Ingunn Fride Tvete

Relevant factors can have shifting prognostic impacts on cardiovascular disease (CVD) occurrences among in patients with breast cancer (BC) over time. CVD incidence and its driving factors vary among different CVDs. We examined the time to the first occurrence of heart attack, atrial fibrillation, embolic stroke, angina pectoris, embolism, peripheral vascular disease, and heart failure (HF). We particularly focused on the influence of molecular subtype, adjusting for age, tumor stage, and radiation therapy.

Advice on fishing opportunities is based on stock assessment models. Modern stock assessment frameworks are designed to account for uncertainty in model parameters. However, some parameters are often fixed at specific values and assumed to be known precisely. Paradoxically, these fixed values often relate to parameters we understand the least—such as the natural mortality rate. For example, in the assessment of Norwegian Spring-Spawning Herring, the natural mortality rate is assumed to be exactly 0.9 for age 2 fish and 0.15 for older fish. In this study, we investigate how sensitive the assessment results—and, more specifically, the resulting fishing quotas (total allowable catch, TAC)—are to assumptions regarding natural mortality and maturity-at-age for both Norwegian Spring-Spawning Herring and North-East Arctic Cod. The assessment models for both stocks are formulated within the SAM framework. Furthermore, we explore a simple approach for adjusting harvest control rules that seeks to preserve the TACs when fundamental fixed assumptions are altered. Our intention is that this serves as an exploratory tool to investigate sensitivity to new assumptions, and is not intended to replace a more formal process for defining new biological reference points and harvest control rules. The results indicate that, under the current harvest control rules, the TACs for both herring and cod may be sensitive to assumptions regarding natural mortality rates and maturity-at-age. For herring, sensitivity to natural mortality is significantly greater than is reflected by the estimation uncertainty in model parameters. However, when basic assumptions are changed, it is also natural to consider corresponding adjustments to the harvest control rules. Our proposed simple adjustments to the control rules reduce sensitivity to these assumptions in many cases, though not in all.

Introduction Global Trigger Tool (GTT) is a retrospective review method where inpatient medical records are randomly sampled and reviewed by trained GTT teams to identify and monitor adverse event (AE) rates over time. Tracking AEs over time is a useful way to indicate if targeted changes result in improved patient safety. The method presupposes that the teams are consistent in their record reviews. The objective of our study was to examine several teams’ ability to reproduce their findings from a previous review. There is no consensus in the GTT literature regarding this reproducibility. Methods Eight teams from six Norwegian hospitals applied the GTT method to a total of 958 randomly selected inpatient medical records. Each inpatient record was previously reviewed in 2016-2018 and then reexamined in 2023. We estimated the teams’ agreement between the previous and new ratings, with focus on the teams’ reproducibility for rating the presence of at least one AE or not. The teams’ ratings of the number of AEs and the AE severity level were also considered. We computed and compared several well-known agreement measures. The study was approved by Regional Committees for Medical and Health Research Ethics in Norway. The participating hospitals’ Data Protection Officers have given their approval. Results Overall there was good to very good agreement between the teams’ previous and new ratings for the presence of at least one AE or not. The unadjusted agreement for all teams together was 84.9%, and on team level it ranged between 76.7% and 89.2%. The agreement for all teams together, adjusted for agreement by chance, ranged from Fleiss’ κ: 0.673 (0.625 – 0.722) to Gwet’s AC1: 0.718 (0.674 – 0.762). At team level, we found some differences in the reproducibility of the presence of at least one AE or not. The ability to reproduce previous findings on the number of AEs and AE severity level varied more across teams. Conclusion Our findings support the use of the GTT method as a tool for identifying and monitoring AE rates over time, with the aim of reducing patient harm. It appears to be more challenging to obtain good consistency when rating the number of AEs and AE severity level than the presence of at least one AE or not. We believe there is a need for better training and auxiliary resources for the teams if the goal is to improve the reproducibility of the number of AEs and AE severity level.

Acoustic surveys of mixed fish aggregations often rely on manual allocation of acoustic energy to target species, with auxiliary information such as trawl catches and target strength distributions aiding interpretation. However, different teams of experts may use the same auxiliary data differently. In this experiment, seven teams of experts interpreted the same acoustic data, and we compared their classification to target categories to quantify uncertainty in the manual classification process. The teams largely agreed on the total acoustic energy attributable to organisms, but there was significant variation in how the teams split this energy on different target categories. This was caused by differences in applied thresholds for separating plankton and fish, as well as disagreements in species classification. For all target categories, the variation due to teams was lower than the overall variability across acoustic segments, but when scaled up to the number of segments in a typical survey, the team effect either dominated or was of similar magnitude as the segment variability. These results imply a need for further standardisation and uncertainty estimation of expert evaluations in acoustic surveys involving manual interpretation of echo sounder data.

Introduction: All Norwegian hospital trusts have measured adverse event rates since 2011 using the Global Trigger Tool (GTT). As they have different GTT teams, results have not been compared between them and interrater reliability has not been established. All Norwegian GTT teams undergo the same national training, which prompted an interest in exploring the feasibility of comparing results between hospital trusts. Objective: To organize a research project testing interrater reliability between 20 GTT teams in 13 hospital trusts and one hospital. Methods: Sending medical records securely between hospital trusts was a difficult challenge. Due to privacy regulations, accessing electronic medical records across hospital trusts was not possible. The research project limited the inclusion of data from the medical records to no more than 30 days prior to and after hospital admission. This made the medical record extraction more time consuming. Two hospital trusts used a robot for extracting medical records. The Regional committee for medical and health research ethics (REK) consented to the research project. Results: Digital mail for public enterprises (DPE) was recently developed in Norway to send and receive electronic post securely. This became the solution for distributing the medical records, and required that several of the hospital trusts had to implement the DPE solution. 920 medical records were converted to PDFs by and distributed from 14 GTT teams, to between one and four other GTT teams involved in the project. The National Archives of Norway approved the required records retention and disposal plan, which detailed the disposal of all PDF versions of the medical records throughout the workflow. Conclusion: The logistical challenges and solutions associated with securely sending 920 medical records between different hospital trusts nationwide, makes the experiences from this research project relevant for other national settings that might wish to take a similar approach.

Atlantic salmon aquaculture may benefit from improved tools for behavioural monitoring and data-derived models that predict behaviour in commercial scale production cages. In the present study, timeseries depth registrations from individual farmed Atlantic salmon in commercial cages have been compiled from various projects, with the aim to resolve general swimming depth behaviour during the marine production stage. By implementing acoustic depth sensor tags, swimming depth data from 126 individuals of Atlantic salmon from ten different cages and five different farm sites were analysed over study periods lasting from 195 to 316 days. The study covers all seasons and were conducted at a latitude where there is hardly daylight during winter solstice nor nighttime or dusk during summer solstice. Average hourly swimming depth registrations for individual salmon were analysed by applying generalized additive modelling (GAM), where the main effects, hour of the day, temperature and sunlight hours were modelled as smooth terms in a non-linear way. The main effects were further modelled conditioned on the presence or absence of submerged lights and/or skirts used to shield the fish from salmon lice infestations. The results reveal that Atlantic salmon generally resided higher in the water column during nighttime than in daytime in all seasons except in the summer. The general tendency for diurnal depth patterns was most pronounced in winter and spring in cages without submerged lights, where average swimming depths varied from about 10–12 m during daytime to about 5–6 m during nighttime. The use of submerged lights in the cages disrupted the diurnal depth patterns and lead the fish to swim deeper in the water column during night-time in months with few sunlight hours. There was no substantial effect of the use of skirts on swimming depths. In addition to these general diurnal and day of the year trends, there were large individual variations in swimming depth. The study emphasises the utility of behavioural traits, particularly in modelling expected depth patterns as a surveillance tool in conjunction with real-time biomonitoring during the ongrowing phase at sea for Atlantic salmon.

Objectives We compared Monoamine oxidase B (MAO-B) – and dopamine agonist (DA) monotherapy patients with respect to survival, considering gender, age, first prescriber’s specialty and relevant co-morbidity, and compared their specialist health care contacts and hospitalizations. Methods With data from health registries, we considered 21,047 patients without redemptions for MAO-B, DA or levodopa 6 months prior to their first MAO-B or DA redemption in 2006 and followed them throughout 2016. We considered Cox proportional hazard regression models for comparing the risk of death among MAO-B and DA monotherapy patients. Results MAO-B-users had a higher mortality than DA-users, [HR: 1.587, 95% CI: 1.056; 2.384] for patients under 74 years. There was an increased mortality risk with increasing age, women had lower risk than men and previous diabetes-, antihypertensive-, and cardiac drug users had higher risk compared to patients without such history. Previous use of hypothyroid drugs and having a specialist as first prescriber were not significant risk factors. Among patients without hospitalizations 13.7% died, while among patients who spent at least one night in hospital 36.73% died. The median duration of a hospitalization among those who died and not were 17.5 and 7 days. Among the small proportion with specialist health care contacts circulatory- and respiratory-system diseases were the most frequent cause of contact. Conclusions DAs were most frequently given when initiating Parkinson’s treatment. DA-users had a lower mortality risk compared to MAO-B-users and less specialist health care contact.

Mortality in the production of farmed salmonids is a major constraint to the sustainability of this form of animal husbandry. We have developed a model for the daily mortality in salmon farming over a full production cycle from stocking to harvest, considering different environmental and production factors. These factors included sea temperature, salinity, day within year, fish weight at stocking, stocking day, four types of lice treatments and the possible occurrence of pancreas disease (PD). We considered a generalized additive model following full production cycles, allowing for non-linear descriptions of how relevant factors relate to the daily mortality. We saw a high overall mortality rate immediately after stocking, which decreased the first three months in the cycle and thereafter increased. We found that the total mortality could be reduced by 21% if avoiding all lice treatments, and similarly reduced by 20% if no PD infections occurred. If avoiding jointly PD and all lice treatments, the accumulated mortality could be reduced by 34%. A single thermal or hydrogen peroxide treatment was associated with a mortality of around 1.6% and 1.3%, respectively. This modeling approach gave a unique opportunity to model how different factors interact on the overall global mortality and can easily be extended by other factors, such as additional fish diseases.

We consider the challenge in estimating the natural mortality, M, in a standard statistical fish stock assessment model based on time series of catch- and abundance-at-age data. Though anecdotal evidence and empirical experience lend support to the fact that this parameter may be difficult to estimate, the current literature lacks a theoretical justification. We first discuss the estimatability of a time-invariant theoretically and present necessary conditions for a constant M to be identifiable. We then investigate the practical usefulness of this by estimating from simulated data based on models fitted to 19 fish stocks. Using the same data sets, we next explore several model formulations of time varying M, with a pre-specified mean value. Cross validation is used to assess the prediction performance of the candidate models. Our results show that a time-invariant M can be estimated with reasonable precision for a few stocks with long time series and typically high values of the true . For most stocks, however, the estimation uncertainty of M is very large. For time-varying M, we find that accounting for variability across age and time using a simple model significantly improves the performance compared to a time-invariant M. No significant improvement is obtained by using complex models, such as, those with time dependencies in variability around mean values of M.

Objective. To investigate the use of dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors in the Norwegian population, between 1 July 2006 and 31 December 2016. Our primary endpoint was time until need for levodopa among new monotherapy users of dopamine agonists and MAO-B inhibitors. Methods. A prospective cohort study including all patients, aged 50 years or above, who had at least one prescription for a dopamine agonist or a MAO-B inhibitor dispensed in the study period. We used data from the Norwegian Prescription Database (NorPD). As we wished to focus on new Parkinson patients, we excluded patients who had levodopa dispensed less than 180 days prior to their first dopamine agonist or MAO-B inhibitor redemption. We explored the demographics and the time until monotherapy was insufficient treatment (defined as need for levodopa prescription). Results. We included 22958 new monotherapy users. Of these, 22108 used dopamine agonists and 850 used MAO-B inhibitors. The mean number of days until the first prescription of levodopa was dispensed was higher among the dopamine agonist users (621 days) compared to the MAO-B inhibitor users (352 days). The proportion of dopamine agonist users who started levodopa treatment during the study period was less than 7%, while the corresponding proportion of MAO-B inhibitor users was almost 59%. Conclusions. We found that new dopamine agonist users had a much greater delay in the need for levodopa than new MAO-B inhibitor users. It seems to be beneficial to initiate treatment with dopamine agonists when starting pharmacological treatment for new Parkinson patients.

This paper considers a general state-space stock assessment modeling framework that integrates a population model for a fish stock and a data model. This way observed data are linked to unobserved quantities in the population model. Using this framework, we suggest two modifications to improve accuracy in results obtained from the stock assessment model SAM and similar models. The first suggestion is to interpret the “process error” in these models as stochastic variation in natural mortality, and therefore include it in the data model. The second suggestion is to consider the observed catch as unbiased estimates of the true catch and modify the observation error accordingly. We demonstrate the efficacy of these modifications using empirical data from 14 fish stocks. Our results indicate that the modifications lead to improved fits to data and prediction performance, as well as reduced prediction bias.

Purpose To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson’s disease. Methods We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson’s disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson’s Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. Results Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. Conclusions Dopamine agonists were found to be effective as treatment for Parkinson’s disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson’s disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.

Introduction: In Norway, disability pension (DP) has been more prevalent over the later years, with mental disorders being a frequent cause. Previous analyses have questioned whether receiving DP is beneficial for mental health by considering changes in antidepressant drug consumption. To explore this further, we examined changes in antianxiety and hypnotic drug consumption following DP onset. Methods: Based on national Norwegian register data, this retrospective study encompassed 8617 working-age individuals (25-50 years) who became DP during 2005 to 2013. We compared their benzodiazepines (BZD) and Z-hypnotic consumption 1 year pre- and postdisability pension onset. Results: About 80% of the individuals did not change their altogether benzodiazepine/Z-hypnotic consumption. Among individuals with an initial consumption ≤1 defined daily dose (DDD), 18.9% increased their consumption to above 1 DDD. Individuals in the age-group 45 to 50 versus 24 to 34 years had a lower risk of dose escalation (odds ratio [OR], 0.756, 95% confidence interval [CI]: 0.601-0.957). Individuals who used Z-hypnotics only had a higher risk of dose escalation compared to the joint benzodiazepine/Z-hypnotic user group (OR, 1.594, 95%CI: 1.284-1.970). Conclusion: In general, we cannot see that DP is associated with changes in benzodiazepine/Z-hypnotic consumption, but younger users and individuals using Z-hypnotics only had a greater risk of dose escalation compared to the older users and users with combined BZD and Z-hypnotic use.

Aims To the best of our knowledge, there are no systematic reviews or meta‐analyses that compare rasagiline, selegiline and safinamide. Therefore, we aimed to perform a drug class review comparing all available monoamine oxidase type B (MAO‐B) inhibitors in a multiple treatment comparison. Methods We performed a systematic literature search to identify randomized controlled trials assessing the efficacy of MAO‐B inhibitors in patients with Parkinson's disease. MAO‐B inhibitors were evaluated either as monotherapy or in combination with levodopa or dopamine agonists. Endpoints of interest were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score and serious adverse events. We estimated the relative effect of each MAO‐B inhibitor versus the comparator drug by creating three networks of direct and indirect comparisons. For each of the networks, we considered a joint model. Results The systematic literature search and study selection process identified 27 publications eligible for our three network analyses. We found the relative effects of rasagiline, safinamide and selegiline treatment given alone and compared to placebo in a model without explanatory variables to be 1.560 (1.409, 1.734), 1.449 (0.873, 2.413) and 1.532 (1.337, 1.757) respectively. We also found all MAO‐B inhibitors to be efficient when given together with levodopa. When ranking the MAO‐B inhibitors given in combination with levodopa, selegiline was the most effective and rasagiline was the second best. Conclusions All of the included MAO‐B inhibitors were effective compared to placebo when given as monotherapy. Combination therapy with MAO‐B inhibitors and levodopa showed that all three MAO‐B inhibitors were effective compared to placebo, but selegiline was the most effective drug.

Purpose The antipsychotic agent quetiapine was introduced in Norway in 2003. We have assessed changes in dispensed prescriptions, including dosing, of quetiapine in Norway from 2004 to 2015. Methods Data on the sales of antipsychotics and antidepressants were drawn from the Norwegian Prescription Database. A total of 47,474 outpatients filled 195,622 prescriptions of quetiapine. Reimbursement codes, use of antipsychotics or antidepressants 12 months prior to the first prescription of quetiapine and estimated mean volume used measured as defined daily doses (DDDs) per day were used as proxies for diagnoses. We conducted a regression analysis with DDD per day as a function of possible explanatory variables. Results The number of users filling at least two prescriptions of quetiapine per year increased from 584 in 2004 to 8506 in 2015 and the mean dose declined from 1.58 DDD per day (SD 8.00) to 0.48 DDD per day (SD 2.27). The latter is much lower than recommended for treatment of psychoses. In 2015, 60.1% of the 8506 quetiapine users did not seek reimbursement for the treatment of a major psychiatric disorder and only 2.6% of the patients were prescribed 1 DDD or more per day and reimbursed in accordance with the drug’s primary indication, psychosis. A reported diagnosis of psychosis was not associated with higher quetiapine doses. Conclusions In 2015, the pattern of quetiapine dispensing in Norway most likely reflects predominant off-label use. This is unsettling considering poorly documented effects in non-psychotic disorders, profound side effects, significant toxicity and growing concern regarding abuse.

Objective: To compare how newly initiated treatment with benzodiazepines, Z-hypnotics or both associates with the reception of disability pension among 40,661 individuals of a working age. Design: Prescription register study. Setting: Norwegian nationwide prescriptions socio-economic and disability status data. Methods: Cox regression analyses. Subjects: New benzodiazepine or Z-hypnotic users. Main outcome measure: Time to receive disability pension given benzodiazepine or Z-hypnotic use or both. Additional analyses focused on the benzodiazepine first redeemed. Results: Among new users 8.65% of Z-hypnotic users, 12.29% of benzodiazepines users and 13.96% of combined Z-hypnotic and benzodiazepine users became disability pensioners. Z-hypnotic users were weaker associated with becoming disability pensioners (HR = 0.78, CI: 0.73–0.84) and combined users were stronger associated (HR = 1.09, CI: 1.01–1.17), than benzodiazepine users. Women had higher risk than men for becoming disability pensioners. Higher age, lower education, previous drug use and psychiatrist as first prescriber were risk factors. Comparing first benzodiazepine redeemed; clonazepam initiators were stronger associated with becoming disability pensioners than diazepam initiators were (HR = 2.22, CI: 1.81–2.71). No differences between other benzodiazepine users were found. Conclusions: Adjusting for known risk factors gave lower risk for Z-hypnotic users compared to benzodiazepine users for receiving disability pension. Combined use increased the risk further. Clonazepam initiators are especially at risk. These findings may be helpful in prescribing situations to identify and guide individuals at risk for becoming disability pensioners.

BACKGROUND: The nature of differences in the timing of tooth formation between ethnic groups is important when estimating age. AIM: To calculate age of transition of the mandibular third (M3) molar tooth stages from archived dental radiographs from sub-Saharan Africa, Malaysia, Japan and two groups from London UK (Whites and Bangladeshi). MATERIALS AND METHODS: The number of radiographs was 4555 (2028 males, 2527 females) with an age range 10-25 years. The left M3 was staged into Moorrees stages. A probit model was fitted to calculate mean ages for transitions between stages for males and females and each ethnic group separately. The estimated age distributions given each M3 stage was calculated. To assess differences in timing of M3 between ethnic groups, three models were proposed: a separate model for each ethnic group, a joint model and a third model combining some aspects across groups. The best model fit was tested using Bayesian and Akaikes information criteria (BIC and AIC) and log likelihood ratio test. RESULTS: Differences in mean ages of M3 root stages were found between ethnic groups, however all groups showed large standard deviation values. The AIC and log likelihood ratio test indicated that a separate model for each ethnic group was best. Small differences were also noted between timing of M3 between males and females, with the exception of the Malaysian group. These findings suggests that features of a reference data set (wide age range and uniform age distribution) and a Bayesian statistical approach are more important than population specific convenience samples to estimate age of an individual using M3. CONCLUSION: Some group differences were evident in M3 timing, however, this has some impact on the confidence interval of estimated age in females and little impact in males because of the large variation in age.

Background Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation. Aim To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time. Design and setting This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30–60 years, with first redemption for diazepam or oxazepam. Method Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber’s specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of ≥1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model. Results New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51). Conclusion Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness.

Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2 g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2 g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements’ replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (≤2 μM (0.6 mg/L) and >2 μM) and THC (≤0.01 μM (0.003 mg/L) and >0.01 μM). The safety margins were for diazepam 19.5% (≤2 μM) and 34% (>2 μM), for THC 19.5% (≤0.01 μM) and 24.9% (>0.01 μM). Concentration dependent safety margins for BAC were based on a dataset of 29 500 alcohol positive specimens, and were in the range 10.4% (0.1 g/kg) to 4.0% (4.0 g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The safety margins for these drugs were in the range 34–41%.

This final report describes the results of the research conducted in the project «Development of improved methods or basis for medical age assessments of minors and young adults». The aim of the project has been to contribute to develop improved methods for measuring physical developments of a child or young adult and for assessing the chronological age based on such measurements, giving an improved basis for such assessments. The project has brought together various international experts, both from the medical and odontology fields. The project has been an international collaboration with a group of partners with experience from both practical age estimation and research, from both of the currently used radiographic methods in Norway (wrist and teeth) and new MRI approaches. Several disciplines have been incorporated in the project: odontology, pediatrics, radiography, statistical modeling and image analysis. Additional descriptions of methods and results from the statistical analyses and image analysis can be found in four additional notes. The project is funded by The Norwegian Directorate of Immigration.

Aims: We aimed to evaluate bleeding risk in clinical practice in patients with atrial fibrillation (AF) being prescribed dabigatran, rivaroxaban, or apixaban compared with warfarin. Methods: Using nationwide registries (Norwegian Patient Registry and Norwegian Prescription Database), we identified AF patients with a first prescription of oral anticoagulants between January 2013 and June 2015. Patients were followed until discontinuation or switching of oral anticoagulants, death, or end of follow-up. The primary endpoint was major or clinically relevant non-major (CRNM) bleeding. Results: In total 32 675 AF patients were identified (58% men, median age 74 years): 11 427 patients used warfarin, 7925 dabigatran, 6817 rivaroxaban, and 6506 apixaban. After a median follow-up of 173 days (25th, 75th percentile 84, 340), 2081 (6.37%) patients experienced a first major or CRNM bleeding. Using a Cox proportional hazard model adjusting for baseline characteristics, use of apixaban [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.61–0.80, P < 0.001] and dabigatran (HR 0.74, 95% CI 0.66–0.84, P < 0.001) were associated with a lower risk of major or CRNM bleeding compared with warfarin whereas use of rivaroxaban was not (HR: 1.05, 95% CI 0.94–1.17, P = 0.400). Use of dabigatran and rivaroxaban were associated with higher risk of gastrointestinal bleeding, whereas use of apixaban and dabigatran were associated with lower risk of intracranial bleeding, compared with warfarin. Conclusion: In this nationwide cohort study in AF patients, apixaban and dabigatran were associated with a lower risk of major or CRNM bleeding compared with warfarin. The risk of gastrointestinal bleeding was higher with rivaroxaban and dabigatran compared with warfarin.

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.

Objective: Antipsychotic agents have serious metabolic adverse effects, among them dyslipidemia, which may necessitate secondary prophylaxis with cholesterol-lowering drugs. Second-generation antipsychotics (SGAs), particularly clozapine and olanzapine, are known to confer a higher risk of metabolic adverse effects than first-generation antipsychotics (FGAs). However, little is known regarding the real-life number of antipsychotic-treated patients receiving statins. Method: By extracting data from the Norwegian prescription database, all patients 18–69 years old that started treatment with an antipsychotic during 2004–2012 formed the basis for analysis (n = 301,713). The primary outcome measure was the proportion of FGA and SGA users prescribed with cholesterol-lowering agent during the same period. We used Cox proportional hazards regression to evaluate the risk of redeeming a cholesterol-lowering drug for formerly antipsychotic drug-naive patients (n = 147,218). Results: Statin prescription rates in patients receiving antipsychotic agents were lower (5.3%) than comparable rates in studies covering the general population (34%) and lower than would be expected based on the recognized negative impact of antipsychotics on serum lipids. Statin prescription rates were affected by patient age, antipsychotic dose, and the number of antipsychotic agents prescribed, but rates were only 5% elevated in patients receiving SGAs compared to patients receiving FGAs (P = .048). Conclusions: Our results may support the notion that patients treated with antipsychotic agents receive suboptimal care with regard to metabolic adverse effects.

Aim The World Health Organization recommends the defined daily dose (DDD) as the standard unit of measurement for antibiotic use, but this is not applicable in children. We aimed to assess paediatric antibiotic use in a Norwegian tertiary care hospital using a novel weight-adjusted method. Methods We obtained antibiotic purchase data from the hospital pharmacy and administrative data for all admissions from 2002 to 2009 to the paediatric wards at Oslo University Hospital, Rikshospitalet. Recommended daily doses per 100 kg days (RDDs/kg days) were calculated based on national guidelines for paediatric antibiotic use, length of stay and estimated weight for sex and age using national growth references. Results Total antibiotic use increased significantly from 51.8 to 65.5 RDDs/100 kg days. We found statistically significant annual increases in the consumption of carbapenems (18.0%), third-generation cephalosporins (6.0%) and imidazole derivatives (6.6%) and a considerable difference between total antibiotic use measured in RDDs/100 kg days and DDDs/100 bed days for neonates. Conclusion Weight-adjusted antibiotic use provided a more meaningful description of the quantities of antibiotics consumed than DDDs/100 bed days, particularly for neonates. Total antibiotic use, use of meropenem, third-generation cephalosporins and imidazole derivatives increased significantly despite low prevalence of antibiotic-resistant pathogens.

OBJECTIVE: To identify risk factors for becoming an excessive user over time. SETTING: Prescription database study over five years. SUBJECTS AND METHOD: Norwegians between 30 and 60 years with a first dispensation of a benzodiazepine during 2006, encompassing 23 227 individuals. A Cox hazard regression model was defined, initially stratifying on gender, age, county, previous relevant drug dispensations, household income, education level, and vocational rehabilitation support. MAIN OUTCOME MEASURE: The time from the first redemption until excessive use was defined as using more than two DDDs per day on average within a three-month period. RESULTS: Women's risk was lower than men's for excessive use (HR = 0.42, CI 0.35-0.51). Initial oxazepam, alprazolam, or nitrazepam/flunitrazepam use indicated higher risk compared with diazepam (HR = 1.51, CI 1.24-1.85, HR = 2.75, CI 1.54-4.91, HR = 1.67, CI 1.29-2.16). Previous antidepressants or lithium, antipsychotics or opioids, anti-alcohol and smoke cessation treatment indicated a higher risk compared with no such use (HR = 1.4, CI 1.16-1.69, HR = 1.92, CI 1.54-2.4, and HR = 2.88, CI 2-4.15). Higher education and average or high household income were associated with a low risk compared with low education and income (HR = 0.68, CI 0.57-0.81, HR = 0.58, CI 0.46-0.73, and HR = 0.37, CI 0.26-0.54). Working in the private or public sector was associated with a low risk compared with no registered work (HR = 0.53, CI 0.4-0.71 and HR = 0.57, CI 0.45-0.74). CONCLUSION: The prevalence of excessive use over a five-year observation period was 2.34%. Risk factors were indications of psychiatric illness, first benzodiazepine choice, low income, and education. Excessive users were also characterized by a more severe disease, indicated by having prescription fulfilments by a psychiatrist and by switching benzodiazepines. Key points Guidelines state that benzodiazepines should be used for a short time and excessive use indicates drug dependency. Of all new benzodiazepine users 2.34% became excessive users, defined as consuming above two defined daily doses (DDDs) per day on average over three months, within a five-year period. Previous use of other psychotropic drugs, opioids and anti-alcohol and smoke cessation drugs, first benzodiazepine prescribed, low household income, and low education were risk factors for excessive use. Excessive users were characterized by switching benzodiazepines and having prescription fulfilments by a psychiatrist suggesting a more severe disease.

Several methods for imputing the number of responders from summary continuous outcome data in randomized controlled trials exist. A method by Furukawa and others was used in the quite common case that only such summary continuous outcome measures, but not the actual numbers of responders, are reported in order to estimate response rates (probabilities) for different treatments and response ratios between treatments in such trials. The authors give some empirical justification, but encourage search for theoretical support and further empirical exploration. In particular, a problem that needs to be addressed is that randomness in baseline score is not taken into consideration. This will be done in the present paper. Assuming a binormal model for the data, we compare theoretically the true response rate for a single treatment arm to the theoretical response rate underlying two versions of the suggested imputation method. We also assess the performance of the method numerically for some choices of model parameters. We show that the method works satisfactorily in some cases, but can be seriously biased in others. Moreover, assessing the uncertainty of the estimates is problematic. We suggest an alternative Bayesian estimation procedure, based directly on the normal model, which avoids these problems and provides more precise estimates when applied to simulated data sets.

Insurance claims are often modelled by a standard Poisson model with fixed effects. With such a model, no individual adjustments are made to account for unobserved heterogeneity between policyholders. A Poisson model with random effects makes it possible to detect policyholders with a high or low individual risk. The premium can then be adjusted accordingly. Others have applied such models without much focus on the model’s prediction performance. As the usefulness of an insurance claims model typically is measured by its ability to predict future claims, we have chosen to focus on this aspect of the model. We model insurance claims with a Poisson random effects model and compare its performance with the standard Poisson fixed effects model. We show that the random effects model both fits the data better and gives better predictions for future claims for high risk policy holders than the standard model.

Within a company's customer relationship management strategy, finding the customers most likely to leave is a central aspect. We present a dynamic modelling approach for predicting individual customers’ risk of leaving an insurance company. A logistic longitudinal regression model that incorporates time-dynamic explanatory variables and interactions is fitted to the data. As an intermediate step in the modelling procedure, we apply generalised additive models to identify non-linear relationships between the logit and the explanatory variables. Both out-of-sample and out-of-time prediction indicate that the model performs well in terms of identifying customers likely to leave the company each month. Our approach is general and may be applied to other industries as well.

BAKGRUNN Totalsalget av benzodiazepiner og z-hypnotika (zopiklon og zolpidem) i Norge har økt siden midten av 1990-årene. Vi har med utgangspunkt i reseptregisterdata studert medikamentvalg og forbruksmønstre over år i forskjellige aldersgrupper og for begge kjønn. MATERIALE OG METODE Tall for utlevering av benzodiazepiner og z-hypnotika ved norske apotek for årene 2004 – 11 ble innhentet fra Reseptregisteret. Befolkningstall ble innhentet fra Statistisk sentralbyrå. Forbruk er regnet i antall definerte døgndoser (DDD). RESULTATER Av dem som fikk utlevert benzodiazepiner eller z-hypnotika utgjorde mottakere av mer enn 2 DDD daglig (storbrukerne) en liten gruppe. Vi registrerte et omfattende forbruk av z-hypnotika blant eldre kvinner, og mange fikk forskrevet en mengde tilsvarende en fast daglig dose på 1 – 2 DDD. Totalforskrivningen av alprazolam og nitrazepam/flunitrazepam var lav, men hos dem som fikk utlevert disse medikamentene, var høye doser ikke uvanlig. Bare en liten del av pasientene som fikk forskrevet klonazepam, fikk dette forskrevet med refusjonspunkt. Forskrivning av flere benzodiazepiner og z-hypnotika samtidig er fortsatt ikke uvanlig. FORTOLKNING Forskrivingen av z-hypnotika til eldre, spesielt kvinner, kan tyde på at mange i denne gruppen bruker sovemidler fast, hvilket er i strid med retningslinjene. En betydelig andel av klonazepamforskrivningen skjer utenfor godkjent indikasjon. For de studerte medikamentene er storbrukerandelen lav, men siden bruken er utbredt, angår dette likevel et betydelig antall mennesker.

Association between previous antibiotic use and emergence of antibiotic resistance has been reported for several microorganisms. The relationship has been extensively studied, and although the causes of antibiotic resistance are multi-factorial, clear evidence of antibiotic use as a major risk factor exists. Most studies are carried out in countries with high consumption of antibiotics and corresponding high levels of antibiotic resistance, and currently, little is known whether and at what level the associations are detectable in a low antibiotic consumption environment. We conduct an ecological, retrospective study aimed at determining the impact of antibiotic consumption on antibiotic-resistant Pseudomonas aeruginosa in three hospitals in Norway, a country with low levels of antibiotic use. We construct a sophisticated statistical model to capture such low signals. To reduce noise, we conduct our study at hospital ward level. We propose a random effect Poisson or binomial regression model, with a reparametrisation that allows us to reduce the number of parameters. Inference is likelihood based. Through scenario simulation, we study the potential effects of reduced or increased antibiotic use. Results clearly indicate that the effects of consumption on resistance are present under conditions with relatively low use of antibiotic agents. This strengthens the recommendation on prudent use of antibiotics, even when consumption is relatively low.

Objectives This study investigated and quantified risk factors of dose escalation, as an indication of drug misuse and dependency of benzodiazepines and congeners, among presumably drug naïve patients in the Norwegian drug prescription database, observed over 3 years. Design Observational study. Setting Prescription database study. Participants We defined an excessive user as one redeeming more than two defined daily doses per day in 3 months. Primary and secondary outcome measures We examined the risk of excessive use over time and the effect of risk factors through multistate logistic regression and scenarios. Results Most of the 81 945 patients had zopiclone or zolpidem as the initial drug (63.8%), followed by diazepam (25.3%), oxazepam (6.1%), nitrazepam/flunitrazepam (2.9%), hydroxyzine/buspirone (1.6%) and alprazolam (0.3%). At any time 23% redeemed prescriptions, about 34% did not redeem any prescriptions beyond any 3-month period and 0.9% ended up as excessive users. Patients previously using drugs, such as opioids, antialcohol or smoke cessation treatment, had a higher risk to become excessive users compared to patients who had not. Patients whose first prescription was for oxazepam or nitrazepam/flunitrazepam had a higher risk of becoming an excessive user compared to those who started with diazepam. A specialist in general practice as the first-time prescriber was associated with a lower risk compared to doctors without specialty. Conclusions Most benzodiazepine use occurred according to guidelines. Still, some experienced dose escalation over time, and risk factors were previous use of other psychotropic drugs, long time use, choice of first-time drug and prescriber's specialty. This could incite doctors to have a cessation plan when issuing first-time prescriptions.

Objective. To assess the drug utilization patterns for proton pump inhibitors (PPIs) prescriptions dispensed in periods with and without restrictions on reimbursement in a public healthcare system. Material and methods. Data on all PPI prescriptions dispensed for gastroesophageal reflux disease (GERD) was retrieved from the Norwegian Prescription Database (NorPD) from 1 January 2004 to 31 January 2008. PPI utilization patterns were studied in new and current users of PPI in periods affected and not affected by a change in prescription policy. Results. The policy change resulted in 39% of esomeprazole patients discontinuing PPI therapy during a 12-month period while 23% discontinued PPI therapy during a period not affected by the policy change. The shift frequency to a different PPI was low, 5% and 7% respectively, during periods not affected by policy change. Despite a required shift in most esomeprazole patients, 64% still continued on esomeprazole. Among the 36% who shifted from esomeprazole to a different PPI, 25% subsequently shifted back to esomeprazole. In new PPI users, the proportion of esomeprazole users declined from 57% before to 20% after the introduction of the policy change. Conclusions. Despite GERD being a chronic disease in most patients, there was a high degree of alteration seen in the utilization patterns of PPIs. A high proportion discontinued PPI therapy indicating mild symptoms or remission. The switching between different PPIs was low indicating good efficacy and tolerability in most patients. The policy change was more effective in new PPI users compared with the mandated shift in ongoing esomeprazole users.

The current study presents a novel objective measure for characterizing sexually active groups (SAG 3-5) and relates this measure to other behaviors of lactating Holstein-Friesian cows. Cows in SAG 3-5 were required to participate in a minimum of 1 estrus behavior per 5min while staying within 3m (2 cow lengths) of its partner(s) for a minimum of 5min. Twenty Holstein-Friesian cows were video-monitored continuously through 1 complete estrous cycle (22d). Standing behavior, SAG 3-5, secondary estrus signs (SEC), and other social and agonistic behaviors were recorded continuously. The period of mounting estrus (MTE) was divided into the 3 parts: prestand, standing estrus (STE), and poststand. The mean durations of MTE, prestand, STE, and poststand period were 12.9±1.84, 4.0±1.93, 7.1±1.44, and 1.8±0.57h (n=13). The fractions of time spent in SAG 3-5 during MTE, prestand, STE, and poststand period were 13, 8, 19, and 1% (n=11). During MTE, cows participated, on average, in 5.8±1.24 SAG 3-5 and initiated 9.5±2.99 mounts, with mean durations of 0.25±0.03h and 4.00±0.36s, respectively. The novel measure SAG 3-5 was a sign of long duration not confined only to groups of STE cows. On one day when no cows were in estrus and during the periods 4 to 24h before and after MTE, no SAG 3-5 behaviors were observed. Luteal-phase cows participated in SAG 3-5 only when the partner was a single cow in estrus. The time spent in SAG 3-5 increased between 1 and 3h before MTE and the prestand period (3 vs. 8%) and reached a peak level during STE. From STE to poststand, time spent in SAG 3-5 decreased considerably (19 vs. 1%). The observed decrease in nonmutual agonistic behaviors 4 to 24h before MTE is suggested as an early sign of pre-estrus. Changes in SAG 3-5, agonistic behaviors, and SEC are suggested as indicators of the specific stages of MTE. Increased SEC initiated and SAG 3-5 were indicators of late pre-estrus and early estrus (prestand). Peak levels of SAG 3-5, SEC, and social agonistic behaviors were indicators of STE. A sudden decrease in behaviors, preceded by frequent interactions, was indicative of late estrus (poststand). On the basis of the findings reported here, we propose that SAG 3-5, as well as proceptive and receptive patterns of SEC and agonistic behaviors, be included in estrus detection protocols. Updated knowledge of these behavioral interactions may assist when determining the stage of estrus and the optimal time to breed dairy cows.