SUMMARY N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m6A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m6A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m6A modification has fundamental and broad functions in mammalian cells.

Abstract:The Nordic countries have a long tradition of registry-based epidemiological research. Many population-based health registries were established in the 1960s, with use of unique personal identifiers facilitating linkage between registries. In recent years, each country has established a national database to track prescription drugs dispensed to individuals in ambulatory care. The objectives were to present an overview of the prescription databases established in the Nordic countries, as well as to elaborate on their unique potential for record linkage and cross-national comparison of drug utilization. Five Nordic countries collect drug exposure data based on drugs dispensed at pharmacies and have the potential to link these data to health outcomes. The databases together cover 25 million inhabitants (Denmark: 5.5 million; Finland: 5.3 million; Iceland: 0.3 million; Norway: 4.8 million; and Sweden: 9.2 million). In 2007, the registries encompassed 17 million prescription drug users (68% of the total population). We provide examples of how these databases have been used for descriptive drug utilization studies and analytical pharmacoepidemiological studies linking drug exposure to other health registries. Comparisons are facilitated by many similarities among the databases, including data source, content, coverage and methods used for drug utilization studies and record linkage. There are, however, some differences in coding systems and validity, as well as in some access and technical issues. To perform cross-national pharmacoepidemiological studies, resources, networks and time are needed, as well as methods for pooling data. Interpretation of results needs to account for inter-country heterogeneity and the possibility of spurious relationships. The Nordic countries have a unique potential for collaborative high-quality cross-national pharmacoepidemiological studies with large populations. This research may assist in resolving safety issues of international interest, thus minimizing the risk of either over-reacting on possible signals or underestimating drug safety issues.

None.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Mothers are using medicines during pregnancies; the extent varies across the world and is generally difficult to compare.• In this registry-based study, we examined more than 100 000 Norwegian pregnancies and described the drug prescription pattern of both fathers and mothers around conception and during pregnancy (mothers). WHAT THIS STUDY ADDS• In every trimester of pregnancy, about 30% of the mothers was dispensed a drug.• The total drug exposure did not seem to diminish throughout pregnancy.• One-quarter of the fathers was dispensed drugs during the last 3 months prior to conception. AIMSThe primary aim of this study was to describe the use of prescribed drugs in both mothers and fathers before and during pregnancy in Norway. METHODSThis population-based cohort study was based on data retrieved from the Medical Birth Registry of Norway and the Norwegian Prescription Database. These registries cover the entire population of Norway. Information on >100 000 births during [2004][2005][2006] in the birth registry was linked to prescription data. Prescriptions issued to mothers just prior to, during and after the pregnancies as well as prescriptions to fathers just prior to conception were identified. RESULTSAmong mothers, 83% were prescribed drugs during the period 3 months prior to estimated conception until 3 months after giving birth. The mothers who received drugs were prescribed on average 3.3 different Anatomical Therapeutic Chemical (ATC) codes (range 1-38). During pregnancy, 57% were prescribed drugs. In the first trimester, 33% of mothers were dispensed drugs, while the figure was 29% for mothers in the last trimester. Among fathers, 25% used prescribed drugs during the 3 months prior to conception, with on average 1.9 different ATC codes (range 1-22). CONCLUSIONLarge proportions of both fathers and mothers were dispensed drugs prior to conception or during pregnancy. While there is a high awareness of the issues involved in maternal drug use in pregnancy, possible teratogenic effects of drug use in fathers shortly before conception should be further explored.British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2008 Br J Clin Pharmacol / 65:5 / 653-660 / 653 IntroductionDuring the last 40 years, several studies have been published on possible associations between maternal drug use and birth defects [1]. Physicians and pregnant women are, in many cases, aware of possible teratogenic effects connected to the use of specific drugs. However, a number of pregnancies are not planned. This may lead to exposure to drugs which are not recommended for pregnant women before the women are aware of their pregnancies and typically during organogenesis in the first trimester. Some women, however, need drugs during pregnancy to treat chronic conditions, e.g. asthma, epilepsy, diabetes mellitus or psychiatric disorders. In addition to possible birth defects, drug use later in pregnancy may also influence the course of the pregnancy and the hea...

The objective of this study was to assess international trends in antipsychotic use, using a standardised methodology. A repeated cross-sectional design was applied to data extracts from the years 2005 to 2014 from 16 countries worldwide. During the study period, the overall prevalence of antipsychotic use increased in 10 of the 16 studied countries. In 2014, the overall prevalence of antipsychotic use was highest in Taiwan (78.2/1000 persons), and lowest in Colombia (3.2/1000). In children and adolescents (0-19 years), antipsychotic use ranged from 0.5/1000 (Lithuania) to 30.8/1000 (Taiwan). In adults (20-64 years), the range was 2.8/1000 (Colombia) to 78.9/1000 (publicly insured US population), and in older adults (65+ years), antipsychotic use ranged from 19.0/1000 (Colombia) to 149.0/1000 (Taiwan). Atypical antipsychotic use increased in all populations (range of atypical/typical ratio: 0.7 (Taiwan) to 6.1 (New Zealand, Australia)). Quetiapine, risperidone, and olanzapine were most frequently prescribed. Prevalence and patterns of antipsychotic use varied markedly between countries. In the majority of populations, antipsychotic utilisation and especially the use of atypical antipsychotics increased over time. The high rates of antipsychotic prescriptions in older adults and in youths in some countries merit further investigation and systematic pharmacoepidemiologic monitoring.

Objective To assess whether maternal use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of persistent pulmonary hypertension in the newborn, and whether such an effect might differ between specific SSRIs.Design Population based cohort study using data from the national health registers.Setting Denmark, Finland, Iceland, Norway, and Sweden, 1996-2007. Participants More than 1.6 million infants born after gestational week 33.Main outcome measures Risks of persistent pulmonary hypertension of the newborn associated with early and late exposure to SSRIs during pregnancy and adjusted for important maternal and pregnancy characteristics. Comparisons were made between infants exposed and not exposed to SSRIs.Results Around 30 000 women had used SSRIs during pregnancy and 11 014 had been dispensed an SSRI later than gestational week 20. Exposure to SSRIs in late pregnancy was associated with an increased risk of persistent pulmonary hypertension in the newborn: 33 of 11 014 exposed infants (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000); adjusted odds ratio 2.1 (95% confidence interval 1.5 to 3.0). The increased risks of persistent pulmonary hypertension in the newborn for each of the specific SSRIs (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude. Filling a prescription with SSRIs before gestational week 8 yielded slightly increased risks: adjusted odds ratio 1.4 (95% confidence interval 1.0 to 2.0). ConclusionsThe risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold. The increased risk seems to be a class effect. IntroductionPersistent pulmonary hypertension of the newborn is a life threatening condition that occurs in up to 2 per 1000 liveborn infants and most often in those born full term or post term. [1][2][3] In this condition the pulmonary vascular resistance fails to decrease after birth and the ductus arteriosus must remain open to ensure circulation. Persistent pulmonary hypertension of the newborn and persistent fetal circulation are often used synonymously. 4 The pathophysiology is not clearly mapped out, but persistent pulmonary hypertension of the newborn might result from constricted pulmonary vasculature or because the vasculature is hypoplastic or remodelled.3 The constricted form is most commonly caused by meconium aspiration, the hypoplastic form can be seen in connection with diaphragmatic hernia, and presumably certain drugs can cause a remodelling of the vasculature.Depression during pregnancy is common, and estimated rates vary from 7% to 25%. 5 6 Use of selective serotonin reuptake inhibitors (SSRIs) is increasing among pregnant women, and use in late pregnancy may be a risk factor for persistent pulmonary hypertension of the newborn.7 During the past 15 years six studies have specifically assessed this association, with inconsistent findings from no association to a sixfold increased risk. [7][8][...

Objective To assess whether use of specific selective serotonin reuptake inhibitors (SSRIs) or venlafaxine in early pregnancy is associated with an increased risk of birth defects, with emphasis on cardiovascular birth defects even when accounting for lifestyle or other familial confounding. Design Multicountry population based cohort study, including sibling controlled design. Setting Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) identified from nationwide health registers at different periods in 1996-2010. Population The full study cohort included women giving birth to 2.3 million live singletons. The sibling cohort included 2288 singleton live births. The sibling controlled analyses included sibling pairs who were discordant for exposure to SSRIs or venlafaxine and birth defects. Main outcome measure Prevalence of birth defects, including subtypes of cardiac defects. Odds ratio of birth defects from logistic and conditional logistic regression. Results Among 36 772 infants exposed to any SSRI in early pregnancy, 3.7% (n=1357) had a birth defect compared with 3.1% of 2 266 875 unexposed infants, yielding a covariate adjusted odds ratio of 1.13 (95% confidence interval 1.06 to 1.20). In the sibling controlled analysis the adjusted odds ratio decreased to 1.06 (0.91 to 1.24). The odds ratios for any cardiac birth defect with use of any SSRI or venlafaxine were 1.15 (95% confidence interval 1.05 to 1.26) in the covariate adjusted analysis and 0.92 (0.72 to 1.17) in the sibling controlled analysis. For atrial and ventricular septal defects the covariate adjusted odds ratio was 1.17 (1.05 to 1.31). Exposure to any SSRI or venlafaxine increased the prevalence of right ventricular outflow tract obstruction defects, with a covariate adjusted odds ratio of 1.48 (1.15 to 1.89). In the sibling controlled analysis the adjusted odds ratio decreased to 0.56 (0.21 to 1.49) for any exposure to SSRIs or venlafaxine and right ventricular outflow tract obstruction defects. Conclusions In this large Nordic study no substantial increase was found in prevalence of overall cardiac birth defects among infants exposed to SSRIs or venlafaxine in utero. Although the prevalence of septal defects and right ventricular outflow tract defects was higher in exposed infants, the lack of an association in the sibling controlled analyses points against a teratogenic effect of these drugs.

While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation.