Publications by authors named "Ingvild Odsbu"

23 Publications

  • Page 1 of 1

A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder.

Curr Med Res Opin 2021 Mar 8:1-11. Epub 2021 Mar 8.

Optum Epidemiology, Boston, MA, USA.

Objective: 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.

Methods: 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.

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 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.

Conclusions: The results suggest no association between mirabegron use and risk of cancer, compared with antimuscarinic medications, in either men or women. EU PAS Register Number: EUPAS16088.
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http://dx.doi.org/10.1080/03007995.2021.1891035DOI Listing
March 2021

Risk of common infections among individuals with psoriasis in Sweden: A nationwide cohort study comparing secukinumab to ustekinumab.

Pharmacoepidemiol Drug Saf 2020 12 25;29(12):1562-1569. Epub 2020 Sep 25.

Centre for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Solna, Sweden.

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.
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http://dx.doi.org/10.1002/pds.5132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756328PMC
December 2020

On the path towards universal coverage of hepatitis C treatment among people receiving opioid agonist therapy (OAT) in Norway: a prospective cohort study from 2013 to 2017.

BMJ Open 2020 08 26;10(8):e036355. Epub 2020 Aug 26.

Department of Addiction Medicine, Helse Bergen HF, Bergen, Norway.

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 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.
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http://dx.doi.org/10.1136/bmjopen-2019-036355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451452PMC
August 2020

Potentially addictive drugs dispensing to patients receiving opioid agonist therapy: a register-based prospective cohort study in Norway and Sweden from 2015 to 2017.

BMJ Open 2020 08 7;10(8):e036860. Epub 2020 Aug 7.

Department of Addiction Medicine, Haukeland University Hospital, Bergen, Norway.

Objectives: To 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.

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 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.

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.
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http://dx.doi.org/10.1136/bmjopen-2020-036860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418685PMC
August 2020

In utero opioid exposure and risk of infections in childhood: A multinational Nordic cohort study.

Pharmacoepidemiol Drug Saf 2020 12 7;29(12):1596-1604. Epub 2020 Aug 7.

Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.

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.
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http://dx.doi.org/10.1002/pds.5088DOI Listing
December 2020

Uptake and predictors of direct-acting antiviral treatment for hepatitis C among people receiving opioid agonist therapy in Sweden and Norway: a drug utilization study from 2014 to 2017.

Subst Abuse Treat Prev Policy 2020 06 30;15(1):44. Epub 2020 Jun 30.

Department of Addiction Medicine, Haukeland University Hospital, Bergen, Norway.

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.
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http://dx.doi.org/10.1186/s13011-020-00286-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325258PMC
June 2020

Dispensation of attention deficit hyperactivity disorder (ADHD) medications in patients receiving opioid agonist therapy; a national prospective cohort study in Norway from 2015 to 2017.

BMC Psychiatry 2020 03 12;20(1):119. Epub 2020 Mar 12.

Department of Addiction Medicine, Haukeland University Hospital, Bergen, Norway.

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.
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http://dx.doi.org/10.1186/s12888-020-02526-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068965PMC
March 2020

Antidiabetic medication use during pregnancy: an international utilization study.

BMJ Open Diabetes Res Care 2019 2;7(1):e000759. Epub 2019 Nov 2.

Centre for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1136/bmjdrc-2019-000759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861111PMC
September 2020

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study.

Drug Saf 2019 10;42(10):1179-1190

RTI Health Solutions, 3040 East Cornwallis Road, Research Triangle Park, NC, 27709, USA.

Introduction: The serotonin 5-HT 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.
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http://dx.doi.org/10.1007/s40264-019-00835-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739451PMC
October 2019

Indirect Effects of Pneumococcal Childhood Vaccination in Individuals Treated With Immunosuppressive Drugs in Ambulatory Care: A Case-cohort Study.

Clin Infect Dis 2019 04;68(8):1367-1373

Department of Vaccine Preventable Diseases, Norwegian Institute of Public Health.

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.
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http://dx.doi.org/10.1093/cid/ciy714DOI Listing
April 2019

Prescribed opioid analgesic use developments in three Nordic countries, 2006-2017.

Scand J Pain 2019 04;19(2):345-353

Norwegian Centre for Addiction Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

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.
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http://dx.doi.org/10.1515/sjpain-2018-0307DOI Listing
April 2019

Mutations of DnaA-boxes in the oriR region increase replication frequency of the MiniR1-1 plasmid.

BMC Microbiol 2018 04 3;18(1):27. Epub 2018 Apr 3.

State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock,School of Life Sciences, Inner Mongolia University, Hohhot, 010070, China.

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.
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http://dx.doi.org/10.1186/s12866-018-1162-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883639PMC
April 2018

Trends in Resistance to Extended-Spectrum Cephalosporins and Carbapenems among Escherichia coli and Klebsiella spp. Isolates in a District in Western India during 2004-2014.

Int J Environ Res Public Health 2018 01 19;15(1). Epub 2018 Jan 19.

Department of Public Health Sciences, Karolinska Institutet, 17177 Stockholm, Sweden.

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 and 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 and spp. isolates were above 78.4% and 84.9% throughout the study period, respectively. and 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 and from 45.1-93.1% in spp. Significantly higher proportions of non-susceptible and ESBL-producing isolates were found among isolates from inpatients compared to isolates from outpatients for both and spp. ( < 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.
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http://dx.doi.org/10.3390/ijerph15010155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800254PMC
January 2018

High Proportions of Multidrug-Resistant Acinetobacter spp. Isolates in a District in Western India: A Four-Year Antibiotic Susceptibility Study of Clinical Isolates.

Int J Environ Res Public Health 2018 01 19;15(1). Epub 2018 Jan 19.

Department of Public Health Sciences, Karolinska Institutet, 17177 Stockholm, Sweden.

The purpose of the study was to determine the proportions of multidrug-resistant (MDR) spp. isolates from the district of Nashik in Western India during the period from 2011-2014. Antibacterial susceptibility testing of isolates from inpatients and outpatients was performed using Kirby-Bauer disc diffusion method to determine inhibitory zone diameters. Proportions of non-susceptible isolates were calculated from the antibacterial susceptibility data. MDR was defined as an isolate being non-susceptible to at least one antibacterial agent in at least three antibacterial categories. The change in proportions of MDR isolates; extended-spectrum β-lactamase (ESBL)-producing isolates; and non-susceptible isolates to specific antibacterial categories over calendar time was investigated by logistic regression. The proportions of MDR and ESBL-producing isolates ranged from 89.4% to 95.9% and from 87.9% to 94.0%; respectively. The proportions of non-susceptible isolates to aminoglycosides; carbapenems; antipseudomonal penicillins/β-lactamase inhibitors; cephalosporins; folate pathway inhibitors; or penicillins/β-lactamase inhibitors exceeded 77.5%. Proportions of fluoroquinolone and tetracycline non-susceptible isolates ranged from 65.3% to 83.3% and from 71.3% to 75.9%; respectively. No changes in trends were observed over time; except for a decreasing trend in fluoroquinolone non-susceptible isolates (OR = 0.75 (95% CI, 0.62-0.91)). Significantly higher proportions of non-susceptible; MDR and ESBL-producing isolates were found among isolates from the respiratory system compared to isolates from all other specimen types ( < 0.05). High proportions of MDR spp. isolates were observed in the period from 2011-2014. Antimicrobial stewardship programmes are needed to prevent the emergence and spread of antibiotic resistance.
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http://dx.doi.org/10.3390/ijerph15010153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800252PMC
January 2018

Increased prescribing of systemic tetracyclines and isotretinoin for treatment of acne.

J Antimicrob Chemother 2017 05;72(5):1510-1515

Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.

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.
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http://dx.doi.org/10.1093/jac/dkw586DOI Listing
May 2017

A Spatial Control for Correct Timing of Gene Expression during the Escherichia coli Cell Cycle.

Genes (Basel) 2016 Dec 23;8(1). Epub 2016 Dec 23.

School of Life Sciences, Inner Mongolia University, Hohhot 010021, China.

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 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.
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http://dx.doi.org/10.3390/genes8010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294996PMC
December 2016

Prenatal exposure to anxiolytics and hypnotics and language competence at 3 years of age.

Eur J Clin Pharmacol 2015 Mar 30;71(3):283-91. Epub 2014 Dec 30.

Division of Epidemiology, Norwegian Institute of Public Health, P.O.Box 4404, Nydalen, Oslo, Norway,

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.
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http://dx.doi.org/10.1007/s00228-014-1797-4DOI Listing
March 2015

DNA compaction in the early part of the SOS response is dependent on RecN and RecA.

Microbiology (Reading) 2014 May 10;160(Pt 5):872-882. Epub 2014 Mar 10.

Department of Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

The nucleoids of undamaged Escherichia coli cells 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.
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http://dx.doi.org/10.1099/mic.0.075051-0DOI Listing
May 2014

Single transmembrane peptide DinQ modulates membrane-dependent activities.

PLoS Genet 2013 7;9(2):e1003260. Epub 2013 Feb 7.

Centre for Molecular Biology and Neuroscience (CMBN), University of Oslo and Oslo University Hospital, Rikshospitalet, Oslo, Norway.

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.
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http://dx.doi.org/10.1371/journal.pgen.1003260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567139PMC
June 2013

Hydrophilic interaction chromatography of nucleoside triphosphates with temperature as a separation parameter.

J Chromatogr A 2011 Sep 27;1218(35):5981-6. Epub 2011 Jan 27.

Department of Chemistry, University of Oslo, Blindern, N 0315 Oslo, Norway.

Eight deoxynucleoside triphosphates (dNTPs) and nucleoside triphosphates (NTPs): ATP, CTP, GTP, UTP, dATP, dCTP, dGTP and dTTP, were separated with two 15 cm ZIC-pHILIC columns coupled in series, using LC-UV instrumentation. The polymer-based ZIC-pHILIC column gave significantly better separations and peak shape than a silica-based ZIC-HILIC column. Better separations were obtained with isocratic elution as compared to gradient elution. The temperature markedly affected the selectivity and could be used to fine tune separation. The analysis time was also affected by temperature, as lower temperatures surprisingly reduced the retention of the nucleotides. dNTP/NTP standards could be separated in 35 min with a flow rate of 200 μL/min. In Escherichia coli cell culture samples dNTP/NTPs could be selectively separated in 7 0min using a flow rate of 100 μL/min.
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http://dx.doi.org/10.1016/j.chroma.2011.01.066DOI Listing
September 2011

A reduction in ribonucleotide reductase activity slows down the chromosome replication fork but does not change its localization.

PLoS One 2009 Oct 28;4(10):e7617. Epub 2009 Oct 28.

Department of Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773459PMC
October 2009

Growth rate dependent numbers of SeqA structures organize the multiple replication forks in rapidly growing Escherichia coli.

Genes Cells 2009 May 15;14(5):643-57. Epub 2009 Apr 15.

Department of Cell Biology, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet, University of Oslo, 0310 Oslo, Norway.

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.
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http://dx.doi.org/10.1111/j.1365-2443.2009.01298.xDOI Listing
May 2009

Specific N-terminal interactions of the Escherichia coli SeqA protein are required to form multimers that restrain negative supercoils and form foci.

Genes Cells 2005 Nov;10(11):1039-49

Department of Cell Biology, Institute for Cancer Research, Montebello, 0310 Oslo, Norway.

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.
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http://dx.doi.org/10.1111/j.1365-2443.2005.00898.xDOI Listing
November 2005