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IntroductionAntibiotics represent the most common type of medication used during pregnancy and infancy. Antibiotics have been proposed as a possible factor in changes in microbiota composition, which may play a role in the aetiology of autism and attention deficit/hyperactivity disorder (ADHD). Our aim was to investigate the association between maternal and early-life antibiotic use and autism and ADHD in childhood.MethodsThis Swedish nation-wide population-based cohort study included all first live singleton births (N = 483,459) between January 2006 and December 2016. The association of dispensed antibiotics with autism and ADHD in children aged = 1 antibiotic during the exposure period (from 3 months pre-conception to delivery), and 41.6% (n = 201,040) of the children received >= 1 antibiotic in early life (aged

Introduction Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. Objective To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. Methods This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005–2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel–Haenszel (MH) meta-analyses. Results The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98–1.34) for major congenital malformations and 1.72 (1.02–2.91) for stillbirth, which attenuated to 1.25 (0.74–2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03–1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67–1.42) for autism spectrum disorders, and 1.00 (0.78–1.29) for intellectual disability. Conclusions Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis. Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries

International audience; PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13–16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2–0.9) to 0.5 (95% CI, 0.3–1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8–1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

Purpose To determine risk of respiratory tract infections, urinary tract infections and candidiasis in secukinumab users compared to ustekinumab users among individuals with psoriasis in Sweden. Methods This was a Swedish population‐based register‐linked new‐user cohort study on individuals with psoriasis and psoriasis arthritis treated with secukinumab (2015‐2017) and ustekinumab (2009‐2017). Ever‐never exposure definition was used, that is, each individual's follow‐up time was attributed to the drug they were first exposed to. Risk of severe respiratory and urinary tract infections and candidiasis (diagnosis codes from out‐patient specialist visits and in‐patient hospitalisations) and respiratory and urinary tract infections treated in primary care (proxied by dispensation of antibiotics) was determined by adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox regression. We also give crude incidence rates and rate ratios. Results In total, 1955 new users of secukinumab (n = 848) and ustekinumab (n = 1107) were identified. There was a slightly increased risk of respiratory and urinary tract infections treated in primary care among secukinumab users compared to ustekinumab users (HR: 1.22, 95% CI: 1.03‐1.43). Non‐significant differences in estimated risk of severe respiratory and urinary tract infections (HR: 0.96, 95% CI: 0.57‐1.61) and candidiasis (HR: 1.80, 95% CI: 0.84‐3.84) treated in the hospital setting were observed. Conclusion We observed a slightly increased risk of respiratory and urinary tract infections treated in primary care among secukinumab users compared to ustekinumab users. Larger studies with longer follow‐up are needed to draw conclusions on relative safety.

Previous studies have defined long-term opioid use in varying ways, decreasing comparability, reproducibility, and clinical applicability of the research. Based on recommendations from recent systematic reviews, we aimed to develop methodology to estimate the prevalence of use persisting more than three months utilizing one of the Nordic prescription registers. We used the Norwegian Prescription Register (NorPD) to extract data on all opioid dispensations between January 1st, 2004, and October 31st, 2019. New users of opioids (washout 365 days) were defined as long-term users if they filled two criteria: 1) they had ≥2 dispensations of opioids, 91-180 days apart; 2) days 0-90 included ≥90 dispensed administration units (e.g., tablets) of opioids. Overall, there were 2,543,224 new users of opioids during the study period. Of these, 354,666 (13.9%) filled the criteria for long-term opioid use at least once. Compared to those who did not fill the criteria (short-term users), long-term users were older, more likely women, and used tramadol, oxycodone, and buprenorphine more frequently as their first opioid. In conclusion, we found that 1/7 of opioid users continued use longer than 3 months. Future outcome research should identify the clinically most important dose requirements for long-term opioid use criteria.

Aleksi Hamina,1,* Ingvild Odsbu,2,* Petter Christian Borchgrevink,3,4 Li-Chia Chen,5 Thomas Clausen,1 Ketil Arne Espnes,6,7 Kine Gjesdal,8,9 Marte Handal,1,10 Sirpa Hartikainen,11 Vidar Hjellvik,10 Marianne Therese Smogeli Holter,12 Trond Høibø,13 Geana Paula Kurita,14– 16 Harald Christian Langaas,7 Torgeir Gilje Lid,8,9 Torunn Hatlen Nøst,3,17 Per Sjøgren,15 Svetlana Skurtveit1,2 On behalf of the POINT study group1Norwegian Centre for Addiction Research (SERAF), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 2Department of Mental Disorders, Division of Mental and Physical Health, the Norwegian Institute of Public Health, Oslo, Norway; 3Department of Pain and Complex Disorders, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 4Institute of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; 5Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK; 6Department of Clinical Pharmacology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 7Regional Medicines Information and Pharmacovigilance Centre (RELIS), Department of Clinical Pharmacology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 8Faculty of Health Sciences, University of Stavanger, Stavanger, Norway; 9Center for Alcohol and Drug Research (KORFOR), Stavanger University Hospital, Stavanger, Norway; 10Department of Chronic Diseases, Division of Mental and Physical Health, the Norwegian Institute of Public Health, Oslo, Norway; 11School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 12Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway; 13Research Unit for General Practice, NORCE Norwegian Research Centre, Bergen, Norway; 14Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 15Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; 16Department of Anaesthesiology, Pain and Respiratory Support, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; 17Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway*These authors contributed equally to this workCorrespondence: Ingvild Odsbu, Department of Mental Disorders, Division of Mental and Physical Health, Norwegian Institute of Public Health, PO Box 222 Skøyen, Oslo, 0213, Norway, Tel +47 41454379, Email ingvild.odsbu@fhi.noAim: The POINT project aims to provide evidence to optimise chronic pain management, prevent adverse consequences of opioids, and improve chronic pain patients’ pain relief, functional capacity, and quality of life. We describe the outline of the project and its work packages. More specifically, we describe a cohort of persons with chronic pain and a cohort of long-term opioid users identified from a national registry linkage.Data Sources: The project utilises data from nationwide healthcare and population registers in Norway. Using the Norwegian Prescription Database, we identified a cohort of persons who have been dispensed drugs reimbursed for chronic pain and a cohort of persons who used opioids long term from 2010 to 2019. Data from the Norwegian Registry for Primary Health Care and the Norwegian Patient Registry (2008– 2019), Cancer Registry (1990– 2018) Cause of Death Registry (2010– 2019) and demographic and socioeconomic registers from Statistics Norway (2010– 2019) were linked to the cohorts.Study Population: There were 568,869 participants with chronic pain. Sixty-three percent of the cohort was women, and the mean age was 57.1 years. There were 336,712 long-term opioid users (58.6% women; 60.9 years). In chronic pain and long-term opioid user cohorts, the most frequent musculoskeletal diagnosis was back pain diagnosed in primary care (27.6% and 30.7%). Psychiatric diagnoses were also common.Main Variables: Upcoming studies will utilise psychiatric and somatic diagnoses from the patient registers, drug use from the prescription register, causes of death, demographics, and socioeconomic status (eg, education, income, workability, immigrant status) as exposures or outcomes.Conclusion and Future Plans: The two cohorts have numerous pain-related diagnoses, especially in the musculoskeletal system, and noticeably frequent somatic and psychiatric morbidity. The POINT project also includes later work packages that explore prescriber and patient perspectives around safe and effective treatment of chronic pain.Keywords: opioids, chronic pain, healthcare registers

Background: Pharmaceutical opioid (PO) overdose deaths have increased in many Western countries. There are indications that those dying from a PO overdose differ from those dying from other types of overdoses. These differences might pose a challenge as the majority of current preventive measures are tailored toward those with the characteristics of “conventional” overdose deaths. Objective: We investigated differences in the characteristics of persons who died from PO overdoses compared to all other overdoses. Material and Methods: Using the Norwegian Cause of Death Registry, we retrieved information on overdoses classified according to ICD-10 and identified PO overdoses (T40.2; T40.4) and all other overdoses (T40.X; T43.6) in 2010–2019. By linking data from nationwide registers, we analyzed data on opioid dispensations and the history of mental and behavioral disorders. 1,224 persons were registered with PO overdoses and 1,432 persons with other overdoses. Results: Persons in the PO overdose group were older and were more frequently women (35.0% vs. 20.5%) than persons with other overdoses. They had a higher prevalence of chronic pain (35.8% vs. 13.2%), history of cancer (8.1% vs. 1.8%), filled prescriptions of analgetic opioids more frequently the month before death (38.8% vs. 12.0%), and used threefold higher doses of prescribed opioids compared to individuals in all other overdose group (66 vs. 26 oral morphine equivalents/day). In the PO overdose group, oxycodone and fentanyl were more frequently dispensed, while codeine was more frequently dispensed in the other overdose groups. A lower proportion of those in the PO overdose group had recorded diagnoses of substance use disorders, schizophrenia, and hyperkinetic disorder compared to the other overdose groups. Conclusion: Persons dying from overdoses on POs often differ from the population targeted by existing prevention strategies, as they are more frequently older women with chronic pain and using high doses of prescription opioids.

Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996–2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87–1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70–2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26–2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72–1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83–1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53–1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551–562.

Background: Major depressive disorder (MDD) is a common psychiatric disorder associated with a high disease burden. This study gives a comprehensive overview of the prevalence, outcomes, treatment, and genetic epidemiology of MDD within and across the Scandinavian countries. Methods: This study has aimed to assess and compare across Norway, Denmark, and Sweden 1) the prevalence and trajectories of MDD and comorbidity, 2) outcomes and treatment, and 3) heritability (Denmark and Sweden only). The analyses leveraged data on 272,944 MDD cases (and 6.2 million non-cases) from Norway, Sweden, and Denmark in specialist care in national longitudinal health registers covering 1975–2013. Relying on harmonized public data global comparisons of socioeconomic and health metrics were performed to assess to what extent findings are generalizable. Findings: MDD ranked among the most prevalent psychiatric disorders. For many cases, the disorder trajectory was severe, with varying proportions experiencing recurrence, developing comorbid disorders, requiring inpatient treatment, or dying of suicide. Important country differences in specialist care prevalence and treatment were observed. Heritability estimates were moderate (35–48%). In terms of socioeconomic and health indices, the Scandinavian nations were comparable to one another and grouped with other Western nations. Interpretation: The Scandinavian countries were similar with regards to MDD epidemiological measures, but we show that differences in health care organization need to be taken into consideration when comparing countries. This study demonstrates the utility of using comprehensive population-wide registry data, outlining possibilities for other applications. The findings will be of use to policy makers for developing better prevention and intervention strategies. Funding: Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS), US National Institutes of Mental Health R01 MH123724 (to PFS), European Union's Horizon 2020 Research and Innovation Program ( 847776 and 964874, to OA) and European Research Council grant (grant agreement ID 101042183, to YL).

Background Increased and inappropriate antimicrobial use are the key drivers of the emergence of antimicrobial resistance, and there have been widespread concerns around potential antimicrobial misuse, overuse and their consequences during the COVID-19 pandemic. To better understand the impact of the pandemic on antimicrobial use, particularly in light of the resurgence of COVID-19 cases since the summer of 2020, we assessed trends in antimicrobial prescription fills and hospital requisitions in Sweden during 2020 against those of preceding years. Methods We performed a descriptive study using population-based data from the Swedish Prescribed Drug Register and the Swedish e-Health Agency. The weekly number of prescriptions filled and the total volume sold to inpatient care institutions in defined daily doses (DDDs) per 1000 inhabitants for systemic antibacterials (Anatomical Therapeutic Chemical therapeutic subgroup J01 excluding J01XX), antimycotics (J02), antivirals (J05) and antiprotozoals (P01) were computed and evaluated from time series graphs. A time series linear regression with ordinary least squares (OLS) estimation was used to model 2015–2019 data and predict the expected number of prescriptions filled and volumes sold in DDDs per 1000 inhabitants during 2020 with 95% confidence limits. Results From mid-March 2020, the weekly rate of antibiotic and antiprotozoal prescriptions filled plummeted to unprecedentedly low levels for the rest of the year; while unprecedentedly high numbers of antiviral prescriptions were filled weekly between mid-February and mid-March 2020. There was a net reduction in annual dispensing of antibiotics by 17%; of antiprotozoals by 21%; and of antivirals by 0.3% during 2020 compared to 2019. Inpatient care requisitions of antiprotozoals and antibiotics surged to 6-year highs during March 2020, resulting in a 127% increase in DDDs of antiprotozoals sold from 2019. The volume of antibiotics and antivirals sold to inpatient care institutions in 2020 decreased by 3% and 13% compared to 2019, respectively. Conclusions The overall decline in antimicrobial prescriptions filled in Sweden during 2020 were in part, collateral dividends of the COVID-19 pandemic.

Aim: We aimed to describe opioid maintenance treatment (OMT) to pregnant women in Norway and study the background characteristics of the pregnant women compared to the general population of pregnant women and to a previous clinical cohort study of OMT in pregnancy. Methods: Population-based cohort study with linked data from the Norwegian Medical Birth Registry, the Norwegian Prescription Database, the Norwegian Patient Registry, and Statistics Norway. The study population consisted of women giving birth between 2005-2015 in Norway. We defined OMT pregnancies as pregnancies where the woman was dispensed OMT medications (methadone, buprenorphine, or buprenorphine/ naloxone) at least once during pregnancy. Results: The study population consisted of 420,808 women with 645,440 pregnancies ending in a live birth in Norway in 2005-2015 (the general pregnant population). Of these, 261 women (0.6‰) had altogether 306 OMT pregnancies. The mean number of pregnancies was 28 OMT pregnancies per year and quite stable during the study period. Women with OMT pregnancies were older, smoked tobacco more frequently, had lower education, and fewer of them had a partner, compared to the general population of pregnant women. In most pregnancies, the women were treated with buprenorphine (n=183 (59.8%)), while in 120 (39.2%) pregnancies, the woman received methadone. From 2008, buprenorphine replaced methadone as the most frequently used drug. In only 38 (12.4%) pregnancies, OMT treatment was initiated in pregnancy. In 201 (66%) pregnancies, the woman used OMT medications in all trimesters. For these women, the mean amount of dispensed drug was 3.4 DDD/day (85 mg/day) in pregnancy for methadone and 1.9 DDD/day (15.2 mg/day) for buprenorphine. Conclusion: The number of OMT pregnancies per year has been low and stable in the period 2005-2015. Following Norwegian recommendations, there has been a shift from treatment with methadone towards buprenorphine. The women receiving OMT during pregnancy had more risk factors for adverse outcomes than the general pregnant population but were quite similar to the previous clinical cohort.

Bakgrunn: Opioider for behandling av langvarige smerter kan forskrives på blå resept, men bør ikke brukes samtidig med andre vanedannende legemidler. Hensikt: Å undersøke bruk av opioider på blå resept i perioden 2009-2019, samt å studere bruk av andre vanedannende legemidler (benzodiazepiner og z-hypnotika) blant dem som fikk opioider på blå resept i 2019. Metode: Data ble hentet fra Reseptregisteret. En prevalent opioidbruker i 2019 ble definert som en person med minst én utlevering av et smertestillende opioid på blå resept for langvarige smerter også i 2018. Bruk av andre vanedannende legemidler ble definert som minst én utlevering av et annet vanedannende legemiddel i løpet av samme år. Resultater: Totalt 18 443 personer (67% kvinner) fikk utlevert opioider på blå resept i 2019, en økning fra 5 568 i 2009 via 10 693 i 2016 og 16 133 i 2017. Av de 18 443 var 14 202 (77%) prevalente opioidbrukere. Blant de prevalente brukerne fikk 88% utlevert 100 mg orale morfinekvivalenter (OMEQ) eller mindre per dag. Totalt fikk 54% av de prevalente opioidbrukerne utlevert minst ett annet vanedannende legemiddel i 2019. Z-hypnotika var oftest forekommende blant de som brukte 100 mg OMEQ eller mindre per dag, mens benzodiazepiner alene eller i kombinasjon med z-hypnotika dominerte blant opioidbrukerne som fikk utlevert mer enn 100 mg OMEQ per dag. Mengden utlevert av andre vanedannende legemidler økte med mengden opioider brukt per dag. En større andel kvinner enn menn fikk utlevert andre vanedannende legemidler i 2019. Konklusjon: Studien indikerer at bruk av andre vanedannende legemidler forekommer hos en stor andel av dem som får forskrevet opioider på blå resept. Dette er tegn på et uheldig forskrivningsmønster som bør studeres nærmere. Background: Approximately 30% of the adult Norwegian population reports experiencing chronic pain, i.e. pain persisting more than three months. Opioids are indicated to treat moderate-to-severe pain. Since 2008, opioids can be reimbursed when prescribed for the treatment of chronic pain in Norway. Opioids have addictive potential and should, according to international and Norwegian recommendations, not be used concomitantly with other addictive drugs such as benzodiazepines (anxiolytics and sedatives) or benzodiazepine-related drugs (z-hypnotics). Aim of study: The aim of the study was to investigate opioid use within the reimbursement scheme in the period 2009-2019 and to calculate the prevalence of use of benzodiazepines and z-hypnotics among prevalent users receiving opioids on reimbursable prescriptions in 2019. Methods: The data were retrieved from the Norwegian Prescription Database. The study population consisted of individuals aged 18 years or older with at least one dispensation of an opioid reimbursed for chronic pain in the period 2009-2019. A prevalent user receiving opioids on reimbursable prescriptions in 2019 was defined as an individual filling at least one reimbursed opioid prescription in both 2018 and 2019. Use of other addictive drugs was defined as being dispensed at least one benzodiazepine and/or z-hypnotic in 2019 among prevalent opioid users. Results: Our results show an increase in the number of individuals receiving opioids on reimbursable prescriptions for the treatment of chronic pain in the period from 2009 to 2019. In 2019, there were 18,443 users of opioids on reimbursable prescriptions (67% women). Of these, 14,202 (77%) were prevalent opioid users.Among the prevalent opioid users, 90% of the women and 84% of the men received opioids corresponding to use of up to 100 mg oral morphine equivalents (OMEQ) per day, while a small proportion (1.5% of the women, 2.9% of the men) received more than the recommended maximum dosage of 300 mg OMEQ per day. In total, 54% of the opioid users were dispensed at least one other addictive drug in 2019. Z-hypnotics were most frequently dispensed to opioid users using 100 mg OMEQ or less per day, whereas benzodiazepines alone or in combination with z-hypnotics were more frequently dispensed to opioid users using more than 100 mg OMEQ per day. The total amount of dispensed benzodiazepines and/or z-hypnotics increased with an increasing number of OMEQs used per day. Women received other addictive drugs more frequently than men. In total, 24% of all the opioid users were first prescribed an opioid under the reimbursement scheme. Interpretation of results: Our study shows that more than half of the individuals receiving opioids on reimbursable prescriptions for the treatment of chronic pain also received other addictive drugs the same year albeit recommendations discourage the use of more than one addictive drug at a time. Also, one-fourth of the individuals received opioids as the first drug under the reimbursement scheme although non-opioid analgesics should preferably be prescribed first. There is a need for observational studies using linked data from national health- and population registers to gain more knowledge about the risk factors for and consequences of use of other addictive drugs among opioid users.

Introduction During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder. Objective The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use. Methods We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012–December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated. Results Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73–0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76–0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings. Conclusions This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01095-7., Plain Language Summary During clinical trials, mirabegron, which is a treatment for overactive bladder, was associated with small increases in heart rate and blood pressure. This study was conducted to compare the frequency of cardiac events following the use of mirabegron or antimuscarinics, a group of treatments also used to treat overactive bladder. We obtained the data for this study from four countries: Denmark, Sweden, the UK and the USA. We identified people who were new users of mirabegron or antimuscarinics from 2012 to 2018 using prescription or dispensing records. Occurrences of major cardiac events, heart attack, stroke, death due to cardiac events and death from any cause were evaluated. Overall, we identified 152,026 times when mirabegron or antimuscarinics were each used as new treatments. Most of the people in the study were women (63.1%) and at least 65 years old (72.6%). There were no notable differences between the treatment groups with regard to how often major cardiac events, heart attack or stroke occurred. Further, death due to cardiac events and death from any cause were no higher with mirabegron compared with antimuscarinics. We obtained similar results when the data were assessed for patients who were at high risk for cardiac events or split by age (less than 65 years or at least 65 years) or a history of overactive bladder medication use. In conclusion, this large study involving data from several countries found no higher risk of major cardiac events, heart attack, stroke or death among people prescribed mirabegron compared with antimuscarinics. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01095-7.

Objective: This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designedto compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinicmedications.Methods: Cohorts of mirabegron initiators during 2012–2018 were propensity-score matched to antimuscarinicmedication initiators within real-world data sources (Danish National Registers, SwedishNational Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incidentcancer cases were identified during follow-up from direct linkage to cancer registers or validatedthrough medical record review or through physician questionnaires. Comparisons of sex-specific compositecancer outcomes (cancer of the lung/bronchus, colon/rectum, melanoma of skin, urinary bladder,non-Hodgkin lymphoma, kidney/renal pelvis, pancreas, prostate in men and breast and uterus inwomen) were made overall and for person-time in the first year and after the first year following startof treatment, for all ages and for the subgroup 65 years.Results: Among the 80,637 mirabegron initiators matched to 169,885 antimuscarinic medication initiators,68% were at least 65 years of age and 66% were women. Over 5000 incident cancer cases wereobserved overall. Incidence rates were higher for men than women for composite and individual canceroutcomes. The pooled fixed effects hazard ratios for composite cancer outcomes (all ages) were1.05 (95% confidence interval [CI]: 0.98–1.14) for women and 1.06 (95% CI: 0.98–1.14) for men. Resultswere similar in persons 65 years.Conclusions: The results suggest no association between mirabegron use and risk of cancer, comparedwith antimuscarinic medications, in either men or women.Registration: EU PAS Register Number: EUPAS16088

Introduction: During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased heart rate and systolic/diastolic blood pressure vs placebo in patients with overactive bladder (OAB). We studied the association between mirabegron and cardiovascular (CV) outcomes in an observational post-marketing safety study using real-world data. Methods: The study population was identified within five data sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (US), and Humana (US). Episodes of time when patients were new users of mirabegron or antimuscarinic medications (AMs) from 2012 to 2018 were sourced from prescription/dispensing information and matched on propensity scores. Major adverse CV events (MACE), acute myocardial infarction (AMI), stroke, and CV and all-cause mortality were identified from register linkage or validated through medical record review or physician questionnaires. Incidence rates of these outcomes during person-time of current use were estimated along with hazard ratios (HRs) from Cox models. Results: In total, 152,026 mirabegron episodes were matched to an equal number of AM episodes. The study population was 63.2% female and 72.6% were ≥65 years old. Baseline CV risk factors were similar between matched groups. There were no appreciable differences in the incidence rates of MACE, AMI, and stroke among current users of mirabegron relative to AMs (Table). The incidence rates of CV mortality (HR: 0.83, 95% confidence interval [CI]: 0.73, 0.95) and all-cause mortality (HR: 0.80, CI: 0.76, 0.84) were no higher with mirabegron vs AMs. Results restricted to episodes at high risk for CV events or stratified by age ( Conclusions: This large, multinational study found no higher risk of MACE, AMI, stroke, or CV or all-cause mortality among current users of mirabegron relative to users of AMs.

ObjectivesWe aimed to calculate cumulative hepatitis C virus (HCV) treatment coverage among individuals enrolled in opioid agonist therapy (OAT) in Norway between 2013 and 2017 and to document the treatment transition to direct-acting antiviral (DAA) agents. Moreover, we aimed to describe adherence to DAAs in the same cohort.DesignProspective cohort, registry data.SettingSpecialist healthcare service (secondary)Participants and outcomesThis observational study was based on data from The Norwegian Prescription Database. We studied dispensed OAT and HCV treatment annually to calculate the cumulative frequency, and employed secondary sources to calculate prevalence, incidence and HCV treatment coverage from 2013 to 2017, among the OAT population. Factors associated with adherence to DAAs were identified a priori and subject to logistic regression.Results10 371 individuals were identified with dispensed OAT, 1475 individuals of these were identified with dispensed HCV treatment. Annual HCV treatment coverage increased from 3.5% (95% CI: 3.2 to 4.4) in 2013 to 17% (95% CI: 17 to 20) in 2017, giving a cumulative HCV coverage among OAT patients in Norway of 38.5%. A complete shift to interferon-free treatment regimens occurred, where DAAs accounting for 32% of HCV treatments in 2013 and 99% in 2017. About two-thirds of OAT patients were considered adherent to their DAA regimens across all genotypes. High level of OAT continuity was associated with improved adherence to DAAs (adjusted OR 1.4, 95% CI: 1 to 2, p=0.035).ConclusionsA large increase in HCV treatment coverage attributed by a complete shift to interferon-free regimens among the Norwegian OAT population has been demonstrated. However, treatment coverage is inadmissibly too low and a further substantial scale-up in HCV treatment is required to reach the universal targets of controlling and eliminating the HCV endemic.

ObjectivesTo compare the use of benzodiazepines, z-hypnotics, gabapentinoids, opioids and centrally acting stimulants (CAS) among patients who had received opioid agonist therapy (OAT) in Norway and Sweden during the period 2015 - 2017.DesignA register-based prospective cohort study using information about dispensed drugs from the Norwegian Prescription Database and Swedish Prescribed Drug Register.SettingPatients who were dispensed OAT opioids from pharmacies.ParticipantsA total of 7176 Norwegian and 3591 Swedish patients on OAT were included.Outcome measuresThe number and frequency of potentially addictive drugs dispensed were calculated for the two countries. The mean daily doses of dispensed benzodiazepines and z-hypnotics were summarised by calculating benzodiazepines in diazepam equivalents and z-hypnotics in zopiclone equivalents.ResultsIn 2017, 46% of patients in Norway, and 15% in Sweden, were dispensed a benzodiazepine. Moreover, 14% in Norway and 26% in Sweden received z-hypnotics. Gabapentinoids were dispensed to 10% of patients in Norway and 19% of patients in Sweden. In Norway, 6% and 12% of the patients received strong and weak non-OAT opioids, respectively, whereas in Sweden 10% were dispensed strong non-OAT opioids and 5% weak non-OAT opioids . CAS were dispensed to 4% in Norway and 18% in Sweden. The mean daily doses of benzodiazepines were 16 and 17 mg diazepam equivalents in Norway and Sweden, respectively. For z-hypnotics, the mean daily dose was 8 mg zopiclone equivalents in both countries. ‘Benzodiazepines and z-hypnotics’ was the most dispensed drug combination in 2017. Similar results were found in 2015 and 2016.ConclusionsNearly half of those patients who were dispensed an OAT opioid in Norway and Sweden were dispensed potentially addictive drugs. The differences identified between Norway and Sweden might be related to differences in eligibility guidelines and restrictions with respect to OAT.

Background Treatment with direct-acting antiviral agents (DAAs) offers an opportunity to eliminate hepatitis C virus (HCV) endemic among people who inject drugs (PWID) and people enrolled in opioid agonist therapy (OAT) programs. The objective of this study was to estimate and to compare HCV treatment uptake after the introduction of DAAs among patients receiving OAT in Sweden and Norway. We also aimed to evaluate predictors of DAAs treatment among OAT patients in both countries. Methods This observational study was conducted with data from The Swedish Prescribed Drug Register and The Norwegian Prescription Database. We studied dispensed medications to calculate HCV treatment among OAT patients from 2014 to 2017 in Sweden and Norway. HCV prevalence was estimated from primary and secondary sources. Dispensations of medicines from different therapeutic areas, which served as proxy for co-morbidities in 2017, were conditionally adjusted for age, gender, and OAT medications. Logistic regression was used to evaluate these parameters. Results In total 3529 individuals were identified with dispensed OAT in the Swedish cohort and 7739 individuals in the Norwegian cohort. HCV treatment was utilized by 407 persons in Sweden and 920 in Norway during the study period. Annual HCV and DAA treatment uptake increased in both countries. The estimated cumulative HCV treatment uptake at the end of 2017 was 31% in Norway and 28% in Sweden. DAA treatment was associated with increased age (aOR 1.8; 95% CI 1.0–3.2) and the dispensation of drugs used for diabetes (aOR 3.2; 95% CI 1.8–5.7) in Sweden. In Norway, lipid modifying agents and antibacterials were associated with decreased odds (aOR 0.4; 95%CI 0.2–0.9, aOR 0.8; 95%CI 0.6–1.0). Conclusions An increase in DAA treatment and HCV treatment uptake was observed among Swedish and Norwegian OAT patients whilst introducing new direct-acting antiviral treatment regimens. However, more than two thirds of the OAT population in Norway and Sweden were untreated at the beginning of 2018. A further scale-up is crucial in order to control and eliminate the HCV endemic among OAT patients.

Background Treatment with direct-acting antiviral agents (DAAs) offers an opportunity to eliminate hepatitis C virus (HCV) endemic among people who inject drugs (PWID) and people enrolled in opioid agonist therapy (OAT) programs. The objective of this study was to estimate and to compare HCV treatment uptake after the introduction of DAAs among patients receiving OAT in Sweden and Norway. We also aimed to evaluate predictors of DAAs treatment among OAT patients in both countries. Methods This observational study was conducted with data from The Swedish Prescribed Drug Register and The Norwegian Prescription Database. We studied dispensed medications to calculate cumulative frequency of HCV treatment among OAT patients from 2014 to 2017 in Sweden and Norway. Dispensations of medicines from different therapeutic areas, which served as proxy for co-morbidities in 2017, were adjusted for age, gender, and OAT medications and studied in a logistic regression model. Results In total 3,529 individuals were identified with dispensed OAT in the Swedish cohort and 7,739 individuals in the Norwegian cohort. HCV treatment was utilized by 407 persons in Sweden and 920 in Norway during the study period. Annual HCV treatment uptake increased in both countries, giving a cumulative frequency of around one-third in both countries at the end of the study period. DAA treatment was associated with increased age (aOR 1.8; 95% CI 1.0-3.2) and dispensation of drugs used for diabetes (aOR 3.2; 95% CI 1.8-5.7) in Sweden. In Norway, lipid modifying agents and antibacterials were associated with decreased odds (aOR 0.4; 95%CI 0.2-0.9, aOR 0.8; 95%CI 0.6-1.0). Conclusions An increase in DAA treatment and HCV treatment uptake was observed among Swedish and Norwegian OAT patients during the introduction period of new direct-acting treatment regimens. However, a further scale-up is crucial to be able to control and eliminate the HCV endemic among OAT patients.

Background It is estimated that up to a third of patients on opioid agonist therapy (OAT) have attention deficit hyperactivity disorder (ADHD). Treatment by ADHD medication, including a centrally acting stimulant (CAS) or atomoxetine is one of the essential approaches. This study evaluates the use of dispensed ADHD medications in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of ADHD medications, co-dispensations of other potentially addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are investigated. Methods Information about all dispensed ADHD medication, OAT opioids, and the defined potentially addictive drugs were recorded from the Norwegian Prescription Database. Dispensation rates, the types, and the doses of dispensed ADHD medications were estimated by summarizing the number of dispensations, and the dispensed doses. Logistic regression analyses were employed to assess the associations between ADHD medication, and OAT opioid use, and dispensations of other potentially addictive drugs and DAAs against hepatitis C infection. Results A total of 9235 OAT patients were included. The proportion of patients who were dispensed ADHD medication increased from 3.5 to 4.6% throughout the study period. The three most dispensed CAS were short- and intermediate-acting methylphenidate (55%), lisdexamphetamine (24%), and dexamphetamine (17%) in 2017. Buprenorphine, rather than methadone, as OAT opioid (adjusted odds ratio: 1.6, CI: 1.2–2.1) was associated with being dispensed ADHD medication. Among patients who received CAS and OAT opioids each calendar year, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). Sixty percent of patients receiving ADHD medications were also dispensed other addictive drugs concomitantly in 2017. Similar results were found in 2015 and 2016. Conclusion Co-prescription of ADHD medications was low among patients on OAT in Norway, considering a high prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs were common in this population. Understanding the underlying reasons for such prescribing is essential, and research on how to optimize ADHD medication of patients with ADHD receiving OAT is needed.

Background The extent to which iatrogenically-immunosuppressed individuals benefit from indirect effects of childhood vaccination with pneumococcal conjugate vaccines (PCVs) is unknown. We determined how the sequential introduction of PCV7 (2006) and PCV13 (2011) in the Norwegian childhood vaccination program has affected the epidemiology of invasive pneumococcal disease (IPD) in individuals treated with immunosuppressants in ambulatory care. Methods We conducted a case-cohort study comprising 7926 IPD cases reported to the Norwegian Surveillance System for Communicable Diseases in 2005-2014 and 249998 individuals randomly selected from the National Registry in 2012. We defined immunosuppressive treatment groups based on dispensed prescriptions retrieved from the Norwegian Prescription Database. Incidences and age-adjusted relative risks (RR) were estimated. Results IPD incidences decreased in all groups. The PCV13 incidence decreased by 5-12% across groups. The non-PCV13 incidence increased by 4-10%, mostly in individuals on chemotherapy (overlapping 95% confidence intervals). In the PCV13 era, the RR for IPD was highest (significant) and the percentage of cases caused by the polysaccharide vaccine PPV23 serotypes lowest (numerical) in individuals on chemotherapy (RR = 20.4, PPV23 = 52%), followed by individuals on corticosteroids (RR = 6.2, PPV23 = 64%), other immunosuppressants (RR = 5.6, PPV23 = 68%), and no immunosuppressants (RR = 1 [reference], PPV23 = 74%). Conclusions IPD incidences declined after PCV introduction in both immunocompetent and iatrogenically-immunosuppressed individuals, underscoring the benefit of childhood vaccination for the entire population. Still, individuals treated with immunosuppressants in ambulatory care are at increased risk of IPD caused by a more diverse group of serotypes.

INTRODUCTION AND OBJECTIVE:The β3-adrenergic agonist mirabegron is an alternative to antimuscarinics (AMs) for treatment of overactive bladder. During mirabegron development, a greater number of ca...

Purpose There is an increasing number of children with in utero exposure to opioids. Knowledge about opioid safety in pregnancy, particularly for outcomes later in childhood is scarce. It has been suggested that opioids can modulate immune system and increase the risk of infections. Our goal was to study the impact of in utero opioid exposure on the immune system and the risk of infections in childhood. Methods This population-based cohort study used nationwide registers from Denmark, Norway, and Sweden. Among pregnant women we identified users of opioids for two different indications, opioids used in opioid maintenance therapy (OMT) and opioids used for treatment of pain. We followed the exposed children and studied susceptibility for infections measured as number of antibiotic prescriptions expressed as Incidence rate ratios (IRRs) and diagnoses in specialist health care expressed as hazard ratios (HRs). Results After adjustment we did not observe increased risk for filling antibiotic prescriptions in children exposed to OMT opioids compared with OMT discontinuers (IRR, 1.08; 95% CI 0.81-1.44 in Norway and Sweden, and IRR, 0.74; 95% CI 0.63-0.88 in Denmark), or for diagnosis of infection in specialist health care (HR 0.83; 95% CI 0.55-1.26 in Norway and Sweden, and 0.82; 95% CI 0.62-1.10 in Denmark). Conclusions In this population-based cohort study, we did not observe increased risk of infections among children prenatally exposed to OMT opioids when compared to OMT discontinuers, nor long-term analgesic opioids exposed when compared to short-term analgesic opioids exposed.

Background It is estimated that about a third of patients on opioid agonist therapy (OAT) have Attention Deficit Hyperactivity Disorder (ADHD). Treatment by centrally acting sympathomimetics (CAS) is one of the essential approaches. This study evaluates the use of CAS in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of CAS, and co-dispensations of other addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are evaluated. Methods Information about all dispensed CAS, OAT opioids, and the defined addictive drugs were recorded from the Norwegian Prescription Database. The number and the doses of dispensed drugs were used to estimate dispensation rates, the types, and the doses of dispensed CAS. Logistic regression analyses were employed to assess the associations between CAS and OAT opioid use, and dispensations of other addictive drugs and DAA against hepatitis C infection. Results A total of 9,235 OAT patients were included. The proportion of patients who used both CAS and OAT opioids increased from 4 % to 5 % during the study period. The three most dispensed CAS were methylphenidate (59 %), lisdexamphetamine (24 %), and dexamphetamine (17 %). Buprenorphine as OAT opioid (adjusted odds ratio: 1.59, CI: 1.24-2.05) was associated with being dispensed CAS. Among patients who received CAS annually throughout the study period, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). About 60 % of these patients were also dispensed other addictive drugs concomitantly in 2017. Conclusion Co-dispensation of CAS was low among patients on OAT in Norway, considering a higher prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs are common in this population. Understanding the underlying causes of such prescribing is essential, and research on how to optimize CAS treatment of people with ADHD receiving OAT is needed.

Publisher's version (útgefin grein)., Objective Diabetes in pregnancy and consequently the need for treatment with antidiabetic medication (ADM) has become increasingly prevalent. The prevalence and patterns of use of ADM in pregnancy from 2006 onward in seven different countries was assessed. Research design and methods Data sources included individually linked data from the nationwide health registers in Denmark (2006-2016), Finland (2006-2016), Iceland (2006-2012), Norway (2006-2015), Sweden (2006-2015), state-wide administrative and claims data for New South Wales, Australia (2006-2012) and two US insurance databases: Medicaid Analytic eXtract (MAX; 2006-2012, public) and IBM MarketScan (2012-2015, private). The prevalence of ADM use was calculated as the proportion of pregnancies with at least one filled prescription of an ADM in the 90 days before pregnancy or within the three trimesters of pregnancy. Results Prevalence of any ADM use in 5 279 231 pregnancies was 3% (n=147 999) and varied from under 2% (Denmark, Norway, and Sweden) to above 5% (Australia and US). Insulin was the most used ADM, and metformin was the most used oral hypoglycemic agent with increasing use over time in all countries. In 11.4%-62.5% of pregnancies with prepregnancy use, ADM (primarily metformin) was discontinued. When ADM treatment was initiated in late pregnancy for treatment of gestational diabetes mellitus, insulin was most often dispensed, except in the US, where glibenclamide was most often used. Conclusions Prevalence and patterns of use of ADM classes varied between countries and over time. While insulin remained the most common ADM used in pregnancy, metformin use increased significantly over the study period., g This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies project (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366) both awarded to KF at Norwegian Institute of Public Health (NIHP). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). GB was supported by the Swedish Society of Medicine (InPreSS grant) and the Stockholm County Council (clinical postdoctoral appointment). HZ was funded by a Scientia Fellowship awarded by UNSW. BTB, SH-D and KFH were supported by the grant R01HD097778 from the Eunice Kennedy Shriver National Institute for Child Health & Human Development. YY’s salary is paid by unrestricted grants from the Lundbeck Foundation (R232-2016-2462 and R265-2017-4069), unrelated to this work. The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Background The MiniR1–1 plasmid is a derivative of the R1 plasmid, a low copy cloning vector. Results Nucleotide sequencing analysis shows that the MiniR1–1 plasmid is a 6316 bp circular double-stranded DNA molecule with an oriR1 (origin for replication). The plasmid carries the repA, tap, copA and bla genes, and genes for ORF1 and ORF2. MiniR1–1 contains eight DnaA-binding sites (DnaA-boxes). DnaA-box1 is in the oriR1 region and fully matched to the DnaA-box consensus sequence, and DnaA-box8, with one mismatch, is close to the copA gene. The presence of the MiniR1–1 plasmid leads to an accumulation of the D-period cells and an increase in cell size of slowly growing Escherichia coli cells, suggesting that the presence of MiniR1–1 delays cell division. Mutations in the MiniR1–1 DnaA-box1 and DnaA-box8 significantly increase the copy number of the plasmid and the mutations in DnaA-box1 also affect cell size. It is likely that titration of DnaA to DnaA-boxes negatively controls replication of the MiniR1–1 plasmid and delays cell division. Interestingly, DnaA weakly interacts with the initiator protein RepA in vivo. Conclusion DnaA regulates the copy number of MiniR1–1 as a negative factor through interacting with the RepA protein. Electronic supplementary material The online version of this article (10.1186/s12866-018-1162-3) contains supplementary material, which is available to authorized users.

Surveillance data on the level of resistant bacteria is needed to inform strategies to reduce the development and spread of antibiotic resistance. The aim of this study was to determine the non-susceptibility trends to extended-spectrum cephalosporins and carbapenems among Escherichia coli and Klebsiella spp. isolates from the district of Nashik in Western India during the period 2004–2014. Antibacterial susceptibility testing of clinical isolates was performed using Kirby-Bauer disc diffusion method to determine inhibitory zone diameters. The change in proportions of non-susceptible bacteria over calendar time was investigated with spline transformations in a logistic regression model. For the extended-spectrum cephalosporins, the proportions of non-susceptible E. coli and Klebsiella spp. isolates were above 78.4% and 84.9% throughout the study period, respectively. E. coli and Klebsiella spp. isolates exhibited carbapenem non-susceptibility levels as high as 76.9% and 84.1% respectively. The proportions of extended-spectrum betalactamase (ESBL)-producing isolates ranged from 38.3–85.9% in E. coli and from 45.1–93.1% in Klebsiella spp. Significantly higher proportions of non-susceptible and ESBL-producing isolates were found among isolates from inpatients compared to isolates from outpatients for both E. coli and Klebsiella spp. (p < 0.050). The high proportions of non-susceptible isolates observed show that there is great need to focus on optimal use of antibiotics to reduce the development of antibiotic resistance.

The aim of the study was to examine if there was an association between use of anxiolytics and hypnotics in pregnancy and language competence in the offspring at age 3 years.The Norwegian Mother and Child Cohort Study (MoBa) is a prospective pregnancy cohort where the mothers were asked to report on their medication use at pregnancy week 17-18, 30, and at 6 months postpartum. A woman was defined as a user of anxiolytics and hypnotics during pregnancy if she had reported use of benzodiazepines or benzodiazepine-related drugs during pregnancy. Children's language competence was measured at age three by maternal report on a validated language grammar scale. We used ordinal logistic regression with estimated standard errors allowing for clustering of multiple pregnancies.Forty-five thousand and two hundred sixty-six women with 51,748 pregnancies were included in the study. The women reported use of anxiolytics and/or hypnotics in 395 pregnancies (0.8 %). The odds ratios of being in a group with lower language competence were 1.2 (0.9-1.5) and 1.7 (1.0-2.8) for short-term and long-term anxiolytics and hypnotics use, respectively. When adjusting for SSRI use during pregnancy, the odds ratios were 1.1 (0.83-1.41) and 1.4 (0.84-2.33), respectively. Children whose mothers took no anxiolytics and hypnotics during or before pregnancy were reference group.The results refute any strong association between prenatal use of anxiolytics and hypnotics and lower language competence in the offspring at age 3 years.

The nucleoids of undamagedEscherichia colicells have a characteristic shape and number, which is dependent on the growth medium. Upon induction of the SOS response by a low dose of UV irradiation an extensive reorganization of the nucleoids occurred. Two distinct phases were observed by fluorescence microscopy. First, the nucleoids were found to change shape and fuse into compact structures at midcell. The compaction of the nucleoids lasted for 10–20 min and was followed by a phase where the DNA was dispersed throughout the cells. This second phase lasted for ~1 h. The compaction was found to be dependent on the recombination proteins RecA, RecO and RecR as well as the SOS-inducible, SMC (structural maintenance of chromosomes)-like protein RecN. RecN protein is produced in high amounts during the first part of the SOS response. It is possible that the RecN-mediated ‘compact DNA’ stage at the beginning of the SOS response serves to stabilize damaged DNA prior to recombination and repair.