: 72.3-82.5), followed by those with co-occurring malformations (21.9%; CI: 17.2-27.3) or a diagnosed syndrome (0.4%, CI: <0.1-2.0). Among infants with co-occurring malformations, cardiovascular (10.9%; CI: 6.8; 12.2) and intestinal (9.0%; CI: 5.9-12.2) malformations were most frequently recorded. Prevalence was higher among infants classified as premature but not influenced by infant sex or parental nativity., Conclusion: Gastroschisis prevalence in Denmark increased during 1994-2021, similar to international reports, without increase in co-occurring malformations. Future work with this cohort will characterize healthcare received, comorbidities, and outcomes across the lifespan., Levels of Evidence: Level III (High-quality prospective cohort study)., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that may have influenced the work in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To evaluate the association between maternal BMI and congenital heart defects (CHDs) in the offspring when including live births, stillbirths, aborted and terminated pregnancies and to investigate if maternal interpregnancy weight changes between the first and second pregnancy influences the risk of foetal CHDs., Methods: A nationwide cohort study of all singleton pregnancies in Denmark from 2008 to 2018. Data were retrieved from the Danish Foetal Medicine Database, which included both pre- and postnatal diagnoses of CHDs. Children or foetuses with chromosomal aberrations were excluded. Odds ratios were calculated with logistic regression models for CHDs overall, severe CHDs and five of the most prevalent subtypes of CHDs., Results: Of the 547 105 pregnancies included in the cohort, 5 442 had CHDs (1.0%). Risk of CHDs became gradually higher with higher maternal BMI; for BMI 25-29.9 kg/m 2 , adjusted odds ratio (aOR) 1.17 (95% CI 1.10-1.26), for BMI 30-34.9 kg/m 2 , aOR 1.21 (95% CI 1.09-1.33), for BMI 35-39.9 kg/m 2 , aOR 1.29 (95% CI 1.11-1.50) and for BMI ≥ 40 kg/m 2 , aOR 1.85 (95% CI 1.54-2.21). Data was adjusted for maternal age, smoking status and year of estimated due date. The same pattern was seen for the subgroup of severe CHDs. Among the atrioventricular septal defects (n = 231), an association with maternal BMI ≥ 30 kg/m 2 was seen, OR 1.67 (95% CI 1.13-2.44). 109 654 women were identified with their first and second pregnancies in the cohort. Interpregnancy BMI change was associated with the risk of CHDs in the second pregnancy (BMI 2 to < 4 kg/m 2 : aOR 1.29, 95% CI 1.09-1.53; BMI ≥ 4 kg/m 2 : aOR 1.36, 95% CI 1.08-1.68)., Conclusion: The risk of foetal CHDs became gradually higher with higher maternal BMI and interpregnancy weight increases above 2 BMI units were also associated with a higher risk of CHDs., (© 2024. The Author(s).)

Objective: To determine whether mitochondrial haplogroups function as disease-modifiers or as susceptibility factors in preeclampsia using a traditional haplogroup association model., Methods: This retrospective study haplotyped 235 control and 78 preeclamptic pregnancies from Denmark using either real-time PCR or Sanger sequencing depending on the rarity of the haplogroup., Results: No significant association between haplogroups and the risk of preeclampsia was found, nor was any role for haplogroups in disease severity uncovered., Conclusion: Mitochondrial haplogroups are not associated with preeclampsia or the severity of preeclampsia in the Danish population. However, this study cannot exclude a role for less common mtDNA variation. Models that can examine these should be applied in preeclamptic patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Congenital talipes equinovarus (clubfoot) is a common musculoskeletal anomaly, with a suspected multifactorial etiopathogenesis. Herein, we used publicly available data to ascertain liveborn infants with clubfoot delivered in Denmark during 1994-2021, and to classify co-occurring congenital anomalies, estimate annual prevalence, and compare clubfoot occurrence with maternal smoking rates, a commonly reported risk factor. Characterizing this nationwide, liveborn cohort provides a population-based resource for etiopathogenic investigations and life course surveillance., Methods: This case-cohort study used data from the Danish National Patient Register and Danish Civil Registration System, accessed through the publicly available Danish Biobank Register, to identify 1,315,282 liveborn infants delivered during 1994-2021 in Denmark to Danish parents. Among these, 2,358 infants (65.1% male) were ascertained with clubfoot and classified as syndromic (co-occurring chromosomal, genetic, or teratogenic syndromes) and nonsyndromic (isolated or co-occurring multiple congenital anomalies [MCA]). Annual prevalence estimates and corresponding 95% confidence intervals (CIs) for children with nonsyndromic clubfoot were estimated using Poisson regression and compared with population-based, maternal annual smoking rates obtained from publicly available resources., Results: Infants most often presented with nonsyndromic clubfoot (isolated = 88.6%; MCA = 11.4%); limb and heart anomalies were the most frequently identified MCAs. Prevalence (per 1,000 liveborn infants) was 1.52 (CI 1.45-1.58) for isolated and 0.19 (CI 0.17-0.22) for MCA clubfoot. Prevalence estimates for both isolated and MCA clubfoot remained relatively stable during the study period, despite marked decreases in population-based maternal smoking rates., Conclusions: From 1994 to 2021, prevalence of nonsyndromic clubfoot in Denmark was relatively stable. Reduction in population-level maternal smoking rates did not seem to impact prevalence estimates, providing some support for the suspected multifactorial etiopathogenesis of this anomaly. This nationwide, liveborn cohort, ascertained and clinically characterized using publicly available data from the Danish Biobank Register, provides a population-based clinical and biological resource for future etiopathogenic investigations and life course surveillance., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Pre-eclampsia (PE) is a leading cause of perinatal morbidity and mortality worldwide. Low-dose aspirin can prevent PE in high risk pregnancies if started early. However, despite intense research into the area, early pregnancy screening for PE risk is still not a routine part of pregnancy care. Several studies have described the application of artificial intelligence (AI) and machine learning (ML) in risk prediction of PE and its subtypes. A systematic review of available literature is necessary to catalogue the current applications of AI/ML methods in early pregnancy screening for PE, in order to better inform the development of clinically relevant risk prediction algorithms which will enable timely intervention and the development of new treatment strategies. The aim of this systematic review is to identify and assess studies regarding the application of AI/ML methods in early pregnancy screening for PE., Methods: A systematic review of peer-reviewed as well as the pre-published cohort, case-control, or cross-sectional studies will be conducted. Relevant information will be accessed from the following databases; PubMed, Google Scholar, Scopus, Embase, Web of Science, Cochrane Library, Arxiv, BioRxiv, and MedRxiv. The studies will be evaluated by two reviewers in a parallel, blind assessment of the literature, a third reviewer will assess any studies in which the first two reviewers did not agree. The free online tool Rayyan, will be used in this literature assessment stage. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist will be used to guide the review process and the methods of the studies will be assessed using the Newcastle-Ottawa scale. Narrative synthesis will be conducted for all included studies. Meta-analysis will also be conducted where data quality and availability allow., Ethics and Dissemination: The review will not require ethical approval and the findings will be published in a peer-reviewed journal using the PRISMA guidelines., Trial Registration: Trial registration: The protocol for this systematic review has been registered in PROSPERO [CRD42022345786]. https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42022345786., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Casper Wilstrup is founder and CEO of Abzu, a company developing AI/ML based research tools. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Hedley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In Denmark, a nationwide COVID-19 lockdown was implemented on March 12, 2020 and eased on April 14, 2020. The COVID-19 lockdown featured reduced prevalence of extremely preterm or extremely low birthweight births. This study aims to explore the impact of this COVID-19 lockdown on term birthweights in Denmark. We conducted a nationwide register-based cohort study on 27,870 live singleton infants, born at term (weeks 37-41), between March 12 and April 14, 2015-2020, using data from the Danish Neonatal Screening Biobank. Primary outcomes, corrected for confounders, were birthweight, small-for-gestational-age (SGA), and large-for-gestational-age (LGA), comparing the COVID-19 lockdown to the previous five years. Data were analysed using linear regression to assess associations with birthweight. Multinomial logistic regression was used to assess associations with relative-size-for-gestational-age (xGA) categories. Adjusted mean birthweight was significantly increased by 16.9 g (95% CI = 4.1-31.3) during the lockdown period. A dip in mean birthweight was found in gestational weeks 37 and 38 balanced by an increase in weeks 40 and 41. The 2020 lockdown period was associated with an increased LGA prevalence (aOR 1.13, 95% CI = 1.05-1.21). No significant changes in proportions of xGA groups were found between 2015 and 2019. The nationwide COVID-19 lockdown resulted in a small but significant increase in birthweight and proportion of LGA infants, driven by an increase in birthweight in gestational weeks 40 and 41., Competing Interests: Dr Breindahl has a patent (NeoHelp) with royalties paid. Dr Breindahl has nothing else to disclose. All other authors have nothing else to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 de Knegt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study, we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using these data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype-phenotype associations with an autism spectrum disorder. One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome-sequenced sub-cohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research study, comprising 72 hydrocephalus patients and 4181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and an autism spectrum disorder. The median age at diagnosis for the hydrocephalus patients was 0 years (range 0-27 years), the median age at analysis was 22 years (11-35 years), and 70.5% were males. The median age for controls was 18 years (range 11-26 years) and 53.3% were males. Fifty-two putative hydrocephalus-associated variants in 34 genes were identified in 42 patients (58.3%). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (odds ratio 1.51, 95% confidence interval 0.92-2.51, P = 0.096 ), which was driven by a significant enrichment of rare protein truncating variants (odds ratio 2.71, 95% confidence interval 1.17-5.58, P = 0.011 ). Fourteen of the genes with high-impact variants are part of the ciliome, whereas another six genes affect cilia-dependent processes during neurogenesis. Furthermore, 15 of the 34 genes with high-impact variants and three of eight genes with protein truncating variants were associated with an autism spectrum disorder. Because symptoms of other diseases may be neglected or masked by the hydrocephalus-associated symptoms, we suggest that patients with congenital hydrocephalus undergo clinical genetic assessment with respect to ciliopathies and an autism spectrum disorder. Our results point to the significance of hydrocephalus as a ciliary disease in some cases. Future studies in brain ciliopathies may not only reveal new insights into hydrocephalus but also, brain disease in the broadest sense, given the essential role of cilia in neurodevelopment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The world has seen numerous infectious disease outbreaks in the past decade. In many cases these outbreaks have had considerable perinatal health consequences including increased risk of preterm delivery (e.g., influenza, measles, and COVID-19), and the delivery of low birth weight or small for gestational age babies (e.g., influenza, COVID-19). Furthermore, severe perinatal outcomes including perinatal and infant death are a known consequence of multiple infectious diseases (e.g., Ebola virus disease, Zika virus disease, pertussis, and measles). In addition to vaccination during pregnancy (where possible), pregnant women, are provided some level of protection from the adverse effects of infection through community-level application of evidence-based transmission-control methods. This review demonstrates that it takes almost 2 years for the perinatal impacts of an infectious disease outbreak to be reported. However, many infectious disease outbreaks between 2010 and 2020 have no associated pregnancy data reported in the scientific literature, or pregnancy data is reported in the form of case-studies only. This lack of systematic data collection and reporting has a negative impact on our understanding of these diseases and the implications they may have for pregnant women and their unborn infants. Monitoring perinatal health is an essential aspect of national and global healthcare strategies as perinatal life has a critical impact on early life mortality as well as possible effects on later life health. The unpredictable nature of emerging infections and the potential for adverse perinatal outcomes necessitate that we thoroughly assess pregnancy and perinatal health implications of disease outbreaks and their public health interventions in tandem with outbreak response efforts. Disease surveillance programs should incorporate perinatal health monitoring and health systems around the world should endeavor to continuously collect perinatal health data in order to quickly update pregnancy care protocols as needed., Competing Interests: Author PH held an unpaid position at Brazen Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Malange, Hedermann, Lausten-Thomsen, Hoffmann, Voldstedlund, Aabakke, Eltvedt, Jensen, Breindahl, Krebs, Christiansen and Hedley.)

The serum adiponectin/leptin ratio (A/L ratio) is a surrogate marker of insulin sensitivity. Pre-eclampsia (PE) is associated with maternal metabolic syndrome and occasionally impaired fetal growth. We assessed whether the A/L ratio in first-trimester maternal serum was associated with PE and/or birth weight. Adiponectin and leptin were quantitated in first-trimester blood samples (gestational week 10+3−13+6) from 126 women who later developed PE with proteinuria (98 mild PE; 21 severe PE; 7 HELLP syndrome), and 297 controls, recruited from the Copenhagen First-Trimester Screening Study. The A/L ratio was reduced in PE pregnancies, median 0.17 (IQR: 0.12−0.27) compared with controls, median 0.32 (IQR: 0.19−0.62) (p < 0.001). A multiple logistic regression showed that PE was negatively associated with log A/L ratio independent of maternal BMI (odds ratio = 0.315, 95% CI = 0.191 to 0.519). Adiponectin (AUC = 0.632) and PAPP-A (AUC = 0.605) were negatively associated with PE, and leptin (AUC = 0.712) was positively associated with PE. However, the A/L ratio was a better predictor of PE (AUC = 0.737), albeit not clinically relevant as a single marker. No significant association was found between A/L ratio and clinical severity of pre-eclampsia or preterm birth. PE was associated with a significantly lower relative birth weight (p < 0.001). A significant negative correlation was found between relative birth weight and A/L ratio in controls (β = −0.165, p < 0.05) but not in PE pregnancies), independent of maternal BMI. After correction for maternal BMI, leptin was significantly associated with relative birth weight (β = 2.98, p < 0.05), while adiponectin was not significantly associated. Our findings suggest that an impairment of the A/L ratio (as seen in metabolic syndrome) in the first trimester is characteristic of PE, while aberrant fetal growth in PE is not dependent on insulin sensitivity, but rather on leptin-associated pathways.

The aim of this study was to determine whether COVID-19 restrictions had an impact on Chlamydia trachomatis infections compared with 2018 and 2019. A retrospective nationwide observational study was performed using monthly incidences of laboratory-confirmed chlamydia cases and number of tests, obtained from Danish national surveillance data. Testing rates and positivity rates were compared using Poisson and logistic regression. The first Danish COVID-19 lockdown (12 March to 14 April 2020) resulted in a reduction in the number of chlamydia tests performed (rate ratio 0.72, 95% confidence interval  0.71-0.73) and a consequent reduction in the number of laboratory-identified cases (66.5 vs 88.3 per 100,000 population during the same period in 2018 to 2019). This period was followed by a return of testing and test positivity close to the level seen in 2018 to 2019. The second Danish COVID-19 lockdown (17 December to 31 March 2021) resulted in crude incidence rates of laboratory-confirmed chlamydia infection that were similar to the crude incidence rates seen during same period in 2018 to 2019. In conclusion, the Danish COVID-19 restrictions have had negligible effects on laboratory-confirmed C. trachomatis transmission.

Using provisional or opportunistic data, three nationwide studies (The Netherlands, the USA and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, none of the studies accounted for perinatal deaths. To determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be the result of an increase in perinatal deaths and to assess the impact of extended COVID-19 restrictions, we performed a nationwide Danish register-based prevalence proportion study. We examined all singleton pregnancies delivered in Denmark during the COVID-19 strict lockdown calendar periods (March 12-April 14, 2015-2020, N = 31,164 births) and the extended calendar periods of COVID-19 restrictions (February 27-September 30, 2015-2020, N = 214,862 births). The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period in 2020, while perinatal mortality was not significantly different. During the extended period of restrictions in 2020, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found.Conclusion: Stillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support the design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes. What is Known: • The aetiologies of preterm birth and stillbirth are multifaceted and linked to a wide range of socio-demographic, medical, obstetric, foetal, psychosocial and environmental factors. • The COVID-19 lockdown saw a reduction in extremely preterm births in Denmark and other high-income countries. An urgent question is whether this reduction can be explained by increased perinatal mortality. What is New: • The reduction in extremely preterm births during the Danish COVID-19 lockdown was not a consequence of increased perinatal mortality, which remained unchanged during this period. • The stillbirth rate was reduced throughout the extended period of COVID-19 restrictions., (© 2021. The Author(s).)

Objectives: Human milk oligosaccharides (HMOs) impact the intestinal microbiota by increasing beneficial bacteria in infants and adults, and are safe and well tolerated in these age groups. Effects on intestinal microbiota, safety, and digestive tolerance in children have not been, however, assessed. The aims of this trial were to evaluate if HMOs are able to specifically modulate the intestinal microbiota in children, and to assess safety and digestive tolerance., Methods: In this randomized, double-blinded, placebo-controlled trial, 75 children with overweight (including obesity) ages 6 to 12 years were randomized to receive 2'-fucosyllactose (2'FL), a mix of 2'FL and lacto-N-neotetraose (Mix), or a glucose placebo orally administrated once per day for 8 weeks., Results: The relative abundance of bifidobacteria increased significantly after 4 (P < 0.001) and 8 (P = 0.025) weeks of intervention in the 2'FL-group and after 4 weeks (P = 0.033) in the Mix-group, whereas no change was observed in the placebo group. Compared with placebo, the 2'FL-group had a significant increase in bifidobacteria abundance after 4 weeks (P < 0.001) and 8 weeks (P = 0.010) and the Mix-group showed a tendency to increased bifidobacteria abundance after 4 (P = 0.071) and 8 weeks (P = 0.071). Bifidobacterium adolescentis drove the bifidogenic effect in the 2 groups. Biochemical markers indicated no safety concerns, and the products did not induce digestive tolerance issues as assessed by Gastrointestinal Symptoms Rating Scale and Bristol Stool Form Scale., Conclusions: Both 2'FL and the Mix beneficially modulate intestinal microbiota by increasing bifidobacteria. Furthermore, supplementation with either 2'FL alone or a Mix is safe and well tolerated in children., Competing Interests: L.K.V., I.D.A., and B.M. were employed at Glycom A/S, Denmark. The remaining authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Congenital heart defects (CHDs) are the most common congenital malformations. The aetiology of CHDs is complex. Large cohort studies and systematic reviews and meta-analyses based on these have reported an association between higher risk of CHDs in the offspring and individual maternal metabolic disorders such as obesity, diabetes, hypertension, and preeclampsia, all conditions that can be related to insulin resistance or hyperglycaemia. However, the clinical reality is that these conditions often occur simultaneously. The aim of this review is, in consequence, both to evaluate the existing evidence on the association between maternal metabolic disorders, defined as obesity, diabetes, hypertension, preeclampsia, dyslipidaemia and CHDs in the offspring, as well as the significance of combinations, such as metabolic syndrome, as risk factors., Methods: A systematic literature search of papers published between January 1, 1990 and January 14, 2021 was conducted using PubMed and Embase. Studies were eligible if they were published in English and were case-control or cohort studies. The exposures of interest were maternal overweight or obesity, hypertension, preeclampsia, diabetes, dyslipidaemia, and/or metabolic syndrome, and the outcome of interest was CHDs in the offspring. Furthermore, the studies were included according to a quality assessment score., Results: Of the 2,250 identified studies, 32 qualified for inclusion. All but one study investigated only the individual metabolic disorders. Some disorders (obesity, gestational diabetes, and hypertension) increased risk of CHDs marginally whereas pre-gestational diabetes and early-onset preeclampsia were strongly associated with CHDs, without consistent differences between CHD subtypes. A single study suggested a possible additive effect of maternal obesity and gestational diabetes., Conclusions: Future studies of the role of aberrations of the glucose-insulin homeostasis in the common aetiology and mechanisms of metabolic disorders, present during pregnancy, and their association, both as single conditions and-particularly-in combination, with CHDs are needed., Competing Interests: The authors have declared that no competing interests exist.

Background: The association between autism spectrum disorder and hydrocephalus is not well understood, despite demonstrated links between autism spectrum disorder and cerebrospinal fluid abnormalities. Based on the hypothesis that autism spectrum disorder and hydrocephalus may, at least in some cases, be two manifestations of a shared congenital brain pathology, we investigated the potential association between autism spectrum disorder and hydrocephalus in a large Danish population-based cohort., Methods: Patients and controls were obtained from the Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH2012 case-cohort, which includes all patients with selected psychiatric disorders born in Denmark 1981-2005 along with randomly selected population controls (end of follow-up, December 31, 2016). The associations between individual psychiatric disorders and hydrocephalus were estimated using binary logistic regression with adjustment for age and sex., Results: The cohort consisted of 86,571 individuals, of which 14,654 were diagnosed with autism spectrum disorder, 28,606 were population controls, and the remaining were diagnosed with other psychiatric disorders. We identified 201 hydrocephalus cases; 68 among autism spectrum disorder patients and 40 among controls (OR 3.77, 95% CI 2.48-5.78), which corresponds to an absolute risk of 0.46 % (i.e. approximately one in 217 children with autism spectrum disorder had co-occurring hydrocephalus). The autism spectrum disorder-hydrocephalus association was significant over the entire subgroup spectrum of autism spectrum disorder., Conclusions: Given the considerable risk of hydrocephalus among patients with autism spectrum disorder, we suggest that patients with autism spectrum disorder should be evaluated for co-occurring hydrocephalus on a routine basis as timely neurosurgical intervention is important. Likewise, attention must be paid to traits of autism spectrum disorder in children with hydrocephalus. The results of this study call for future investigations on a potential shared aetiology between hydrocephalus and autism spectrum disorder, including the role abnormal CSF dynamics in the pathogenesis of autism spectrum disorder.

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise to compromised intrauterine growth conditions and aberrant birth weight of offspring. This review was compiled to elucidate the metabolic background of PE and its relationship with adverse intrauterine growth conditions through the examination of leptin as well as to describe possible mechanisms linking leptin to fetal growth restriction. This review illustrates that leptin in PE is dysregulated in maternal, fetal, and placental compartments. There is no single set of unifying mechanisms within the spectrum of PE, and regulatory mechanisms involving leptin are specific to each situation. We conclude that dysregulated leptin is involved in fetal growth at many levels through complex interactions with parallel pregnancy systems and probably throughout the entirety of pregnancy.

To explore the impact of COVID-19 lockdown on premature birth rates in Denmark, a nationwide register-based prevalence proportion study was conducted on all 31 180 live singleton infants born in Denmark between 12 March and 14 April during 2015-2020.The distribution of gestational ages (GAs) was significantly different (p=0.004) during the lockdown period compared with the previous 5 years and was driven by a significantly lower rate of extremely premature children during the lockdown compared with the corresponding mean rate for the same dates in the previous years (OR 0.09, 95% CI 0.01 to 0.40, p<0.001). No significant difference between the lockdown and previous years was found for other GA categories.The reasons for this decrease are unclear. However, the lockdown has provided a unique opportunity to examine possible factors related to prematurity. Identification of possible causal mechanisms might stimulate changes in clinical practice., Competing Interests: Competing interests: MB has a patent (NeoHelp) with royalties paid., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

B-type natriuretic peptide (BNP) is a cardiac hormone secreted predominantly from the ventricles in response to increased ventricular pressure. Along this line, hypertensive patients with left ventricular hypertrophy typically have high circulating BNP concentrations. BNP has natriuretic and vasodilatory actions. Obese persons have low circulating BNP concentrations, and a relative lack of this natriuretic and vasodilatory factor could contribute to obesity-related hypertension. The relationship between BNP, BP, left ventricular mass (LVM), and left ventricular filling pressure among obese persons is not clear. To address this issue, we studied 98 healthy obese medication-free men with normal left ventricular ejection fraction. We measured BP using 24 -h ambulatory (A) BP recordings, LVM and E/e', an estimate of left ventricular filling pressure, using echocardiography, and fasting BNP in serum. Mean systolic ABP ± SD was 114 ± 4 mm Hg in 1 st and 149 ± 8 mm Hg in 4 th systolic ABP quartile, P < 0.001. LVM and E/e' increased across systolic ABP quartiles (mean LVM±SD: 81.5±13.7 g/m 2 in 1 st and 100.1 ± 26.7 g/m 2 in 4 th quartile, P = 0.018; mean E/e'±SD: 5.3±1.6 in 1 st and 7.0 ± 2.0 in 4 th quartile, P = 0.002). In contrast, serum BNP did not increase across systolic ABP quartiles (median (IQR): 6.7 (3.1-12.3) pg/ml in 1 st and 5.3 (2.8-9.7) pg/ml in 4 th quartile, P = 0.75). Unexpectedly, among healthy obese medication-free men, serum BNP does not increase with higher systolic ABP despite evidence of BP-related increases in LVM and E/e'. This further suggests that a relatively low amount of circulating BNP could contribute to obesity-related hypertension in its early stages., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Aims: Pediatric obesity associates with both low-grade inflammation and cardiometabolic risk on the population level. Yet on an individual patient level, overweight/obesity does not always equal increased cardiometabolic risk. In this study, we examine whether low-grade inflammation associates with cardiometabolic risk in Danish children, independent of degree of adiposity. We further assess the value of integrating multiple inflammation markers to identify children with very-high cardiometabolic risk profiles., Method and Results: We studied 2192 children and adolescents aged 6-18 years from an obesity clinic cohort and a population-based cohort, in a cross-sectional study design. Anthropometry, blood pressure, pubertal stage and body composition by dual-energy X-ray absorptiometry were assessed, and biomarkers including fasting serum high sensitivity C-reactive protein (hsCRP), white blood cells (WBC), resistin, lipid profile and glucose metabolism were measured. Adjusted correlation analysis and odds ratios were calculated. We found that, independent of degree of adiposity, having high-normal inflammation marker concentrations associated with increased cardiometabolic risk: for girls, hsCRP >0.57-9.98 mg/L (mid/upper tertile) associated with ~2-fold higher odds of dyslipidemia and hepatic steatosis (vs. lower tertile). For both sexes, WBC >7.0-12.4 10 9 /L (upper tertile) associated with 2.5-fold higher odds of insulin resistance. Lastly, children with multiple inflammation markers in the high-normal range exhibited the most severe cardiometabolic risk profile., Conclusion: Low-grade inflammation associates with cardiometabolic risk in children independent of degree of adiposity. The associations vary with sex and inflammation marker measured. Finally, integrating multiple low-grade inflammation markers identifies a very-high-risk subgroup of children with overweight/obesity and may have clinical value., Competing Interests: Declaration of Competing Interest JH received lecture fees from Novo Nordisk and is the owner of Dr Holm Ltd, which provides medical services, training and supervision. All other authors have nothing to disclose., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Mitochondrial DNA (mtDNA) haplogroup (hg) H has been reported as a susceptibility factor for hypertrophic cardiomyopathy (HCM). This was established in genetic association studies, however, the SNP or SNP's that are associated with the increased risk have not been identified. Hg H is the most frequent European mtDNA hg with greater than 80 subhaplogroups (subhgs) each defined by specific SNPs. We tested the hypothesis that the distribution of H subhgs might differ between HCM patients and controls. The subhg H distribution in 55 HCM index cases was compared to that of two Danish mtDNA hg H control groups ( n = 170 and n = 908, respectively). In the HCM group, H and 12 different H subhgs were found. All these, except subhgs H73, were also found in both control groups. The HCM group was also characterized by a higher proportion of H3 compared to H2. In the HCM group the H3/H2 proportion was 1.7, whereas it was 0.45 and 0.54 in the control groups. This tendency was replicated in an independent group of Hg H HCM index cases ( n = 39) from Queensland, Australia, where the H3/H2 ratio was 1.5. In conclusion, the H subhgs distribution differs between HCM cases and controls, but the difference is subtle, and the understanding of the pathogenic significance is hampered by the lack of functional studies on the subhgs of H.

Background: It is imperative to develop markers for risk stratification and detection of cardiometabolic comorbidities in children with obesity. The adipokines leptin and adiponectin are both involved in fat mass regulation and the development of obesity-related disorders; furthermore, their ratio (leptin/adiponectin ratio) is suggested to be associated with insulin resistance and cardiometabolic risk., Objective: To evaluate associations between fasting serum concentrations of the adipokines (total leptin and adiponectin as well as the L/A ratio) and cardiometabolic comorbidities in children with overweight/obesity., Methods: A total of 2258 children with overweight/obesity or normal weight aged 6 to 18 years were studied. Differences in anthropometrics and adipokine concentrations were tested using Wilcoxon rank-sum test. Associations between the adipokines and cardiometabolic risk were tested using Spearman's correlation and logistic regression, adjusted for age and body mass index SD score (BMI-SDS)., Results: Compared to normal weight children; children with overweight/obesity exhibited higher leptin concentrations, lower adiponectin concentrations, and higher L/A ratios. After adjusting for age and degree of obesity, girls with overweight/obesity in the upper quartile range for the L/A ratio, when compared with girls in the lower quartile range, were more likely to have insulin resistance (odds ratio [OR]: 7.78 [95% confidence interval [CI], 3.78-16.65]), dysglycemia (OR: 3.08 [95% CI, 1.35-7.31]), and dyslipidemia (OR: 2.53 [95% CI, 1.18-5.59]); while boys were more likely to have insulin resistance (OR: 4.45 [95% CI, 2.03-10.10])., Conclusions: Independent of the degree of obesity, leptin, adiponectin, and the L/A ratio were associated with insulin resistance and other cardiometabolic comorbidities in children with overweight/obesity, but the L/A ratio exhibited stronger associations than the respective adipokines., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background The association between thyroid-stimulating hormone (TSH) concentrations and blood pressure is well described in adults, but only studied to a limited extent in children and adolescents and almost entirely in population-based cohorts. The present study investigates the association between TSH and blood pressure, and the influence of leptin and adiponectin, in a cohort of children and adolescents enrolled in obesity treatment compared with a population-based cohort. Methods We studied 4154 children and adolescents aged 6-18 years from an obesity clinic cohort and a population-based cohort from The Danish Childhood Obesity Data- and Biobank. Anthropometrics, blood pressure and biochemical markers, including TSH, leptin and adiponectin concentrations, were collected. Adjusted correlation and interaction analyses were performed. Results Patients from the obesity clinic cohort exhibited higher concentrations of TSH and higher blood pressure than participants from the population-based cohort. TSH standard deviation scores (SDS) were significantly associated with all blood pressure-related variables in the population-based cohort, but only with systolic blood pressure SDS and hypertension in the obesity clinic cohort. The interaction between TSH SDS and adiponectin was found to be independently associated with systolic blood pressure and hypertension in the population-based cohort only. Conclusions The significant associations between TSH, adiponectin and blood pressure, observed in children and adolescents from a population-based cohort, are attenuated or absent in children and adolescents with overweight or obesity, suggesting that childhood obesity distorts the healthy interplay between the thyroid axis, thyroid-adipokine interaction and blood pressure.

Background: Alterations in glucose metabolism that lead to the development of metabolic and cardiovascular disease may begin already in childhood., Objective: This study aims to generate pediatric age and sex-specific reference values for fasting concentrations of glucose, hemoglobin A1c (HbA1c), insulin, C-peptide, and homeostasis model assessment: insulin resistance (HOMA-IR) in Danish/North-European white children and adolescents from a population-based cohort and to compare values from children and adolescents with overweight/obesity with this reference., Methods: The population- and obesity clinic-based cohorts consisted of 2451 and 1935 children and adolescents between 6 and 18 years of age. Anthropometric measurements and blood samples were obtained and percentile curves were calculated., Results: In the population-based cohort, glucose, insulin, and HOMA-IR values increased before the expected onset of puberty (P < .05). Thereafter, all variables decreased in girls (P < .05) and HbA1c decreased in boys (P < .05). Concentrations of all measured markers of glucose metabolism were higher in the obesity clinic-based cohort than the population-based cohort (both sexes P < .001). Specifically, insulin and HOMA-IR continued to increase to 18 years in the clinic-based cohort, particularly among boys., Conclusions: Fasting glucose, insulin, and HOMA-IR change during childhood, making pediatric reference values essential for timely identification of derangements in glucose metabolism. Children and adolescents with obesity exhibit increased concentrations of these biomarkers., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: We aimed to determine the mutation yield and clinical applicability of "molecular autopsy" following sudden arrhythmic death syndrome (SADS) by validating and utilizing low-cost high-throughput technologies: Fluidigm Access Array PCR-enrichment with Illumina HiSeq 2000 next generation sequencing (NGS)., Methods: We validated and optimized the NGS platform with a subset of 46 patients by comparison with Sanger sequencing of coding exons of major arrhythmia risk-genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2). A combined large multi-ethnic international SADS cohort was sequenced utilizing the NGS platform to determine overall molecular yield; rare variants identified by NGS were subsequently reconfirmed by Sanger sequencing., Results: The NGS platform demonstrated 100% sensitivity for pathogenic variants as well as 87.20% sensitivity and 99.99% specificity for all substitutions (optimization subset, n = 46). The positive predictive value (PPV) for NGS for rare substitutions was 16.0% (27 confirmed rare variants of 169 positive NGS calls in 151 additional cases). The overall molecular yield in 197 multi-ethnic SADS cases (mean age 22.6 ± 14.4 years, 68% male) was 5.1% (95% confidence interval 2.0-8.1%), representing 10 cases carrying pathogenic or likely pathogenic risk-mutations., Conclusions: Molecular autopsy with Fluidigm Access Array and Illumina HiSeq NGS utilizing a selected panel of LQTS/BrS and CPVT risk-genes offers moderate diagnostic yield, albeit requiring confirmatory Sanger-sequencing of mutational variants.

Background: Leptin and adiponectin are two key adipocyte secreted hormones and both are involved in several essential physiological mechanisms. Due to their central role in energy homeostasis their ratio, the leptin/adiponectin ratio, is believed to be a marker of metabolic derangement. Pediatric reference values are needed for the risk stratification of individual-measured ratios., Methods: Blood samples were drawn from healthy, Danish schoolchildren following an overnight fast. A ratio was calculated from serum leptin and adiponectin quantifications done using commercially available ELISA Kits., Results: Nine hundred eighty-three participants (583 girls) aged 6-18 years were included. Smoothed percentile curves and age-group specific percentiles were calculated. A correlation with age was demonstrated, with a gradual increase with age in girls and a negative parabolic relation, with a peak in age group 10-14, in boys. The leptin/adiponectin ratio was positively correlated to the body mass index standard deviation score for both girls and boys (p < .001)., Conclusion: The leptin/adiponectin ratio is correlated to age and differs between the sexes in healthy children and adolescents., (Copyright © 2019. Published by Elsevier B.V.)

Thyroid-stimulating hormone (TSH) and thyroid hormones influence the functions of many organ systems, as well as child development and growth. Several studies have reported an association between ethnicity and thyroid hormones. This study aims to explore pediatric serum concentrations of TSH, free triiodothyronine (fT3), and free thyroxine (fT4) and their relation to age and sex and subsequently to present pediatric reference intervals from healthy Danish/North-European white children. A population-based cohort in Denmark of 2411 (1435 girls) healthy school children and adolescents aged 6.0-18.9 years were included. Fasting concentrations of serum TSH, fT3, and fT4 were determined from venous blood samples using immunologic chemiluminescent assays. Age- and sex-dependent percentiles were generated using the GAMLSS function. Median values of fT3 and fT4, but not TSH, were lower in the older age group compared with the youngest age group for both sexes (all p < .05). A significant difference for fT3 was found between the sexes for all age groups (all p < .001). fT4 was negatively correlated with body mass index standard deviation scores in boys. In conclusion, serum concentrations of thyroid hormones vary during childhood and adolescence and differ with age and sex.

Objective: Preeclampsia (PE) is a serious complication of pregnancy, the pathogenesis of which is largely unknown. We hypothesize that adipocytokines may play a role in the pathogenesis of PE, particularly in obese women, and evaluate leptin and adiponectin as potential first trimester markers for predicting PE., Study Design: A cohort of 2503 pregnancies, containing 93 PE pregnancies, was divided into women with normal weight, moderate, or severe obesity. All pregnancies had serum adiponectin and leptin measured in first trimester. Logistic regression was used to model PE with maternal characteristics and concentrations of the biomarkers., Results: In obese women a lower concentration of adiponectin was found in PE pregnancies; the concentration was lowest in the severely obese (p = 0.005). No association was found in normal weight women (p = 0.72). Leptin concentration had no association with PE in normal weight and moderately obese (p = 0.175-0.072), however in women with severe obesity a lower level of leptin was found (p = 0.049). The AUC was 0.73 for the ROC curve of combined maternal characteristics and adiponectin. Using adiponectin in women with moderate to severe obesity the sensitivity was 72.9% and the specificity was 49%., Conclusions: In severely obese women, PE is associated with low serum adiponectin and leptin concentrations in first trimester. This indicates that the inability of adipokine regulation to adapt to severe obesity may play a role in the pathogenesis of PE. Adipocytokines may contribute in identification of risk pregnancies among severe obese., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease., Competing Interests: The authors have declared that no competing interests exist.

Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. An analysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 Danes without a psychiatric diagnosis and 2,538 schizophrenia patients, revealed marked inter-allelic differences in mitochondrial haplogroup affiliation and nuclear ancestry. This bi-genomic dependence could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation and nuclear ancestry. The extensive bi-genomic dependence documented here is a major concern when interpreting historic, as well as designing future, mtDNA association studies., Competing Interests: The authors have declared that no competing interests exist.

Background: The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ., Methods: We conducted gene-based and gene-set analyses using summary association results from the Psychiatric Genomics Consortium Schizophrenia Phase 2 (PGC-SCZ2) genome-wide association study comprising 35,476 cases and 46,839 control subjects. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2290 cases and 21,621 control subjects., Results: In the PGC-SCZ2 sample, 1186 mitochondrial genes were analyzed, among which 159 had p values < .05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p = .02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be overrepresented in this network of mitochondrial and SCZ risk genes., Conclusions: This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Both women with polycystic ovary syndrome (PCOS) and women with twin pregnancies have increased risk of adverse pregnancy outcome. The aim of this study was to investigate the impact of PCOS and maternal androgen levels on the outcome of dichorionic twin pregnancy., Material and Methods: A retrospective study of 360 women with dichorionic twin pregnancies: 72 women with PCOS from a fertility clinic (years 1997-2010) and 288 women without PCOS from a hospital cohort (years 2005-2007). The obstetrical outcome was extracted from Danish National registers and supplemented by patient file data. In all, 65% of the PCOS group had a registered prepregnancy androgen level and these were stratified into normoandrogenic and hyperandrogenic women. The groups were compared by multiple regression analysis adjusting for mode of conception and prepregnancy body mass index., Results: We found no overall impact of PCOS on the pregnancy outcome; the risks of preeclampsia, gestational diabetes and preterm delivery were comparable within the groups. However, five deliveries in the PCOS group compared with two in the control group occurred before gestational week 28. No difference in the obstetrical outcome between hyperandrogenic and normoandrogenic women was found. The body mass index in the PCOS population was lower than in the non-PCOS, possibly reflecting a higher socioeconomic status and a healthier lifestyle, which may underestimate the impact of a PCOS diagnosis., Conclusion: Neither PCOS nor maternal androgen levels confer additional risks to the outcome of dichorionic twin pregnancies of normal weight women., (© 2017 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Placental protein-13 (PP13) is involved in placental invasion and has been suggested as a maternal serum marker of preeclampsia (PE) development. However, the discriminatory ability of PP13 in first trimester has not been completely clarified., Methods: PP13 was measured in first trimester (week 10+3-13+6) maternal serum from 120 PE pregnancies and 267 control pregnancies and was correlated with clinical parameters. The population screening performance of PP13 in combination with the PE markers pregnancy associated plasma protein A (PAPPA) and free leptin index (fLI) was assessed by Monte Carlo simulation., Results: In severe PE (including HELLP) cases (n=26) the median PP13 concentration was 35.8 pg/mL (range: 17.8-85.5 pg/mL) and in PE pregnancies (n=10) with birth prior to week 34, the median PP13 concentration was 30.6 pg/mL (13.1-50.1 pg/mL), compared to controls with a median of 54.8 pg/mL (range: 15.4-142.6 pg/mL) (p<0.04). The population screening detection rate (DR) for a false-positive rate of 10% for severe PE and HELLP was 26% for PP13, 28% for PP13+PAPP-A, 33% for PP13+fLI, and 40% for PP13+PAPP-A+fLI., Conclusions: PP13 is a marker of severe PE and HELLP syndrome. The screening performance of PP13 can be markedly improved by combining it with fLI and PAPP-A.

Risk stratification and patient management in heart failure (HF) is difficult due to the unpredictable progression of the disease, necessitating the development of reliable diagnostic biomarkers to facilitate decision-making in clinical practice. Pregnancy-associated plasma protein-A (PAPP-A) is a marker of arteriosclerotic heart disease. PAPP-A is a serum protease, which is involved in the insulin-like growth factor 1 (IGF-1) axis where it is inhibited by the proform of the eosinophil major basic protein (proMBP). In this study, we evaluated serum PAPP-A and proMBP as long-term prognostic biomarkers of all-cause mortality in HF. Serum PAPP-A and proMBP concentrations were determined in 683 patients with NYHA III-IV HF recruited in the EchoCardiography and Heart Study (ECHOS) in Denmark. The mean age of the patients (73% male) was 70 at admission. During 7 years of follow-up, 516 patients died. In univariate analysis, both PAPP-A and proMBP, divided into quartiles, showed significant association with mortality. Using a Cox proportional hazard model, hazard ratios for continuous values of PAPP-A and proMBP were HR = 1.42 (CI = 1.23-1.64, p < 0.0001) and HR = 1.36 (CI = 1.22-1.51, p <0.0001), respectively. However, neither PAPP-A nor proMBP were significant independent predictors when the model included age, gender, brain-type natriuretic peptide, medical history of HF, ischemic heart disease, chronic obstructive pulmonary disease, and diabetes mellitus. In conclusion, high levels of PAPP-A and proMBP are associated with increased risk of death from all causes in HF and are potential prognostic markers of adverse outcomes in HF patients.

Background: Resistin is a hormone, mainly produced in macrophages and monocytes, believed to play an important role in the inflammatory response. It has been linked to several chronic diseases such as heart failure, inflammatory bowel disease, and insulin resistance. Pediatric reference levels are needed for the risk stratification and interpretation of individual serum resistin concentrations., Methods: A total of 1191 healthy, non-obese Danish schoolchildren (727 girls) aged 6-18years (median 11.9) were included. Fasting serum resistin concentrations were quantitated by Human Resistin ELISA Development kit, Duo Set (R&D Systems) following optimization., Results: The overall median resistin concentration was 8.93ng/mL (interquartile range (IQR): 6.19-13.33, range 1.57-35.84) in boys and 10.42ng/mL (IQR: 7.25-15.68, range 1.60-44.00) in girls. The resistin concentration correlated to relative BMI in both boys (p=0.02) and girls (p<0.0001). Percentiles for each age group were calculated alongside smoothed percentile curves and an age correlated increase was demonstrated, albeit only in girls (p=0.02) and not in boys (p=0.35)., Conclusion: Fasting serum resistin concentrations differ between sexes in healthy children and adolescents and are correlated both with the sex- and age adjusted BMI, and in girls to age., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Obese persons have low circulating natriuretic peptide (NP) concentrations. It has been proposed that this 'natriuretic handicap' could play a role in obesity-related hypertension. The normal physiological response of the NP system to an increase in blood pressure (BP) is an increase in NP secretion with concomitant higher circulating NP concentrations. In this study, we investigated whether higher BP would also be related to higher circulating NP concentrations in obese men; furthermore, we verified that BP had affected the hearts of our study participants, by determining left ventricular mass (LVM)., Methods: We examined 103 obese healthy medication-free men. We measured 24-hour ambulatory BP (ABP). LVM was calculated using the Cornell voltage-duration product method. Fasting serum concentrations of midregional proatrial NP (MR-proANP), a surrogate for active ANP, were measured. Linear regression analysis was used to calculate age-adjusted standardised regression coefficients (β)., Results: LVM and BP increased across systolic ABP quartiles (mean LVM±SD: 1599.1±387.2 mm ms in first vs 2188.5±551.3 mm ms in fourth quartile, p<0.001; mean systolic ABP±SD: 114.5±4.2 mm Hg in first vs 149.0±7.7 mm Hg in fourth quartile, p<0.001). Systolic ABP was robustly associated with LVM (ß=0.48, p<0.001). Despite evidence of BP-related increases in LVM, serum MR-proANP was negatively associated with systolic ABP (ß=-0.32, p=0.004) and with diastolic ABP (ß=-0.45, p<0.001)., Conclusions: Contrary to known physiological BP responses, MR-proANP was negatively associated with ABP in our study. This suggests that a low amount of circulating NPs could play a role in the early stage of obesity-related hypertension., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Vertical transmission of human immunodeficiency virus (HIV) remains a major global health problem. We assessed the association of mannose binding lectin (MBL) deficiency and vertical transmission of HIV. Novel diagnostics would be a major breakthrough in this regard. MBL is a liver-derived protein and a key component of the innate immune system. MBL levels may be classified as normal, intermediate, or deficient in the plasma and can use MBL2 haplotypes as a proxy. These haplotypes comprise polymorphisms in the MBL2 gene and promoter region and are known to result in varying levels of MBL deficiency. MBL deficiency can be defined as presence of A/O and O/O genotypes in the mothers and their children. MBL deficiency leads to defective opsonization activities of the innate immune system and increased susceptibility to several infections, including HIV-1. We determined the prevalence of MBL deficiency, using MBL2 haplotypes among 622 HIV-positive Zimbabwean mothers and their children aged 9-18 months old, in relation to the HIV-1 vertical transmission risk. The median age of the mothers was 30 (26-34, interquartile range [IQR]) years, and the babies' median age was 13 (11-15, IQR) months old at the time of enrollment. From the sample of 622 mothers who were HIV-1 infected, 574 babies were HIV negative and 48 were HIV-1-positive babies, giving a transmission rate of 7.7%. MBL2 normal structural allele A and variants B (codon 5 A>G), C (codon 57 A>G), and promoter region SNPs -550(H/L) and -221(X/Y) were detected. Prevalence of haplotype-predicted MBL deficiency was 34% among the mothers and 32% among the children. We found no association between maternal MBL2 deficiency and HIV-1 transmission to their children. We found no difference in the distribution of HIV-1 infected and uninfected children between the MBL2 genotypes of the mothers and those of the children. Taken together, the present study in a large sample of mother-infant pairs in Zimbabwe adds to the emerging literature and the hypothesis that MBL2 variation as predicted by haplotypes does not influence the vertical transmission risk for HIV. Research from other populations from the African continent is called for to test this hypothesis further.

Background: The etiology of childhood obesity and the associated morbidity is multifactorial. Recently, data suggesting a prenatal programming towards later childhood obesity and metabolic deregulation through the intrauterine environment has emerged. This study explored the concentrations of adipokines and their mutual relationship at birth in children born to non-diabetic mothers., Methods: Adiponectin, leptin and sOB-R were measured using ELISA-based commercial kits in umbilical cord blood from 60 neonates (30 born large for gestational age [LGA] and 30 born appropriate for gestational age [AGA]). Children exposed to maternal diabetes, chronic disease and preeclampsia were excluded., Results: The LGA group exhibited significantly elevated concentrations of leptin (p<0.001) and of free leptin index (p<0.001) and decreased sOB-R concentrations (p=0.005) when compared to the AGA group, which persisted in multiple regression analysis after taking the gestational age into account (p=0.048, p<0.001 and p<0.001, respectively). Only a trend towards a difference in adiponectin was demonstrated (p=0.057) regardless of adjustment (p=0.150). However, the leptin/adiponectin ratio was elevated in the LGA group (p=0.008), regardless of adjustment (p=0.039)., Conclusion: The data indicate a disturbance of adipokines in macrosomic newborns and that the mutual ratios between adipokines may provide a more sensitive marker of metabolic disturbance than any isolated adipokine.

Objective: To examine whether resistin levels in first trimester maternal serum are associated with insulin resistance or preeclampsia (PE)., Methods: A case-control study of maternal serum resistin concentration conducted using 285 normal pregnancies and 123 PE pregnancies matched for gestational age, parity and maternal age. Samples were taken in gestational weeks 10 +0 -13 +6 ., Results: There was a negative correlation between resistin and clinical severity of PE, but no correlation with IS, TNF-α, body mass index, birth weight and pregnancy length., Conclusions: Resistin is reduced in first trimester of PE pregnancies, particularly in severe PE. Inflammation and IS cannot explain this phenomenon.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA) haplogroups are susceptibility factors for HCM. Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446 variants. After elimination of 312 (69.9%) non-coding and synonymous variants, a further 109 (24.4%) with a global prevalence > 0.1%, three (0.7%) haplogroup associated and 19 (2.0%) variants with a low predicted in silico likelihood of pathogenicity, three variants: MT-TC: m.5772G>A, MT-TF: m.644A>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM.

Background: Childhood obesity is associated with several complications, including cardiovascular comorbidity. Several biomarkers, such as high-sensitive C-reactive protein (hs-CRP), proform of eosinophil major basic protein (Pro-MBP) and pregnancy associated plasma protein-A (PAPP-A), have equally been linked to increased cardiovascular susceptibility. This study investigates these biomarkers during weight loss and regain in obese children., Materials and Methods: A longitudinal study during a 12-week weight loss program with a 28 months follow-up was conducted. Anthropometrics and plasma concentrations of hs-CRP, Pro-MBP, and PAPP-A were measured at baseline; at days 14, 33 and 82 during weight loss; and at months 10, 16, and 28 during follow-up., Results: Fifty-three boys and 62 girls aged 8-15 years with a median body mass index (BMI) standard deviation score (SDS) at baseline of 2.78 (boys), and 2.70 (girls) were included. Ninety children completed the weight loss program and 68 children entered the follow-up program. Pro-MBP and PAPP-A, but not hs-CRP, exhibited individual-specific levels (tracking) during weight loss and regain. The PAPP-A/Pro-MBP correlation was strong, whereas the hs-CRP/PAPP-A correlation was weak during weight fluctuations., Conclusion: Hs-CRP changes reflect weight changes. PAPP-A and Pro-MBP exhibited tracking during weight perturbations and may contribute as early risk markers of cardiovascular susceptibility.

Background: Congenital long QT syndrome (LQTS) is a hereditary cardiac channelopathy characterized by delayed ventricular repolarization, syncope, torsades de pointes and sudden cardiac death. Thirty-three members of five apparently 'unrelated' Danish families carry the KCNH2:c.87C> A; p.F29L founder mutation., Methods and Results: Linkage disequilibrium mapping with microsatellites around KCNH2 enabled us to estimate the age of the founder mutation to be approximately 22 generations, corresponding to around 550 years. Neighbouring-Joining analysis disclosed one early and three later nodes. The median QTc time of the carriers was 490 ms (range: 415-589 ms) and no difference was seen between the different branches of the family. The mutation is malignant with a penetrance of 73%. Ten F29L carriers received implantable defibrillators (ICDs) (median age at implant 20 years), and of those four individuals experienced eight appropriate shocks. Patch-clamp analysis in HEK 293 cells, performed at 34°C disclosed a loss-of-function phenotype with fast deactivation, reduced steady-state inactivation current density and a positive voltage shift in inactivation. Western blotting of HEK 293 cells transfected with KCNH2:WT and KCNH2:c.87C> A revealed a reduced fraction of fully glycosylated hERG:p.F29L suggesting that this mutation results in defective trafficking., Conclusion: The altered channel gating kinetics in combination with defective trafficking of mutated channels is expected to result in reduced repolarizing current density and, thus, a LQTS phenotype.

Background: Low-grade chronic inflammation is a characteristic feature of obesity, the most important lifestyle risk factor for hypertension. Elevated plasma concentrations of the inflammatory biomarker C-reactive protein (CRP) are associated with an increased risk of hypertension, but elevated plasma CRP concentrations are also closely associated with obesity. It is uncertain whether CRP is directly involved in the pathogenesis of hypertension or is only a marker of other pathogenic processes closely related to obesity., Methods: We studied 103 obese men (body mass index (BMI) ≥ 30.0 kg/m(2)); 63 of these men had 24-hour ambulatory blood pressure (ABP) ≥ 130/80 mm Hg and comprised the obese hypertensive (OHT) group. The 40 remaining obese men had 24-hour ABP < 130/80 mm Hg and comprised the obese normotensive (ONT) group. Our control group comprised 27 lean normotensive (LNT) men. All participants were medication-free. We measured plasma CRP concentrations with a high-sensitivity assay and determined body composition by dual energy x-ray absorptiometry scanning., Results: There were no differences in anthropometric measures (BMI, waist circumference, or total fat mass percentage) between OHT and ONT groups (P ≥ 0.08). The obese groups had higher CRP concentrations than the LNT group (OHT: median = 2.30, interquartile range (IQR) = 1.10-4.10mg/L; ONT: median = 2.55, IQR = 1.25-4.80 mg/L; LNT: median = 0.60, IQR = 0.30-1.00 mg/L; P < 0.001), but there was no difference in CRP concentrations between OHT and ONT groups (P = 1.00). In the obese men, CRP was not correlated with either 24-hour systolic (r = 0.04; P = 0.71) or 24-hour diastolic ABP (r = -0.03; P = 0.78)., Conclusions: Obese hypertensive men, matched for anthropometric measurements, have plasma CRP concentrations similar to those of obese normotensive men., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)