Etablierung eines revers–genetischen Systems für feline Coronaviren

Im Rahmen dieser Arbeit erfolgte die Etablierung eines revers-genetischen Systems für ein Serotyp I felines Coronavirus (FCoV). Dabei wurden folgende Ergebnisse erzielt: 1) Als Grundlage für die Etablierung des Systems wurde die komplette Genomsequenz des FCoV Stammes Black bestimmt und anhand dieser Sequenz der Genomaufbau ermittelt. Es ließ sich der für Coronaviren typische Genomaufbau nachweisen. 2) Die Herstellung eines infektiösen Klons beinhaltete die Integration einer kompletten cDNA Kopie des FCoV Stammes Black in das Vaccinia Virus Genom, welches als Vektor diente. Die coronavirale cDNA wurde in vitro transkribiert und die synthetische RNA in Zellen elektroporiert. Rekombinante FCoV ließen sich nachweisen und somit war die synthetische RNA infektiös, also in der Lage, den coronaviralen Replikationszyklus zu initiieren und zu durchlaufen. Die Analyse der gewonnenen rekombinanten Viren erfolgte nach Infektion feliner Zellkulturen mit verschiedenen Ansätzen. Dabei konnte festgestellt werden, dass die rekombinanten Viren die gleichen Eigenschaften wie der ursprüngliche FCoV Stamm Black besitzen. 3) In nachfolgenden Versuchen erfolgte die Herstellung zweier Reportergenexprimierender FCoV mit dem etablierten revers-genetischen System. Dabei wurden im FCoV Stamm Black Genom die akzessorischen Gene 3abc durch das „green fluorescent protein“ (GFP) oder Renilla Luciferase ersetzt. Die stabile Expression der Reportergene konnte in felinen Zellkulturen nachgewiesen werden. 4) Feline Monozyten, Makrophagen und dendritische Zellen (DCs), die als Zielzellen sowohl von FCoV als auch von anderen Coronaviren gelten, wurden mit Wildtyp und den Reportergen-exprimierenden FCoV in vitro infiziert. Die Infektion von monozytären Zellen konnte ausschließlich mit Hilfe der GFP exprimierenden Mutanten nachgewiesen werden.In this study a reverse genetic system for a serotype I feline coronavirus was established. The following results were obtained: 1) As basis for the establishment of a reverse genetic system the complete genomic sequence of FCoV strain Black was determined. The sequence analysis revealed the typical genome organization for coronavirus. 2) For the generation of an infectious clone the full-length FCoV strain Black cDNA was introduced into vaccinia virus as cloning vector. The FCoV cDNA was used for in vitro transcription and the synthesized RNA electroporated into cells. Recombinant FCoV could be detected which showed that the in vitro transcribed RNA was infectious and could initiate the coronavirus replication cycle. The resulting recombinant virus was analyzed in feline cell culture using different approaches. It could be demonstrated that the properties of the recombinant virus are indistinguishable from those of FCoV wild type virus strain Black. 3) In subsequent experiments based on the newly established reverse genetic system, two reporter gene expressing recombinant FCoV were generated. The accessory genes 3abc were replaced by genes encoding the green fluorescent protein (GFP) and Renilla luciferase. The stable expression of these reporter genes was demonstrated in feline cell culture. 4) Feline monocytes, macrophages and dendritic cells (DCs) which are considered to be important target cells for FCoV and other coronaviruses were infected with the wildtype and the reporter gene expressing FCoV. The infection of the monocytic cells was exclusively shown with the GFP expressing mutant

Twin birth rates and obstetric interventions in Iceland : A nationwide study from 1997 to 2018

© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.OBJECTIVE: Twin pregnancies are associated with increased antepartum and intrapartum risks. Limited multiple embryo transfers are associated with decreased twin birth rates. We aimed to study the effect of 2009 Icelandic regulations on twin birth rates and examine obstetric intervention rates for twin births during the study period. METHODS: The study included all births (N = 94 028) in Iceland during 1997-2018. Twin birth rates and obstetric intervention rates were compared over birth year periods using modified Poisson regression adjusted for confounders. RESULTS: An observed decrease in the twin birth rate trend was most notable from 2006 until 2009. Twin birth decreased in 2009-2013 (prevalence ratio [PR] 0.74, 95% confidence interval [CI] 0.64-0.86) and in 2014-2018 (PR 0.74, 95% CI 0.64-0.86) compared with 1997-2002. This decrease was only evident for women aged 30+ years in stratified analysis. Induction of labor rates increased from 26% in 1997-2002 to 44% in 2014-2018 (adjusted rate ratio [ARR] 2.10, 95% CI 1.72-2.57) whereas elective cesarean section (ARR 0.80, 95% CI 0.59-1.07) and urgent cesarean section (ARR 0.79, 95% CI 0.63-1.00) rates appeared to decline. CONCLUSION: Twin births decreased during the study period. International guidelines published before the Icelandic regulations may have affected twin birth rates in Iceland. Induction of labor rates for twins increased while cesarean section rates decreased.Peer reviewe

Trends in labor induction indications : A 20-year population-based study

© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Funding Information: This study was funded by the University of Iceland Research Fund (Rannís). Helga Zoega was supported by a UNSW Scientia Program Award. Publisher Copyright: © 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).INTRODUCTION: Use of labor induction has increased rapidly in most middle- and high-income countries over the past decade. The reasons for the stark rise in labor induction are largely unknown. We aimed to assess the extent to which the rising rate of labor induction is explained by changes in rates of underlying indications over time. MATERIAL AND METHODS: The study was based on nationwide data from the Icelandic Medical Birth Register on 85 620 singleton births from 1997 to 2018. The rate of labor induction and indications for induction was calculated for all singleton births in 1997-2018. Change over time was expressed as relative risk (RR), using Poisson regression with 95% confidence intervals (CI) adjusted for maternal characteristics and indications for labor induction. RESULTS: The crude rate of labor induction rose from 12.5% in 1997-2001 to 23.9% in 2014-2018 (crude RR = 1.91, 95% CI 1.81-2.01). While adjusting for maternal characteristics had little impact, adjusting additionally for labor induction indications lowered the RR to 1.43 (95% CI 1.35-1.51). Induction was increasingly indicated from 1997-2001 to 2014-2018 by gestational diabetes (2.4%-16.5%), hypertensive disorders (7.0%-11.1%), prolonged pregnancy (16.2%-23.7%), concerns for maternal wellbeing (3.2%-6.9%) and maternal age (0.5%-1.2%). No indication was registered for 9.2% of inductions in 2014-2018 compared with 16.3% in 1997-2001. CONCLUSIONS: Our results show that the increase in labor induction over the study period is largely explained by an increase in various underlying conditions indicating labor induction. However, indications for 9.2% of labor inductions remain unexplained and warrant further investigation.Peer reviewe

The combined effect of pre-pregnancy body mass index and gestational weight gain on the risk of pre-labour and intrapartum caesarean section—The ICE-MCH study

Funding Information: A project grant from the Research Fund of the University of Iceland (https://english.hi.is/research/the_university_of_iceland_research_ fund_0, author IT). A personal grant from Finnish Cultural Foundation (https://skr.fi/en, author AE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 2023 Eloranta 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. Copyright: © 2023 Eloranta 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.Women who are obese before pregnancy have a higher risk of caesarean section than normal weight women. We investigated the combined effect of pre-pregnancy weight and gestational weight gain on pre-labour and intrapartum caesarean section risk. We collected data on 22,763 singleton, term, live deliveries in 2003–2014 from the Icelandic Maternal and Child Health Study (ICE-MCH), based on Icelandic registries. These were the Icelandic Medical Birth Registry and the Saga Maternal and Child Health Database. Pre-pregnancy body mass index was categorised into underweight, normal weight, overweight and obese. Gestational weight gain was classified according to the Institute of Medicine's recommendation into below, within and above the recommended range. Logistic regression models, adjusted for maternal and gestational characteristics, were used to calculate adjusted odds ratios (AOR) and 95% confidence intervals (CI) for the risk of caesarean section. Obese women had a higher risk of pre-labour (AOR 1.56, 95% CI 1.34–1.81) and intrapartum caesarean section (AOR 1.92, 95% CI 1.70–2.17) than normal weight women in all categories of gestational weight gain. Gestational weight gain above the recommended range, compared to within the range, increased the risk of intrapartum caesarean section among normal weight (AOR 1.46, 95% CI 1.23–1.73) and overweight women (AOR 1.291, 95% CI 1.04–1.60). Gestational weight gain below the recommended range, compared to within the range, increased the risk of pre-labour caesarean section (AOR 1.64, 95% CI 1.20–2.25), but only among overweight women. Women who are obese before pregnancy have a high risk of caesarean section regardless of gestational weight gain. However, women who are normal weight or overweight before pregnancy and gain weight above the recommended range during pregnancy may also have an increased risk of caesarean section.Peer reviewe

Role of public and private funding in the rising caesarean section rate:a cohort study

Objective: The caesarean section rates have been rising in the developed world for over two decades. This study assessed the involvement of the public and private health sectors in this increase. Design: Population-based, retrospective cohort study. Setting: Public and private hospitals in Western Australia. Participants: Included in this study were 155 646 births to nulliparous women during 1996-2008. Main outcome measures: Caesarean section rates were calculated separately for four patient type groups defined according to mothers' funding source at the time of birth (public/private) and type of delivery hospital ( public/private). The average annual per cent change (AAPC) for the caesarean section rates was calculated using joinpoint regression. Results: Overall, there were 45 903 caesarean sections performed (29%) during the study period, 24 803 in-labour and 21 100 prelabour. Until 2005, the rate of caesarean deliveries increased most rapidly on average annually for private patients delivering in private hospitals (AAPC=6.5%) compared with public patients in public hospitals (AAPC=4.3%, p<0.0001). This increase could mostly be attributed to an increase in prelabour caesarean deliveries for this group of women and could not be explained by an increase in breech deliveries, placenta praevia or multiple pregnancies. Conclusions: Our results indicate that an increase in the prelabour caesarean delivery rate for private patients in private hospitals has been driving the increase in the caesarean section rate for nulliparous women since 1996. Future research with more detailed information on indication for the prelabour caesarean section is needed to understand the reasons for these findings

Neonatal complications in public and private patients:a retrospective cohort study

OBJECTIVE: To use propensity score methods to create similar groups of women delivering in public and private hospitals and determine any differences in mode of delivery and neonatal outcomes between the matched groups. DESIGN: Population-based, retrospective cohort study. SETTING: Public and private hospitals in Western Australia. PARTICIPANTS: Included were 93 802 public and 66 479 private singleton, term deliveries during 1998-2008, from which 32 757 public patients were matched with 32 757 private patients on the propensity score of maternal characteristics. MAIN OUTCOME MEASURES: Neonatal outcomes were compared in the propensity score-matched cohorts using conditional logistic regression, adjusted for antenatal risk factors and mode of delivery. Outcomes included Apgar score <7 at 5 min, neonatal resuscitation (endotracheal intubation or external cardiac massage) and admission to a neonatal special care unit. RESULTS: No significant differences in maternal characteristics were found between the propensity score-matched groups. Private patients were more likely than their matched public counterparts to undergo prelabour caesarean section (25.2% vs 18%, p<0.0001). Public patients had lower rates of neonatal unit admission (AOR 0.67, 95% CI 0.62 to 0.73) and neonatal resuscitation (AOR 0.73, 95% CI 0.56 to 0.95), but higher rates of low Apgar scores at 5 min (AOR 1.31, 95% CI 1.06 to 1.63) despite adjustment for antenatal factors. Additional adjustment for mode of delivery reduced the resuscitation risk (AOR 0.86, 95% CI  0.63 to 1.18) but did not significantly alter the other estimates. CONCLUSIONS: Propensity score methods can be used to generate comparable groups of public and private patients. Despite the rates of low Apgar scores being higher in public patients, the rates of special care admission were lower. Whether these findings stem from differences in paediatric services or clinical factors is yet to be determined

Effect of private insurance incentive policy reforms on trends in coronary revascularisation procedures in the private and public health sectors in Western Australia: A cohort study

Background: The Australian federal government introduced private health insurance incentive policy reforms in 2000 that increased the uptake of private health insurance in Australia. There is currently a lack of evidence on the effect of the policy reforms on access to cardiovascular interventions in public and private hospitals in Australia. The aim was to investigate whether the increased private health insurance uptake influenced trends in emergency and elective coronary artery revascularisation procedures (CARPs) for private and public patients. Methods: We included 34,423 incident CARPs from Western Australia during 1995-2008 in this study. Rates of emergency and elective CARPs were stratified for publicly and privately funded patients. The average annual percent change (AAPC) in trend was calculated before and after 2000 using joinpoint regression. Results: The rate of emergency CARPs, which were predominantly percutaneous coronary interventions (PCIs) with stenting, increased throughout the study period for both public and private patients (AAPC=12.9%, 95% CI=5.0,22.0 and 14.1%, 95% CI=9.8,18.6, respectively) with no significant difference in trends before and after policy implementation. The rate of elective PCIs with stenting from 2000 onwards remained relatively stable for public patients (AAPC=−6.0, 95% C= −16.9,6.4), but increased by 4.1% on average annually (95% CI=1.8,6.3) for private patients (Pdifference=0.04 between groups). This rate increase for private patients was only seen in people aged over 65 years and people residing in high socioeconomic areas.Conclusions: The private health insurance incentive policy reforms are a likely contributing factor in the shift in 2000 from public to privately-funded elective PCIs with stenting. These reforms as well as the increasing number of private hospitals may have been successful in increasing the availability of publicly-funded beds since 2000

Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder : a Nordic cohort study

Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND: Antipsychotics are increasingly used among women of childbearing age and during pregnancy. OBJECTIVE: To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors. FINDINGS: Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD. DISCUSSION: Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics. CLINICAL IMPLICATIONS: Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.Peer reviewe

Prevalence trends and individual patterns of antiepileptic drug use in pregnancy 2006‐2016: A study in the five Nordic countries, United States, and Australia

Publisher's version (útgefin grein)Purpose: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. Methods: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. Results: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). Conclusions: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED.This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS) (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366). Linkage of Danish data was supported by the Danish Council for Independent Research (Project No: DFF‐6110‐00019) and Karen Elise Jensens Fond (2016), and grant NNF18OC0052029 from Novo Nordisk Fonden (Li). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). We thank Anders Engeland (Norwegian Institute of Public Health, University of Bergen, Norway), Anna Heino (National Institute for Health and Welfare, Finland), Mette Nørgaard (Aarhus University, Denmark), Pär Karlsson (Karolinska Institutet, Sweden), Jennifer Yland (Harvard T.H. Chan School of Public Health, USA), Gregory Brill and Helen Mogun (Brigham and Women's Hospital & Harvard Medical School, USA) for providing assistance with analyses. The authors would like to thank the NSW Ministry of Health, the Australian Government Department of Health and Ageing and the Department of Human Services for providing data. The authors also thank the Centre for Health Record Linkage (CHeReL) and the Australian Institute for Health and Welfare for conducting the linkage of records.Peer Reviewe

Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder: a Nordic cohort study

Background Antipsychotics are increasingly used among women of childbearing age and during pregnancy. Objective To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors. Findings Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD. Discussion Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics. Clinical implications Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.</p