Encounters with public and professional understandings of Down syndrome: A qualitative study of parents' experiences.

BACKGROUND: The meanings of neurodevelopmental conditions are socially and culturally defined. We explored how parents of a child with Down syndrome experienced public and professional understandings of Down syndrome. METHOD: Qualitative interviews with 25 parents of a child with Down syndrome living in Denmark. From a reflexive thematic analysis, we developed themes describing understandings (i.e., attitudes or perceptions) of Down syndrome. RESULTS: The parents experienced that the Down syndrome diagnosis acted as a 'label'; this had perceived positive and negative consequences for the child. The parents felt others understood Down syndrome as severe and undesirable. This attitude was tied to the existence of prenatal screening. Finally, to the parents, professional support for their child expressed an understanding of children with Down syndrome as valued individuals. CONCLUSIONS: Parents encountered ambiguous understandings of Down syndrome. This should be recognised by professionals who may shape such understandings.

Association of labour epidural analgesia with neurodevelopmental disorders in offspring: a Danish population-based cohort study.

BACKGROUND: Whether labour epidural analgesia impacts risk of neurodevelopmental disorders in offspring is unsettled, raising public and scientific concerns. We explored the association between maternal labour epidural analgesia and autism spectrum disorder, and specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy in offspring. METHODS: This nationwide population-based cohort study included 624 952 live-born singletons delivered by women who intended to deliver vaginally (i.e. vaginal and intrapartum Caesarean deliveries) in Denmark from 2005 to 2016. A total of 80 862 siblings discordant for exposure to labour epidural analgesia were analysed in a sibling-matched analysis. Both full-cohort and sibling-matched analyses were performed to estimate hazard ratios (HRs) of offspring risk of autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy, according to exposure to labour epidural analgesia, adjusted for maternal socio-economic, pregnancy, and perinatal covariates. RESULTS: In the full cohort, maternal labour epidural analgesia was associated with autism spectrum disorder in offspring (HR 1.11; 95% confidence interval [CI]: 1.04-1.18); however, in the sibling-matched analysis, no association with autism spectrum disorder was found (HR 1.03; 95% CI: 0.84-1.27). The association between labour epidural analgesia and specific developmental disorder (HR 1.12; 95% CI: 1.03-1.22) in the full cohort also disappeared in the sibling-matched analysis (HR 1.01; 95% CI: 0.78-1.31). No association between maternal labour epidural analgesia and the remaining neurodevelopmental disorders was found overall (attention-deficit hyperactivity disorder, HR 0.98; 95% CI: 0.92-1.03; intellectual disability, HR 0.98; 95% CI: 0.85-1.14; epilepsy, HR 0.89; 95% CI: 0.79-1.00) or in the sibling-matched analyses. CONCLUSIONS: Our findings did not support an association between maternal attention-deficit hyperactivity disorder and autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, or epilepsy.

A systematic overview of the spermatotoxic and genotoxic effects of methotrexate, ganciclovir and mycophenolate mofetil.

INTRODUCTION: Immunosuppressant drugs are increasingly being used in the reproductive years. Theoretically, such medications could affect fetal health either through changes in the sperm DNA or through fetal exposure caused by a presence in the seminal fluid. This systematic overview summarizes existing literature on the spermatotoxic and genotoxic potentials of methotrexate (MTX), a drug widely used to treat rheumatic and dermatologic diseases, and mycophenolate mofetil (MMF), which alone or supplemented with ganciclovir (GCV) may be crucial for the survival of organ transplants. MATERIAL AND METHODS: The systematic overview was performed in accordance with the PRISMA guidelines: A systematic literature search of the MEDLINE and Embase databases was done using a combination of relevant terms to search for studies on spermatotoxic or genotoxic changes related to treatment with MTX, GCV or MMF. The search was restricted to English language literature, and to in vivo animal studies (mammalian species) and clinical human studies. RESULTS: A total of 102 studies were identified, hereof 25 human and 77 animal studies. For MTX, human studies of immunosuppressive dosages show transient effect on sperm quality parameters, which return to reference values within 3 months. No human studies have investigated the sperm DNA damaging effect of MTX, but in other organs the genotoxic effects of immunosuppressive doses of MTX are fluctuating. In animals, immunosuppressive and cytotoxic doses of MTX adversely affect sperm quality parameters and show widespread genotoxic damages in various organs. Cytotoxic doses transiently change the DNA material in all cell stages of spermatogenesis in rodents. For GCV and MMF, data are limited and the results are indeterminate, for which reason spermatotoxic and genotoxic potentials cannot be excluded. CONCLUSIONS: Data from human and animal studies indicate transient spermatotoxic and genotoxic potentials of immunosuppressive and cytotoxic doses of MTX. There are a limited number of studies investigating GCV and MMF.

Mode of birth and risk of infection-related hospitalisation in childhood: A population cohort study of 7.17 million births from 4 high-income countries.

BACKGROUND: The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates. METHODS AND FINDINGS: We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%-29%) were by CS, of which 727,755 (43%, range 38%-57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09-1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12-1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06-1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available. CONCLUSIONS: In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated.

Outcomes of monoamniotic twin pregnancies managed primarily in outpatient care-a Danish multicenter study.

INTRODUCTION: Monoamniotic twin pregnancies are high-risk pregnancies, and management by inpatient or frequent outpatient care is recommended. We report the outcomes of a national cohort of monoamniotic twin pregnancies managed primarily as outpatients. MATERIAL AND METHODS: We prospectively analyzed the recorded data from the Danish Fetal Medicine Database, local databases, and medical records of all monoamniotic twin pregnancies diagnosed at the first trimester scan or later, and managed at the six major fetal medicine centers in Denmark over a 10-year period. RESULTS: Sixty-one monoamniotic twin pregnancies were included. Thirteen pregnancies were terminated early. Of the remaining 48 pregnancies with a normal first trimester scan, there were 36 fetal losses (25 spontaneous miscarriages <22+0  weeks, 3 late terminations and 8 intrauterine deaths >22 weeks) and 60 liveborn children (62.5%), all of whom were delivered by cesarean delivery at a median gestational age of 33+0  weeks. Three children had minor malformations and there was 1 pregnancy with twin-to-twin transfusion syndrome. After 26+0  weeks, 78.8% were managed as outpatients. Intrauterine death occurred in 3.8% of outpatients and in 28.6% of inpatients (admitted due to complications). At weeks 32, 33 and 34, the prospective risk of intrauterine death was 6.9%, 4.2% and 5.9%, respectively. CONCLUSION: In this nationwide, unselected population, only 62.5% of fetuses with a normal first trimester scan were born alive. In contrast, the mortality was 3.8% after 26 weeks among the 78.8% of the cohort that was managed as outpatients. More knowledge is still needed to predict which pregnancies are at the highest risk of intrauterine death.

Activity and spatial distribution of Candida antarctica lipase B immobilized on macroporous organic polymeric adsorbents.

A systematic study of the influence of carrier particle size (500-850 µm) and enzyme load (26,200-66,100 lipase activity units (LU)/g dry carrier) on the content and activity of Candida antarctica lipase B (CALB) immobilized by adsorption onto macroporous poly(methyl methacrylate) (PMM) and polystyrene (PS) carriers was conducted. Furthermore, localization of CALB on the carrier was investigated by light and fluorescence microscopy of freeze microtome sliced catalyst particles. Fluorescence microscopy showed localization of enzyme in an outer rim of 50-85 and 10-20 µm thickness for the PMM and PS catalysts, respectively, whereas no rim was observed in the absence of enzyme. Statistical analyses showed that carrier type was the major effect in determining the activities of the catalysts, with enzyme load being the second most significant effect and particle size also exerting a significant, yet smaller, effect. The PMM catalysts showed higher activities compared to PS catalysts, possibly indicating that the microenvironment interactions of CALB with the PMM are more favorable than with the PS carrier, resulting in a higher specific enzyme activity. Furthermore, smaller particles and higher enzyme load had a positive influence on the activities within the investigated ranges, and the carrier type and enzyme load interaction was statistically significant (p < 0.001).

Ultrasound assessment of cervical length at 18-21 weeks' gestation in an Australian obstetric population: comparison of transabdominal and transvaginal approaches.

BACKGROUND: Using a fixed cut-off of ≤25 mm, ultrasound assessment of cervical length during the 18-23 week anomaly scan has been shown to identify approximately 50% of pregnancies that would deliver prior to 34 weeks. AIM: To determine whether a policy of reverting to transvaginal cervical assessment only if the cervix appears short (≤25 mm) on transabdominal assessment affects the efficiency of screening. METHODS: Women with a singleton pregnancy that presented for a routine anomaly scan had their cervical length assessed transabdominally, initially with the maternal bladder full (TABF) and then empty (TABE). Cervical length was then assessed transvaginally (TV). RESULTS: One hundred and ninety-eight women agreed to participate in the study. Identification of the internal and external cervical os was possible during TABF, TABE and TV sonography in 97.0, 82.8 and 100%, respectively. Compared with TV sonography, TABF overestimates cervical length (6.1 mm difference in median values; P < 0.01). There was no significant difference between TV and TABE. However, TABE assessment was not possible in one in six women. If TABF sonography was to be used as a screening tool and using ≤25 mm as the critical cut-off, the sensitivity and specificity was 15.4 and 93.2%, respectively. CONCLUSION: This study has shown that assessment of cervical length using a TA approach is only routinely possible when the bladder is full. However, measurements are significantly overestimated. Therefore, we feel that TV assessment of cervical length is the preferred method of reliable cervical assessment. As such, all women should be offered a TV assessment of cervical length at the time of the fetal anomaly ultrasound as a screening test for preterm birth.

Selective serial multi-antibody biosensing with TOPAS microstructured polymer optical fibers.

We have developed a fluorescence-based fiber-optical biosensor, which can selectively detect different antibodies in serial at preselected positions inside a single piece of fiber. The fiber is a microstructured polymer optical fiber fabricated from TOPAS cyclic olefin copolymer, which allows for UV activation of localized sensor layers inside the holes of the fiber. Serial fluorescence-based selective sensing of Cy3-labelled α-streptavidin and Cy5-labelled α-CRP antibodies is demonstrated.

ABCB1 expression is increased in human first trimester placenta from pregnant women classified as overweight or obese.

Obesity has become a global health challenge also affecting reproductive health. In pregnant women, obesity increases the risk of complications such as preterm birth, macrosomia, gestational diabetes, and preeclampsia. Moreover, obesity is associated with long-term adverse effects for the offspring, including increased risk of cardiovascular and metabolic diseases and neurodevelopmental difficulties. The underlying mechanisms are far from understood, but placental function is essential for pregnancy outcome. Transporter proteins P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are important for trans-placental transport of endogenous substances like lipids and cortisol, a key hormone in tissue maturation. They also hold a protective function protecting the fetus from xenobiotics (e.g. pharmaceuticals). Animal studies suggest that maternal nutritional status can affect expression of placental transporters, but little is known about the effect on the human placenta, especially in early pregnancy. Here, we investigated if overweight and obesity in pregnant women altered mRNA expression of ABCB1 encoding P-gp or ABCG2 encoding BCRP in first trimester human placenta. With informed consent, 75 first trimester placental samples were obtained from women voluntarily seeking surgical abortion (< gestational week 12) (approval no.: 20060063). Villous samples (average gestational age 9.35 weeks) were used for qPCR analysis. For a subset (n = 38), additional villi were snap-frozen for protein analysis. Maternal BMI was defined at the time of termination of pregnancy. Compared to women with BMI 18.5-24.9 kg/m2 (n = 34), ABCB1 mRNA expression was significantly increased in placenta samples from women classified as overweight (BMI 25-29.9 kg/m2, n = 18) (p = 0.040) and women classified as obese (BMI ≥ 30 kg/m2, n = 23) (p = 0.003). Albeit P-gp expression did not show statistically significant difference between groups, the effect of increasing BMI was the same in male and female pregnancies. To investigate if the P-gp increase was compensated, we determined the expression of ABCG2 which was unaffected by maternal obesity (p = 0.291). Maternal BMI affects ABCB1 but not ABCG2 mRNA expression in first trimester human placenta. Further studies of early placental function are needed to understand how the expression of placental transport proteins is regulated by maternal factors such as nutritional status and determine the potential consequences for placental-fetal interaction.

Associations Between ADHD Medication Use in Pregnancy and Severe Malformations Based on Prenatal and Postnatal Diagnoses: A Danish Registry-Based Study.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) medications are increasingly used in pregnancy. Studies on the pregnancy safety of these medications that are restricted to live births may underestimate severe teratogenic effects that cause fetal demise or termination of pregnancy. The present study addresses this limitation by including data from both prenatal and postnatal diagnoses of major malformations. METHODS: A nationwide registry-based study was conducted of 364,012 singleton pregnancies in Denmark from November 1, 2007, to February 1, 2014. Exposures to ADHD medication were obtained from redeemed prescriptions from the Danish Health Services Prescription Database. Outcome data included prenatally diagnosed malformations from the Danish Fetal Medicine Database and postnatally diagnosed malformations from the Danish National Patient Registry. The primary outcome was major malformations overall, and secondary outcomes were malformations of the central nervous system and cardiac malformations. The comparison group was pregnancies with no redeemed prescriptions for ADHD medication. We defined severe cardiac malformations (SCM) as concurrent diagnoses of a cardiac malformation with miscarriage, termination, stillbirth, postnatal death, or cardiac surgery within 1 year of birth. RESULTS: The prevalence of first-trimester exposure to ADHD medication increased during the study period from 0.05% in 2008 to 0.27% in 2013, with the majority (473/569) of the exposures being to methylphenidate. There were 5.1% malformations overall and 2.1% cardiac malformations among the exposed compared to 4.6% and 1.0%, respectively, among the unexposed. For methylphenidate, the adjusted prevalence ratios (PRs) were 1.04 (95% confidence interval [CI], 0.70-1.55) for malformations overall and 1.65 (95% CI, 0.89-3.05) for any cardiac malformations (number needed to harm [NNH] = 92), with septum defects in 10 out of 12 cases. The PR for ventricular septal defect was 2.74 (95% CI, 1.03-7.28) and for SCM, 2.59 (95% CI, 0.98-6.90). CONCLUSIONS: Exposure to methylphenidate was not associated with an increased risk of malformations overall in data that included information from both prenatal and postnatal diagnoses of major malformations. There was an increased risk of cardiac malformations with NNH of 92 based on 12 cases among the exposed. More data are needed on other types of ADHD medication.

Transglycosylating ß-d-galactosidase and α-l-fucosidase from Paenibacillus sp. 3179 from a hot spring in East Greenland.

Thermal springs are excellent locations for discovery of thermostable microorganisms and enzymes. In this study, we identify a novel thermotolerant bacterial strain related to Paenibacillus dendritiformis, denoted Paenibacillus sp. 3179, which was isolated from a thermal spring in East Greenland. A functional expression library of the strain was constructed, and the library screened for ß-d-galactosidase and α-l-fucosidase activities on chromogenic substrates. This identified two genes encoding a ß-d-galactosidase and an α-l-fucosidase, respectively. The enzymes were recombinantly expressed, purified, and characterized using oNPG (2-nitrophenyl-ß-d-galactopyranoside) and pNP-fucose (4-nitrophenyl-α-l-fucopyranoside), respectively. The enzymes were shown to have optimal activity at 50°C and pH 7-8, and they were able to hydrolyze as well as transglycosylate natural carbohydrates. The transglycosylation activities were investigated using TLC and HPLC, and the ß-d-galactosidase was shown to produce the galactooligosaccharides (GOS) 6'-O-galactosyllactose and 3'-O-galactosyllactose using lactose as substrate, whereas the α-l-fucosidase was able to transfer the fucose moiety from pNP-fuc to lactose, thereby forming 2'-O-fucosyllactose. Since enzymes that are able to transglycosylate carbohydrates at elevated temperature are desirable in many industrial processes, including food and dairy production, we foresee the potential use of enzymes from Paenibacillus sp. 3179 in the production of, for example, instant formula.

Linkage between the Danish National Health Service Prescription Database, the Danish Fetal Medicine Database, and other Danish registries as a tool for the study of drug safety in pregnancy.

A linked population-based database is being created in Denmark for research on drug safety during pregnancy. It combines information from the Danish National Health Service Prescription Database (with information on all prescriptions reimbursed in Denmark since 2004), the Danish Fetal Medicine Database, the Danish National Registry of Patients, and the Medical Birth Registry. The new linked database will provide validated information on malformations diagnosed both prenatally and postnatally. The cohort from 2008 to 2014 will comprise 589,000 pregnancies with information on 424,000 pregnancies resulting in live-born children, ∼420,000 pregnancies undergoing prenatal ultrasound scans, 65,000 miscarriages, and 92,000 terminations. It will be updated yearly with information on ∼80,000 pregnancies. The cohort will enable identification of drug exposures associated with severe malformations, not only based on malformations diagnosed after birth but also including those having led to termination of pregnancy or miscarriage. Such combined data will provide a unique source of information for research on the safety of medications used during pregnancy.

Use of laminar flow patterning for miniaturised biochemical assays.

Laminar flow in microfluidic chambers was used to construct low (one dimensional) density arrays suitable for miniaturized biochemical assays. By varying the ratio of flows of two guiding streams flanking a sample stream, precise focusing and positioning of the latter was achieved, and reactive species carried in the sample stream were deposited on functionalized chip surfaces as discrete 50 microm wide lanes. Using different model systems we have confirmed the method's suitability for qualitative screening and quantification tasks in receptor-ligand assays, recording biotin-streptavidin interactions, DNA-hybridization and DNA-triplex formation. The system is simple, fast, reproducible, flexible, and has small sample requirements.

Hydrodynamic guiding for addressing subsets of immobilized cells and molecules in microfluidic systems.

BACKGROUND: The interest in microfluidics and surface patterning is increasing as the use of these technologies in diverse biomedical applications is substantiated. Controlled molecular and cellular surface patterning is a costly and time-consuming process. Methods for keeping multiple separate experimental conditions on a patterned area are, therefore, needed to amplify the amount of biological information that can be retrieved from a patterned surface area. We describe, in three examples of biomedical applications, how this can be achieved in an open microfluidic system, by hydrodynamically guiding sample fluid over biological molecules and living cells immobilized on a surface. RESULTS: A microfluidic format of a standard assay for cell-membrane integrity showed a fast and dose-dependent toxicity of saponin on mammalian cells. A model of the interactions of human mononuclear leukocytes and endothelial cells was established. By contrast to static adhesion assays, cell-cell adhesion in this dynamic model depended on cytokine-mediated activation of both endothelial and blood cells. The microfluidic system allowed the use of unprocessed blood as sample material, and a specific and fast immunoassay for measuring the concentration of C-reactive protein in whole blood was demonstrated. CONCLUSION: The use of hydrodynamic guiding made multiple and dynamic experimental conditions on a small surface area possible. The ability to change the direction of flow and produce two-dimensional grids can increase the number of reactions per surface area even further. The described microfluidic system is widely applicable, and can take advantage of surfaces produced by current and future techniques for patterning in the micro- and nanometer scale.

Numerical modelling of insulin and amyloglucosidase release from swelling Ca-alginate beads.

The release of insulin hexamer (39 kD) and amyloglucosidase (AMG, 97 kD), entrapped in spherical Ca-alginate beads, was investigated. While the release of insulin could be described solely by diffusion this was not the case for the 1.6 (rm/rm) larger AMG protein, where rm is the Stokes-Einstein effective molecular radius. Because the alginate bead size was not constant during the release experiments, it was hypothesised that in addition to the diffusional mass transfer, a non-negligible convective flow of liquid in or out of the beads was present due to swelling or shrinkage, respectively. Although it should be expected that the effective diffusion coefficient of AMG is only slightly lower than that of insulin, the results show that the effective diffusions coefficient of AMG was found to be much smaller. In the case of AMG, it was shown that including bead size changes and the resulting convective flow in the numerical model, release could be described more accurately. The numerical model was able to describe the release characteristics from both shrinking, swelling, and non-swelling alginate beads. To evaluate the effect of bead swelling on the protein release rate, a swelling modulus and a release index was defined, describing the different effects on release of smaller and larger proteins.

Effect of fatty acid chain length on initial reaction rates and regioselectivity of lipase-catalysed esterification of disaccharides.

In a reaction medium mixture of 9:11 t-BuOH and pyridine (v/v) the effect of fatty acid chain length (C-4-C-12) on C. antarctica lipase B (Novozym 435, EC 3.1.1.3) catalysed esterification was studied. alpha and beta maltose 6'-O-acyl esters in an anomeric molar ratio of 1.0:1.1 were synthesised independently of the chain length, but the initial specific reaction rate increased with decreasing chain length of the acyl donor. The product yield followed the same trend with a lauryl ester yield of 1.1% (mol/mol) and a butyl ester yield of 27.6% (mol/mol) after 24 h of reaction. With sucrose as the acyl acceptor the 6'-O-acyl and 6-O-acyl monoesters were formed with fatty acids of chain length C-4 and C-10 while the 6',6-O-acyl diester was formed only with butanoic acid (C-4:0) as acyl donor. The 6'-O-acyl and 6-O-acyl monoesters and the 6',6-O-acyl diester of butanoic acid were produced in a molar ratio of 1.0:0.5:0.2 and with decanoic acid (C-10:0) the 6'-O-acyl and 6-O-acyl monoesters were formed in the ratio of 1.0:0.3. The highest initial reaction rate and yield were obtained with the shortest chain length of the acyl donor. Initial reaction rates and ester yields were affected by the solubility of the disaccharide, with higher reaction rates and yields with maltose than with sucrose, while no formation of esters were observed with either cellobiose or lactose as acyl acceptors.