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Background: The use of medication for Attention-Deficit/Hyperactivity Disorder (ADHD) increased globally throughout the early 2000s. This study examine trends in prevalences and incidences of medication use in Norway from 2006 to 2022. Methods: Data from the Norwegian Prescription Database were used to present one-year-prevalence and incidence rates of ADHD medication (ATC-group N06BA and C02AC02) for the overall population (ages 6–64) and within sex and age subgroups of children (ages 6–17) and adults (ages 18–64). Incident use was defined as the dispensing of medication, with no recorded use in the previous two calendar years. Results: The overall prevalence of ADHD medication use in 6- to 64-year-olds increased from 5.2 to 19.4 per 1000 in the period, most pronounced from 2020 and onwards. While males experienced a nearly threefold increase in use (from 7.3 to 20.6 per 1000), the use among females increased almost sixfold during the study period (from 3.0 to 18.1 per 1000). Consequently, the male-to-female prevalence-ratio decreased from 2.4 to 1. Children exhibited a higher prevalence of use compared to adults throughout the period, although the largest relative increase was observed in adults, particularly in female adults. In children the male-to-female ratio decreased from 3.2 to 2.0, primarily due to an increasing use in 13–17-year-old females. Among adults, prevalences were similar across most age groups, with the highest rates observed among those aged 18–24, where female use exceeded male use by the end of the period. The male-to-female prevalence-ratio in adults decreased from 1.6 to 0.9 during the period. Parallel to prevalent use, overall incident use increased from 1.4 to 5.0 per 1000 during the period, with the most pronounced increase occurring from 2020 and onwards. From this point, incident use among females aged 13–17, 18–24, and 25–34, exceeded that of males. The male-to-female incidence-ratio decreased from 1.8 to 0.9. The overall incidence to prevalence ratio remained similar throughout the period, being 0.27 in 2006 and 0.25 in 2022. Conclusion: A sustained increase in the prevalence of ADHD medication use was observed, with the most pronounced rise occurring among females and adults from 2020 and onwards. By 2022, the overall gender disparity in ADHD medication use had diminished, which should be considered in the context of a steep increase in incident use among adolescent and young adult females starting from 2020. [ABSTRACT FROM AUTHOR]

Background: Over the past 25 years, global opioid consumption has increased. Denmark ranks fifth in opioid use globally, exceeding other Scandinavian countries. Postsurgical pain is a common reason for opioid prescriptions, but opioid use patterns after patient discharge from the hospital are unclear. This study examines trends in opioid prescription among Danish surgical patients over a year. Methods: This register‐based cohort study will use data from Danish governmental databases related to patients undergoing the 10 most frequent surgical procedures in 2018, excluding cancer‐related and minor procedures. The primary outcome will be the dispensed postoperative opioid prescriptions at retail pharmacies over four quarters. Secondary analyses will include associations with sex, age, education attainment, and oral morphine equivalent quotient. Surgical treatments and diagnoses will be identified using NOMESCO procedure codes and ICD‐10 codes. Opioids will be identified by ATC codes N02A and R05DA04. Subjects will be classified as preoperative opioid consumers or non‐opioid consumers based on opioid prescriptions redeemed in the 6 months before surgery. Discussion: The study will use extensive national register‐based data, ensuring consistent data collection and enhancing the generalizability of the findings to similar healthcare systems. The study may identify high‐risk populations for long‐term opioids and provide information to support opioid prescribing guidelines and public health policies. [ABSTRACT FROM AUTHOR]

Background: The utilization patterns of opioid analgesics and the proportion of long-term opioid use after surgery in Norway is largely unknown. Methods: This study aimed to estimate the proportion of one-year long-term prescription opioid use among all Norwegian postoperative opioid users. Complete data from central health registries (NPR, NorPD, Statistics Norway, CoDR) were linked via the personal identification number unique to all citizens. The study period was January 1st 2010 until December 31st 2019. Long-term opioid use was defined as at least two opioid dispensings within two subsequent 90-day periods, with a minimum average use of 10 MME/day for the first 90 days. Results: The study population consisted of 693 495 post-operative opioid users (53.6% women), whereof 73.2% had not used opioids the year before surgery (new users). Among the postoperative opioid users, 3.8% were one-year long-term opioid users. The corresponding figures for new and previous opioid users were 0.4% and 13.1%, respectively. The highest proportions of long-term opioid use were found after transluminal endoscopy, eye surgery and assessments related to surgical procedures. In previous opioid users, the proportion of one-year long-term use was higher among women than men in all age groups, a difference that increased with age. Conclusions: The proportion of postoperative long-term opioid use in Norway is generally low. We detected higher proportions of long-term opioid use after certain types of surgery, but our crude surgery definition warrants further examination. Previous opioid users pose a particular challenge in the management of postoperative pain. Trial registration: The study used national health registry data from the period 2010–2019. A pre-registered analysis plan is available at Open Science Framework. [ABSTRACT FROM AUTHOR]

Background: Knowledge of co-occurring mental disorders (termed 'dual diagnosis') among patients receiving opioid agonist treatment (OAT) is scarce. This study aimed (1) to estimate the prevalence and structure of dual diagnoses in two national cohorts of OAT patients and (2) to compare mental disorders between OAT patients and the general populations stratified on sex and standardized by age. Methods: A registry-linkage study of OAT patients from Czechia (N = 4,280) and Norway (N = 11,389) during 2010–2019 was conducted. Data on mental disorders (F00-F99; ICD-10) recorded in nationwide health registers were linked to the individuals registered in OAT. Dual diagnoses were defined as any mental disorder excluding substance use disorders (SUDs, F10-F19; ICD-10). Sex-specific age-standardized morbidity ratios (SMR) were calculated for 2019 to compare OAT patients and the general populations. Results: The prevalence of dual diagnosis was 57.3% for Czechia and 78.3% for Norway. In Czechia, anxiety (31.1%) and personality disorders (25.7%) were the most prevalent, whereas anxiety (33.8%) and depression (20.8%) were the most prevalent in Norway. Large country-specific variations were observed, e.g., in ADHD (0.5% in Czechia, 15.8% in Norway), implying differences in screening and diagnostic practices. The SMR estimates for any mental disorders were 3.1 (females) and 5.1 (males) in Czechia and 5.6 (females) and 8.2 (males) in Norway. OAT females had a significantly higher prevalence of co-occurring mental disorders, whereas SMRs were higher in OAT males. In addition to opioid use disorder (OUD), other substance use disorders (SUDs) were frequently recorded in both countries. Conclusions: Results indicate an excess of mental health problems in OAT patients compared to the general population of the same sex and age in both countries, requiring appropriate clinical attention. Country-specific differences may stem from variations in diagnostics and care, reporting to registers, OAT provision, or substance use patterns. [ABSTRACT FROM AUTHOR]

Background: Many factors contribute to developing and conducting a successful multi‐data source, non‐interventional, post‐authorization safety study (NI‐PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. Objectives: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post‐marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. Results: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. Conclusions: This large PMR/PASS program was a long‐term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi‐data source NI‐PASS. [ABSTRACT FROM AUTHOR]

Introduction: Antibiotics are often prescribed during pregnancy. Assessing the current state of prenatal antibiotic use is therefore imperative for optimizing prescribing and identifying emerging research priorities. The study aimed to describe recent trends and patterns in antibiotic use during pregnancy among women who gave birth in Sweden, including user characteristics. Material and methods: Population‐based descriptive study using linked nationwide registers. All pregnancies delivered in Sweden from 2007 to 2019 were included. Prevalence of use was defined as the percentage of pregnancies during which at least one prescription forantibiotics was filled. Temporal trends in the prevalence of antibiotic use by calendar year, trimester and weeks of gestation were assessed from time series graphs. Results: Prescriptions for systemic antibiotics were filled in 20.7% of 1 434 431 pregnancies overall, decreasing from 24.7% in 2007 to 18.0% in 2019. Phenoxymethylpenicillin (8.5%), pivmecillinam (6.5%), nitrofurantoin (4.7%), amoxicillin (1.6%) and cefadroxil (1.5%) use were the most prevalent. Their use decreased over the 13‐year period, except for pivmecillinam, which increased from 4.0% to 7.4%. Prevalence of use was highest in the second trimester (9.5%), with weekly trends peaking at 13 and 34 weeks of gestation. Compared with non‐users, antibiotic users more often belonged to the youngest and oldest age strata, carried multipleton pregnancies, had delivered before, had attained a lower education level and smoked in early pregnancy. A higher body mass index, asthma, chronic renal disease and diabetes mellitus were more prevalent among antibiotic users than among non‐users. Conclusions: Although outpatient antibiotic use during pregnancy in Sweden has been declining, one in five pregnancies was exposed to systemic antibiotics. [ABSTRACT FROM AUTHOR]

Purpose: Opioid analgesics (OA) and other pharmaceuticals have been associated with drug‐induced deaths. However, there is a lack of knowledge regarding patterns of use of these pharmaceuticals in the population and regarding such associations. We identify and describe subgroups of people with different patterns of filled prescriptions of OA and other relevant pharmaceuticals and examine associations with drug‐induced deaths. In addition, we estimate the proportion of drug‐induced deaths with a filled OA prescription and OA as cause of death. Methods: A Norwegian population‐based nested case‐control register study with cases (drug‐induced deaths 2010–2018, N = 2388) and population controls matched for age, gender and year of inclusion (N = 21 465). Patterns of filled prescriptions for opioid analgesics (OA), benzodiazepines and benzodiazepine‐related drugs, gabapentinoids, ADHD medication and antidepressants/antipsychotics were explored by k‐means cluster analysis. Associations with drug‐induced deaths were estimated by conditional logistic regression adjusted for sociodemographic characteristics. Overlap of filled OA prescriptions and OA as cause of death was estimated. Results: Five clusters were identified: 'few prescriptions', 'weak OA', 'ADHD medication', 'sedative/psychiatric morbidity' and 'strong OA'. The 'strong OA' cluster had higher socioeconomic status compared to the other groupings. The risk of drug‐induced death was also highest in this cluster (OR = 35.5; CI 25.6–49.3) and, for 68% (CI 64–73) of cases, filled prescriptions for OA was indicated as the underlying cause of death. Conclusions: The cluster analysis identified a subgroup with filled prescriptions of OA and other pharmaceuticals and a higher socioeconomic status than other subgroups. This subgroup had a high risk of drug‐induced death that needs to be addressed. [ABSTRACT FROM AUTHOR]

Background: Conduct disorders (CD) are among the most frequent psychiatric disorders in children and adolescents, with an estimated worldwide prevalence in the community of 2–4%. Evidence-based psychological outpatient treatment leads to significant improvement in about two-thirds of cases. However, there seems to be considerable variation in rates of CD diagnoses and implementation of evidence-based interventions between nations. The aim of this study was to compare administrative prevalence and treatment patterns for CD in children and adolescents seen in health care systems across four Western countries (Denmark, Germany, Norway, and the USA). Methods: Cross-sectional observational study using healthcare data to identify children and adolescents (aged 0–19 years) with an ICD-10 code for CD within the calendar year 2018. Within each country's study population, the prevalence of CD, psychiatric comorbidity, psychopharmacological treatment, and psychiatric hospitalisation was calculated. Results: The prevalence of diagnosed CD differed 31-fold between countries: 0.1% (Denmark), 0.3% (Norway), 1.1% (USA) and 3.1% (Germany), with a male/female ratio of 2.0–2.5:1. The rate of psychiatric comorbidity ranged from 69.7 to 86.1%, with attention-deficit/hyperactivity disorder being most common. Between 4.0% (Germany) and 12.2% (USA) of youths with a CD diagnosis were prescribed antipsychotic medication, and 1.2% (Norway) to 12.5% (Germany) underwent psychiatric hospitalisation. Conclusion: Recognition and characteristics of youths diagnosed with CD varied greatly by country. In some countries, the administrative prevalence of diagnosed CD was markedly lower than the average estimated worldwide prevalence. This variation might reflect country-specific differences in CD prevalence, referral thresholds for mental health care, diagnostic tradition, and international variation in service organisation, CD recognition, and availability of treatment offers for youths with CD. The rather high rates of antipsychotic prescription and hospitalisation in some countries are remarkable, due to the lack of evidence for these therapeutic approaches. These findings stress the need of prioritising evidence-based treatment options in CD. Future research should focus on possible reasons for inter-country variation in recognition and management of CD, and also address possible differences in patient-level outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Among people receiving current or previous opioid maintenance treatment (OMT), the leading cause of premature death is an opioid overdose. However, other causes of mortality remain high in this group. An understanding of causes of deaths across multiple settings can be useful in informing more comprehensive prevention responses. The aim of this study was to describe all non-overdose causes of death in three national cohorts (Czechia, Denmark, and Norway) among OMT patients and to explore associations of non-overdose mortality with age and gender. Methods: This prospective comparative cohort study used national mortality registry databases for OMT patients from Czechia (2000–2019), Denmark (2000–2018), and Norway (2010–2019). Crude mortality rates and age-standardized mortality rates (ASMRs) were calculated as deaths per 1,000 person years for cause-specific mortality. Results: In total, 29,486 patients were included, with 5,322 deaths recorded (18%). We found variations in causes of death among the cohorts and within gender and age groups. The leading non-overdose causes of death were accidents in Czechia and Denmark, and neoplasms in Norway. Cardiovascular deaths were highest in Czechia, particularly for women in OMT (ASMR 3.59 vs. 1.24 in Norway and 1.87 in Denmark). Conclusion: This study found high rates of preventable death among both genders and all age groups. Different demographic structures, variations in risk exposure, as well as variations in coding practices can explain the differences. The findings support increased efforts towards screening and preventative health initiatives among OMT patients specific to the demographic characteristics in different settings. [ABSTRACT FROM AUTHOR]

Background: Physical diseases represent a significant burden for opioid agonist treatment (OAT) patients. This study described physical morbidity in two national cohorts of OAT patients focusing on gender differences. Methods: This population-based cohort study linking multiple health registers investigated physical diseases (ICD-10) in patients receiving OAT in the Czech Republic (N = 4,280) and Norway (N = 11,389) during 2010–2019. Gender-stratified analysis was performed. Results: Overall, we found a large burden of physical morbidity across gender groups in OAT patients. In the Czech Republic and Norway, women in OAT had a significantly higher prevalence of physical diseases across most diagnostic chapters, notably genitourinary diseases and neoplasms. Injuries/external causes and infectious/parasitic diseases were among the most common diseases in both women and men. Viral hepatitis accounted for over half of infectious morbidity in women and men in both cohorts. Conclusions: Our findings support the need for early screening, detection, and treatment of diseases and conditions across organ systems and the integration of health promotion activities to reduce physical morbidity in OAT patients. The gender differences underline the need for a tailored approach to address specific medical conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Opioids may modulate the immune function through opioid receptors on immune cells. Long-term consequences of prenatal opioid exposure on the immune system, such as childhood asthma, are unknown. Objectives: To investigate whether prenatal opioid exposure is associated with the risk of childhood asthma. Methods: Cohort study using linked nationwide registers in Denmark (1996-2015), Norway (2005-2015), and Sweden (2006-2013). Children born by mothers who were chronic opioid analgesics users before pregnancy (n = 14,764) or who were receiving opioid maintenance therapy (OMT) before or during pregnancy (n = 1,595) were identified based on information from each of the medical birth registers and prescription registers. Long-term opioid analgesics exposed children were compared to short-term exposed or unexposed, whereas OMT exposed children were compared to OMT unexposed. Asthma among children ≥1 years of age was defined as two or more filled prescriptions of antiasthmatic medication within 365 days, or a diagnosis of asthma. Hazard ratios (HRs) were calculated using Cox proportional hazards regression with attained age as the time scale. Inverse probability of treatment weights based on propensity scores were applied to adjust for measured confounders. Individual level data from Norway and Sweden were pooled, whereas individual level data from Denmark were analyzed separately. For the opioid analgesics comparisons, adjusted HRs (aHR) from the combined Norwegian/Swedish data and the Danish data were pooled in a fixedeffects meta-analysis. Results: For the opioid analgesics cohort, no increased risk of asthma was observed in long-term exposed children neither compared with unexposed [aHR = 0.99 (95% CI 0.87-1.12)], nor compared with short-term exposed [aHR = 0.97 (0.86-1.10)]. No increased risk of asthma was observed in OMT exposed compared with OMT unexposed children [Norway/Sweden: aHR = 1.07 (0.60-1.92), Denmark: aHR = 1.25 (0.87-1.81)]. Results from sensitivity analyses, where potential misclassification of the outcome and misclassification of OMT exposure were assessed, as well as starting follow-up at 6 years of age, showed that the estimates of association were generally robust. Conclusion: We found no association between prenatal exposure to opioids and risk of childhood asthma. Results were consistent across two different opioid exposure groups with different confounder distributions. [ABSTRACT FROM AUTHOR]

Introduction: Antibiotics 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. Methods: This 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 ≤ 11 years was estimated by applying multivariable logistic regression and generalised estimating equations models. Results: Of the mothers, 25.9% (n = 125,106) were dispensed ≥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 ≤ 2 years). Penicillin was the most prescribed antibiotic class (17.9% of mothers, 38.2% of children). Maternal antibiotic use was associated with an increased risk of autism [odds ratio (OR) = 1.16, 95% confidence interval (CI) 1.09–1.23] and ADHD (OR = 1.29, 95% CI 1.21–1.36) in childhood. Early-life exposure to antibiotics showed an even stronger association [autism (OR = 1.46, 95% CI 1.38–1.55); ADHD (OR = 1.90, 95% CI 1.80–2.00)]. Both maternal and childhood-exposure sub-analyses suggested a dose-response relationship. Conclusion: Maternal and early-life antibiotic use was associated with an increased risk of autism and ADHD in childhood. However, differences were noted by exposure period and antibiotic classes. Plain Language Summary: Antibiotics are commonly prescribed to pregnant women, infants, and toddlers. Antibiotic use during pregnancy may alter the maternal microbiota, which can influence the microbial colonisation of the gastrointestinal system of the foetus. It has been claimed that antibiotic use during pregnancy may have an effect on the gut-brain axis and, as a result, neurodevelopment. Neurodevelopmental disorder (NDD) is a category of illnesses characterised by functional impairments that manifest early in development. The most frequent NDDs are autism and attention-deficit/hyperactivity disorder (ADHD). In this large Swedish nation-wide study, we assessed whether antibiotic use during pregnancy and/or early in life affects the risk of developing autism and ADHD. The study found that both maternal antibiotic usage, as well as early childhood antibiotic use, were associated with an increased risk of autism and ADHD in children. These associations were altered by the quantity, type, and timing of antibiotic exposure. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: 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. [ABSTRACT FROM AUTHOR]

Introduction: Inconsistent results have been reported on the association between folic acid use in pregnancy and risk of GDM. The aim of this study was to estimate the association between folic acid use and GDM in two population-based Nordic cohorts. Material and methods: Two cohort studies were conducted using data from the national population registers in Norway (2005–2018, n = 791,709) and Sweden (2006–2016, n = 1,112,817). Logistic regression was used to estimate the associations between GDM and self-reported folic acid use and prescribed folic acid use, compared to non-users, adjusting for covariates. To quantify how potential unmeasured confounders may affect the estimates, E-values were reported. An exposure misclassification bias analysis was also performed. Results: In Norwegian and Swedish cohorts, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for maternal self-reported folic acid use were 1.10 (1.06–1.14) and 0.89 (0.85–0.93), with E-values of 1.43 (1.31) and 1.50 (1.36), respectively. For prescribed folic acid use, ORs were 1.33 (1.15–1.53) and 1.56 (1.41–1.74), with E-values of 1.99 (1.57) and 2.49 (2.17), in Norway and Sweden respectively. Conclusions: The slightly higher or lower odds for GDM in self-reported users of folic acid in Norway and Sweden respectively, are likely not of clinical relevance and recommendations for folic acid use in pregnancy should remain unchanged. The two Nordic cohorts showed different directions of the association between self-reported folic acid use and GDM, but based on bias analysis, exposure misclassification is an unlikely explanation since there may still be differences in prevalence of use and residual confounding. Prescribed folic acid is used by women with specific comorbidities and co-medications, which likely underlies the higher odds for GDM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 a 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 1 January 2004 and 31 October 2019. New users of opioids (washout 365 days) were defined as long‐term users if they fulfilled 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%) fulfilled the criteria for long‐term opioid use at least once. Compared with those who did not fulfil 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. [ABSTRACT FROM AUTHOR]

This article discusses an international project between the Czech Republic and Norway focused on the use of psychoactive prescription medications and the exchange of research experiences. The project aims to identify data sources for research and monitoring, as well as strengthen collaboration between the two countries. The high prevalence of psychoactive prescription medication use in the Czech Republic and the health consequences associated with it are highlighted, while Norway's measures to address prescription opioid use and overdose deaths are also mentioned. The availability and quality of data in the Czech Republic for research purposes are uncertain, and the project seeks to investigate this. The article provides contact information for the project coordinators and mentions that project outputs are available online. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designed to compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinic medications. Cohorts of mirabegron initiators during 2012–2018 were propensity-score matched to antimuscarinic medication initiators within real-world data sources (Danish National Registers, Swedish National Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incident cancer cases were identified during follow-up from direct linkage to cancer registers or validated through medical record review or through physician questionnaires. Comparisons of sex-specific composite cancer 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 in women) were made overall and for person-time in the first year and after the first year following start of treatment, for all ages and for the subgroup ≥65 years. 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 were observed overall. Incidence rates were higher for men than women for composite and individual cancer outcomes. The pooled fixed effects hazard ratios for composite cancer outcomes (all ages) were 1.05 (95% confidence interval [CI]: 0.98–1.14) for women and 1.06 (95% CI: 0.98–1.14) for men. Results were similar in persons ≥65 years. The results suggest no association between mirabegron use and risk of cancer, compared with antimuscarinic medications, in either men or women. Registration: EU PAS Register Number: EUPAS16088 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives To compare the use of benzodiazepines, zhypnotics, 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. Design A register-based prospective cohort study using information about dispensed drugs from the Norwegian Prescription Database and Swedish Prescribed Drug Register. Setting Patients who were dispensed OAT opioids from pharmacies. Participants A total of 7176 Norwegian and 3591 Swedish patients on OAT were included. Outcome measures The 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. Results In 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 nonOAT 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 8mg 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. Conclusions Nearly 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. [ABSTRACT FROM AUTHOR]

Objectives We 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. Design Prospective cohort, registry data. Setting Specialist healthcare service (secondary) Participants and outcomes This 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. Results 10 371 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). Conclusions A large increase in HCV treatment coverage attributed by a complete shift to interferonfree 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and aims: While the Nordic countries have considerably stricter controls on opioid prescribing for chronic non-cancer pain than other countries, previous research has warned that prescription of strong opioids is increasing. This study examines consumption of and developments in dispensed prescribed opioids to individuals receiving ambulatory care from 2006 to 2017, using publicly available data from each of three Nordic countries' national prescription registries. Methods: Repeated, cross-sectional design. One-year prevalence of all dispensed prescribed opioids in ATC N02A group were reported for Norway, Denmark, and Sweden in the period 2006–2017 by gender. One-year prevalence of the weak opioids tramadol and codeine and the strong opioid oxycodone were then reported separately over this period for each country. The mean defined daily dose (DDD) per user per year, an estimate of the amount of opioids prescribed, was reported for each of the three opioids in 2016. Results: Patterns of dispensed prescribed opioids differ greatly between 2006 and 2017 and between countries, with tramadol increasing in Norway, codeine declining across the board, and oxycodone increasing in all three countries. Norway exceeded Sweden and Denmark in prevalence of all dispensed prescribed opioids, with 12.1% of the female Norwegian population and 9.2% of the male Norwegian population dispensed at least one prescribed opioid as an outpatient in 2016. Norway's high overall prevalence rates are tempered by dispensing the lowest mean doses of both weak opioids compared to Sweden. Similarly, Sweden dispenses the lowest mean doses of oxycodone but to the largest proportion of its population (3.0%). Conclusions: Significant shifts have occurred in the dispensing of prescribed opioids in Norway, Sweden, and Denmark over the past 12 years. The increasing prevalence of oxycodone in all three countries should continue to be monitored. Prescription registries provide a wealth of publicly available data that can be used to monitor and to guide prescribing policies in a more knowledge-based direction. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the prescribing of systemic drugs for the treatment of acne in adolescents in the period 2005-15.Methods: The study population consisted of 14-24-year-old users of tetracyclines, isotretinoin or hormonal therapy retrieved from the Norwegian Prescription Database. The 1 year period prevalence was calculated as the number of patients who had redeemed at least one prescription during the year divided by the mean population. If the user had no prescriptions in the preceding 12 months he/she was defined as a new user. The incidence rate was defined by the number of new users during the year divided by the mean population.Results: Increased prescribing rates for systemic tetracyclines and isotretinoin were observed in the period 2005-15, while a decreased prescribing rate for hormonal therapy was observed from 2007. The majority (75%) of the tetracycline prescriptions were prescribed by general practitioner specialists or physicians with no specialty/under training for a specialty. The average durations of treatment in men and women who only used tetracyclines were 3.3 and 2.8 months, respectively. For men and women that switched to isotretinoin, the average durations of treatment were 4.3 and 3.9 months.Conclusions: The increased use of systemic tetracyclines in general, and the prolonged use of tetracyclines in patients who later switch to isotretinoin, raise the question of whether isotretinoin treatment should be considered at an earlier stage to reduce the use of systemic tetracyclines. [ABSTRACT FROM AUTHOR]

Temporal transcriptions of genes are achieved by different mechanisms such as dynamic interaction of activator and repressor proteins with promoters, and accumulation and/or degradation of key regulators as a function of cell cycle. We find that the TorR protein localizes to the old poles of the Escherichia coli cells, forming a functional focus. The TorR focus co-localizes with the nucleoid in a cell-cycle-dependent manner, and consequently regulates transcription of a number of genes. Formation of one TorR focus at the old poles of cells requires interaction with the MreB and DnaK proteins, and ATP, suggesting that TorR delivery requires cytoskeleton organization and ATP. Further, absence of the protein-protein interactions and ATP leads to loss in function of TorR as a transcription factor. We propose a mechanism for timing of cell-cycle-dependent gene transcription, where a transcription factor interacts with its target genes during a specific period of the cell cycle by limiting its own spatial distribution. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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. Conclusion: The results refute any strong association between prenatal use of anxiolytics and hypnotics and lower language competence in the offspring at age 3 years. [ABSTRACT FROM AUTHOR]

The functions of several SOS regulated genes in Escherichia coli are still unknown, including dinQ. In this work we characterize dinQ and two small RNAs, agrA and agrB, with antisense complementarity to dinQ. Northern analysis revealed five dinQ transcripts, but only one transcript (+44) is actively translated. The +44 dinQ transcript translates into a toxic single transmembrane peptide localized in the inner membrane. AgrB regulates dinQ RNA by RNA interference to counteract DinQ toxicity. Thus the dinQ-agr locus shows the classical features of a type I TA system and has many similarities to the tisB-istR locus. DinQ overexpression depolarizes the cell membrane and decreases the intracellular ATP concentration, demonstrating that DinQ can modulate membrane-dependent processes. Augmented DinQ strongly inhibits marker transfer by Hfr conjugation, indicating a role in recombination. Furthermore, DinQ affects transformation of nucleoid morphology in response to UV damage. We hypothesize that DinQ is a transmembrane peptide that modulates membrane- dependent activities such as nucleoid compaction and recombination. [ABSTRACT FROM AUTHOR]

Background: It has been proposed that the enzymes of nucleotide biosynthesis may be compartmentalized or concentrated in a structure affecting the organization of newly replicated DNA. Here we have investigated the effect of changes in ribonucleotide reductase (RNR) activity on chromosome replication and organization of replication forks in Escherichia coli. Methodology/Principal Findings: Reduced concentrations of deoxyribonucleotides (dNTPs) obtained by reducing the activity of wild type RNR by treatment with hydroxyurea or by mutation, resulted in a lengthening of the replication period. The replication fork speed was found to be gradually reduced proportionately to moderate reductions in nucleotide availability. Cells with highly extended C periods showed a ''delay'' in cell division i.e. had a higher cell mass. Visualization of SeqA structures by immunofluorescence indicated no change in organization of the new DNA upon moderate limitation of RNR activity. Severe nucleotide limitation led to replication fork stalling and reversal. Well defined SeqA structures were not found in situations of extensive replication fork repair. In cells with stalled forks obtained by UV irradiation, considerable DNA compaction was observed, possibly indicating a reorganization of the DNA into a ''repair structure'' during the initial phase of the SOS response. Conclusion/Significance: The results indicate that the replication fork is slowed down in a controlled manner during moderate nucleotide depletion and that a change in the activity of RNR does not lead to a change in the organization of newly replicated DNA. Control of cell division but not control of initiation was affected by the changes in replication elongation. [ABSTRACT FROM AUTHOR]

When the bacterium Escherichia coli is grown in rich medium, the replication and segregation periods may span two, three or four generations and cells may contain up to 24 replication forks. The newly synthesized, hemimethylated DNA at each fork is bound by SeqA protein. The SeqA–DNA structures form distinct foci that can be observed by immunofluorescence microscopy. The numbers of foci were lower than the numbers of replication forks indicating fork co-localization. The extent of co-localization correlated with the extent of replication cycle overlap in wild-type cells. No abrupt increase in the numbers of foci occurred at the time of initiation of replication, suggesting that new replication forks bind to existing SeqA structures. Manipulations with replication control mechanisms that led to extension or reduction of the replication period and number of forks, did not lead to changes in the numbers of SeqA foci per cell. The results indicate that the number of SeqA foci is not directly governed by the number of replication forks, and supports the idea that new DNA may be ‘captured’ by existing SeqA structures. [ABSTRACT FROM AUTHOR]

The Escherichia coli SeqA protein binds preferentially to hemimethylated DNA and is required for inactivation (sequestration) of newly formed origins. A mutant SeqA protein, SeqA4 (A25T), which is deficient in origin sequestration in vivo, was found here to have lost the ability to form multimers, but could bind as dimers with wild-type affinity to a pair of hemimethylated GATC sites. In vitro, binding of SeqA dimers to a plasmid first generates a topology change equivalent to a few positive supercoils, then the binding leads to a topology change in the “opposite” direction, resulting in a restraint of negative supercoils. Binding of SeqA4 mutant dimers produced the former effect, but not the latter, showing that a topology change equivalent to positive supercoiling is caused by the binding of single dimers, whereas restraint of negative supercoils requires multimerization via the N-terminus. In vivo, mutant SeqA4 protein was not capable of forming foci observed by immunofluorescence microscopy, showing that N-terminus–dependent multimerization is required for building SeqA foci. Overproduction of SeqA4 led to partially restored initiation synchrony, indicating that origin sequestration may not depend on efficient higher-order multimerization into foci, but do require a high local concentration of SeqA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]