A Trial-Based Cost-Utility Analysis of a Medication Optimization Intervention Versus Standard Care in Older Adults.

BACKGROUND: Older adults are at greater risk of medication-related harm than younger adults. The Integrated Medication Management model is an interdisciplinary method aiming to optimize medication therapy and improve patient outcomes. OBJECTIVE: We aimed to investigate the cost effectiveness of a medication optimization intervention compared to standard care in acutely hospitalized older adults. METHODS: A cost-utility analysis including 285 adults aged ≥ 70 years was carried out alongside the IMMENSE study. Quality-adjusted life years (QALYs) were derived using the EuroQol 5-Dimension 3-Level Health State Questionnaire (EQ-5D-3L). Patient-level data for healthcare use and costs were obtained from administrative registers, taking a healthcare perspective. The incremental cost-effectiveness ratio was estimated for a 12-month follow-up and compared to a societal willingness-to-pay range of €/QALY 27,067-81,200 (NOK 275,000-825,000). Because of a capacity issue in a primary care resulting in extended hospital stays, a subgroup analysis was carried out for non-long and long stayers with hospitalizations < 14 days or ≥ 14 days. RESULTS: Mean QALYs were 0.023 [95% confidence interval [CI] 0.022-0.025] higher and mean healthcare costs were €4429 [95% CI - 1101 to 11,926] higher for the intervention group in a full population analysis. This produced an incremental cost-effectiveness ratio of €192,565/QALY. For the subgroup analysis, mean QALYs were 0.067 [95% CI 0.066-0.070, n = 222] and - 0.101 [95% CI - 0.035 to 0.048, n = 63] for the intervention group in the non-long stayers and long stayers, respectively. Corresponding mean costs were €- 824 [95% CI - 3869 to 2066] and €1992 [95% CI - 17,964 to 18,811], respectively. The intervention dominated standard care for the non-long stayers with a probability of cost effectiveness of 93.1-99.2% for the whole willingness-to-pay range and 67.8% at a zero willingness to pay. Hospitalizations were the main cost driver, and readmissions contributed the most to the cost difference between the groups. CONCLUSIONS: According to societal willingness-to-pay thresholds, the medication optimization intervention was not cost effective compared to standard care for the full population. The intervention dominated standard care for the non-long stayers, with a high probability of cost effectiveness. CLINICAL TRIAL REGISTRATION: The IMMENSE trial was registered in ClinicalTrials.gov on 28 June, 2016 before enrolment started (NCT02816086).

Community carriage of ESBL-producing Escherichia coli and Klebsiella pneumoniae: a cross-sectional study of risk factors and comparative genomics of carriage and clinical isolates.

The global prevalence of infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) is increasing, and for Escherichia coli, observations indicate that this is partly driven by community-onset cases. The ESBL-E population structure in the community is scarcely described, and data on risk factors for carriage are conflicting. Here, we report the prevalence and population structure of fecal ESBL-producing E. coli and Klebsiella pneumoniae (ESBL-Ec/Kp) in a general adult population, examine risk factors, and compare carriage isolates with contemporary clinical isolates. Fecal samples obtained from 4,999 participants (54% women) ≥40 years in the seventh survey of the population-based Tromsø Study, Norway (2015, 2016), were screened for ESBL-Ec/Kp. In addition, we included 118 ESBL-Ec clinical isolates from the Norwegian surveillance program in 2014. All isolates were whole-genome sequenced. Risk factors associated with carriage were analyzed using multivariable logistic regression. ESBL-Ec gastrointestinal carriage prevalence was 3.3% [95% confidence interval (CI) 2.8%-3.9%, no sex difference] and 0.08% (0.02%-0.20%) for ESBL-Kp. For ESBL-Ec, travel to Asia was the only independent risk factor (adjusted odds ratio 3.46, 95% CI 2.18-5.49). E. coli ST131 was most prevalent in both collections. However, the ST131 proportion was significantly lower in carriage (24%) versus clinical isolates (58%, P < 0.001). Carriage isolates were genetically more diverse with a higher proportion of phylogroup A (26%) than clinical isolates (5%, P < 0.001), indicating that ESBL gene acquisition occurs in a variety of E. coli lineages colonizing the gut. STs commonly related to extraintestinal infections were more frequent in clinical isolates also carrying a higher prevalence of antimicrobial resistance, which could indicate clone-associated pathogenicity.IMPORTANCEESBL-Ec and ESBL-Kp are major pathogens in the global burden of antimicrobial resistance. However, there is a gap in knowledge concerning the bacterial population structure of human ESBL-Ec/Kp carriage isolates in the community. We have examined ESBL-Ec/Kp isolates from a population-based study and compared these to contemporary clinical isolates. The large genetic diversity of carriage isolates indicates frequent ESBL gene acquisition, while those causing invasive infections are more clone dependent and associated with a higher prevalence of antibiotic resistance. The knowledge of factors associated with ESBL carriage helps to identify patients at risk to combat the spread of resistant bacteria within the healthcare system. Particularly, previous travel to Asia stands out as a major risk factor for carriage and should be considered in selecting empirical antibiotic treatment in critically ill patients.

Exploring stakeholders' perspectives on the quality of services provided through community pharmacies.

INTRODUCTION: It is important to understand the factors impacting the quality of services provided through community pharmacies. Exploring how key stakeholders perceive good quality in these services is a logical first step. This could also inform the development of quality measures, such as quality indicators (QIs). AIM: To identify key stakeholders' perspectives on the quality of services provided through community pharmacies in Norway, specifically by exploring their experiences and perceptions about what constitutes good service quality. METHODS: A convenient sampling approach was used to recruit participants for five semi-structured focus groups from Facebook, pharmacy chains, and patient organizations. The interviews with twenty-six participants were conducted via Microsoft Teams. Interviews were transcribed verbatim, and an inductive thematic analysis with a reflexive approach was used. RESULTS: Four main themes emerged from the analysis; 1) sufficient and substantively suitable information to cover individual needs, 2) communication skills and relationships with the pharmacy professionals, 3) customer satisfaction with knowledgeable employees and conveniently located pharmacies, and 4) factors that affect the pharmacy working environment. CONCLUSION: This study has identified areas that pharmacy professionals and customers regard as essential to define good quality of community pharmacy services. Effective communication skills, appropriate provision of information, customer satisfaction, and working environment are all essential factors when developing quality metrics for community pharmacies.

Internet Use for Obtaining Medicine Information: Cross-sectional Survey.

BACKGROUND: The internet is increasingly being used as a source of medicine-related information. People want information to facilitate decision-making and self-management, and they tend to prefer the internet for ease of access. However, it is widely acknowledged that the quality of web-based information varies. Poor interpretation of medicine information can lead to anxiety and poor adherence to drug therapy. It is therefore important to understand how people search, select, and trust medicine information. OBJECTIVE: The objectives of this study were to establish the extent of internet use for seeking medicine information among Norwegian pharmacy customers, analyze factors associated with internet use, and investigate the level of trust in different sources and websites. METHODS: This is a cross-sectional study with a convenience sample of pharmacy customers recruited from all but one community pharmacy in Tromsø, a medium size municipality in Norway (77,000 inhabitants). Persons (aged ≥16 years) able to complete a questionnaire in Norwegian were asked to participate in the study. The recruitment took place in September and October 2020. Due to COVID-19 restrictions, social media was also used to recruit medicine users. RESULTS: A total of 303 respondents reported which sources they used to obtain information about their medicines (both prescription and over the counter) and to what extent they trusted these sources. A total of 125 (41.3%) respondents used the internet for medicine information, and the only factor associated with internet use was age. The odds of using the internet declined by 5% per year of age (odds ratio 0.95, 95% CI 0.94-0.97; P=.048). We found no association between internet use and gender, level of education, or regular medicine use. The main purpose reported for using the internet was to obtain information about side effects. Other main sources of medicine information were physicians (n=191, 63%), pharmacy personnel (n=142, 47%), and medication package leaflets (n=124, 42%), while 36 (12%) respondents did not obtain medicine information from any sources. Note that 272 (91%) respondents trusted health professionals as a source of medicine information, whereas 58 (46%) respondents who used the internet trusted the information they found on the internet. The most reliable websites were the national health portals and other official health information sites. CONCLUSIONS: Norwegian pharmacy customers use the internet as a source of medicine information, but most still obtain medicine information from health professionals and packet leaflets. People are aware of the potential for misinformation on websites, and they mainly trust high-quality sites run by health authorities.

Self-reported medication information needs among medication users in a general population aged 40 years and above - the Tromsø study.

PURPOSE: To determine the prevalence and associated factors of self-reported medication information needs among medication users in a general population aged 40 years and above - The Tromsø Study. METHODS: Cross-sectional study of medication users (n = 10,231) among participants in the Tromsø Study, a descriptive analysis of questionnaire data and multivariable logistic regression (n = 9,194). RESULTS: Sixteen percent of medication users expressed a need for more information about own medications. Overall, medication users agreed to a higher degree to have received information from the GP compared to the pharmacy. Concerned medication users and those disagreeing to have received information about side effects had the highest odds for needing more information (OR 5.07, 95% CI 4.43-5.81) and (OR 2.21, 95% CI 1.83-2.68), respectively. Medication users who used heart medications (e.g., nitroglycerin, antiarrhythmics, anticoagulants) (OR 1.71, 95% CI 1.46-2.01), medication for hypothyroidism (OR 1.36, 95% CI 1.13-1.64) or had moderately health anxiety had expressed need for medication information. Whereas medication users with lower education, those that never used internet to search for health advice, and medication users who disagreed to have received information about reason-for-use were associated with lower odds (OR 0.75, 95% CI 0.62-0.91), (OR 0.85, 95% CI 0.74-0.98) and (OR 0.68, 95% CI 0.53-0.88), respectively. CONCLUSION: This study demonstrated that there is need for more information about own medications in a general population aged 40 years and above and shed light on several characteristics of medication users with expressed information need which is important when tailoring the right information to the right person.

Interdisciplinary collaboration across secondary and primary care to improve medication safety in the elderly (The IMMENSE study) - a randomized controlled trial.

BACKGROUND: Suboptimal medication use contributes to a substantial proportion of hospitalizations and emergency department visits in older adults. We designed a clinical pharmacist intervention to optimize medication therapy in older hospitalized patients. Based on the integrated medicine management (IMM) model, the 5-step IMMENSE intervention comprise medication reconciliation, medication review, reconciled medication list upon discharge, patient counselling, and post discharge communication with primary care. The objective of this study was to evaluate the effects of the intervention on healthcare use and mortality. METHODS: A non-blinded parallel group randomized controlled trial was conducted in two internal medicine wards at the University Hospital of North Norway. Acutely admitted patients ≥ 70 years were randomized 1:1 to intervention or standard care (control). The primary outcome was the rate of emergency medical visits (readmissions and emergency department visits) 12 months after discharge. RESULTS: Of the 1510 patients assessed for eligibility, 662 patients were asked to participate, and 516 were enrolled. After withdrawal of consent and deaths in hospital, the modified intention-to-treat population comprised 480 patients with a mean age of 83.1 years (SD: 6.3); 244 intervention patients and 236 control patients. The number of emergency medical visits in the intervention and control group was 497 and 499, respectively, and no statistically significant difference was observed in rate of the primary outcome between the groups [adjusted incidence rate ratio of 1.02 (95% CI: 0.82-1.27)]. No statistically significant differences between groups were observed for any of the secondary outcomes, neither in subgroups, nor for the per-protocol population. CONCLUSIONS: We did not observe any statistical significant effects of the IMMENSE intervention on the rate of emergency medical visits or any other secondary outcomes after 12 months in hospitalized older adults included in this study. TRIAL REGISTRATION: The trial was registered in clinicaltrials.gov on 28/06/2016, before enrolment started (NCT02816086).

Social network analysis of Staphylococcus aureus carriage in a general youth population.

OBJECTIVES: Staphylococcus aureus carriage increases the risk of infection. We used social network analysis to evaluate whether contacts have the same S. aureus genotype indicating direct transmission or whether contagiousness is an indirect effect of contacts sharing the same lifestyle or characteristics. METHODS: The Fit Futures 1 study collected data on social contact among 1038 high school students. S. aureus carriage was determined from two nasal swab cultures and the genotype was determined by spa-typing of positive throat swabs. RESULTS: S. aureus carriage and spa-type were transmitted in the social network (P < 0.001). The probability of carriage increased by 5% for each S. aureus positive contact. Male sex was associated with a 15% lower risk of transmission compared to the female sex, although the carriage prevalence was higher for men (36% vs 24%). Students with medium physical activity levels, medium/high alcohol use, or normal weight had a higher number of contacts and an increased risk of transmission (P < 0.002). CONCLUSION: We demonstrated the direct social transmission of S. aureus. Lifestyle factors are associated with the risk of transmission, suggesting the effects of indirect social groups on S. aureus carriage, such as friends having more similar environmental exposures. The male predominance in the carriage is determined by sex-specific predisposing host characteristics as the social transmission is less frequent in males than females. Information on social networks may add to a better understanding of S. aureus epidemiology.

Macular Layer Thickness and Effect of BMI, Body Fat, and Traditional Cardiovascular Risk Factors: The Tromsø Study.

Purpose: The purpose of this study was to investigate associations between cardiovascular risk factors and the thickness of retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), and outer retina layers (ORL). Methods: In this population-based study, we included participants from the Tromsø Study: Tromsø6 (2007 to 2008) and Tromsø7 (2015 to 2016). Persons with diabetes and/or diagnosed glaucoma were excluded from this study. Retinal thickness was measured on optical coherence tomography (Cirrus HD-OCT) macula-scans, segmented on RNFL, GCIPL, and ORL and associations were analyzed cross-sectionally (N = 8288) and longitudinally (N = 2595). We used directed acyclic graphs (DAGs) for model selection, and linear regression to adjust for confounders and mediators in models assessing direct effects. Factors examined were age, sex, blood pressure, daily smoking, serum lipids, glycated hemoglobin, body mass index (BMI), total body fat percentage (BFP), and the adjustment variables refraction and height. Results: The explained variance of cardiovascular risk factors was highest in GCIPL (0.126). GCIPL had a strong negative association with age. Women had thicker GCIPL than men at higher age and thinner ORL at all ages (P < 0.001). Systolic blood pressure was negatively associated with RNFL/GCIPL (P = 0.001/0.004), with indication of a U-shaped relationship with GCIPL in women. The negative association with BMI was strongest in men, with significant effect for RNFL/GCIPL/ORL (P = 0.001/<0.001/0.019) and in women for GCIPL/ORL (P = 0.030/0.037). BFP was negatively associated with GCIPL (P = 0.01). Higher baseline BMI was associated with a reduction in GCIPL over 8 years (P = 0.03). Conclusions: Cardiovascular risk factors explained 12.6% of the variance in GCIPL, with weight and blood pressure the most important modifiable factors.

Circulating sex-steroids and Staphylococcus aureus nasal carriage in a general male population.

Male sex is associated with higher risk of both colonisation and infection with Staphylococcus aureus (S. aureus). However, the role of sex-steroids in colonisation among men is largely unknown. Thus, the aim of this study was to investigate possible associations between circulating sex-steroids and nasal carriage of S. aureus in a general male population. The population-based Tromsø6 study (2007-2008) included 752 males aged 31-87 years with serum sex-steroids measured by liquid chromatography tandem mass spectrometry and two nasal swab samples for the assessment of S. aureus carriage. Multivariable logistic regression models were used to study the association between sex-steroid concentrations and S. aureus persistent nasal carriage (two positive swabs vs. others), while adjusting for potential confounding factors.S. aureus persistent nasal carriage prevalence was 32%. Among men aged 55 years and above (median age 65 years), there was an inverse dose-response relationship between serum concentration of testosterone and persistent nasal carriage, and carriers had significantly lower mean levels of testosterone (P = 0.028, OR = 0.94 per nmol/l change in testosterone; 95% CI = 0.90-0.98). This association was attenuated when adjusting for body mass index and age (OR = 0.96 per nmol/l change in testosterone; 95% CI = 0.91-1.01). There was no association in the total population. This large population-based study suggests that testosterone levels may be inversely related to S. aureus persistent nasal carriage in older men. Future studies addressing biological mechanisms underlying the male predisposition to S. aureus colonisation and infection may foster preventive interventions that take sex-differences into account.

Association of area-level education with the regional growth trajectories of rates of antibacterial dispensing to patients under 3 years in Norway: a longitudinal retrospective study.

OBJECTIVE: To examine the association between area-level education and the local growth trajectories in antibacterial dispensing rates in Norwegian municipalities among children under 3 years old. DESIGN: Retrospective, longitudinal study using individual primary care prescription data from the Norwegian Prescription Database for the period 2006-2016. Data were collected on the date of dispensing, the type and amount of antibiotic, the patient's age, sex and municipality of residence and linked to municipality-level statistics on education available from Statistics Norway. We used multilevel growth curve modelling, with a linear trend variable modelled as a random effect and a cross-level interaction between linear trends and the proportion of the population in the municipality having received a university or college education. SETTING: The local government level in Norway. The sample includes all municipalities over the study period. OUTCOME MEASURE: Number of dispensed antibacterial prescriptions per 100 children in individual primary care by municipality and year. RESULTS: We identified a significant negative linear trend in the square root of the dispensing rate for children under 3 years old during the period. This trend varied between municipalities. A negative cross-level interaction term between population education levels and random trends showed that municipalities with an average level of population education saw a reduction in their square root dispensing rates of -0.053 (95% CI -0.066 to -0.039) prescriptions per 100 children. Each additional percentage point in population education contributed a further -0.0034 (95% CI -0.006 to -0.001) reduction to the square root dispensing rate. CONCLUSIONS: Municipalities in which a larger proportion of the local population have high educational achievements have been more successful in reducing antibacterial dispensing rates in children under 3 years old. Adopting area-level strategies and addressing local community disadvantages may help to optimise practices and prescribing patterns across local communities.

Gastrointestinal carriage of Klebsiella pneumoniae in a general adult population: a cross-sectional study of risk factors and bacterial genomic diversity.

Antibiotic resistant Klebsiella pneumoniae is a leading public health threat and gastrointestinal carriage is an established risk factor for subsequent infections during hospitalization. Our study contributes new knowledge of risk factors for gastrointestinal carriage and the genomic population structure of K. pneumoniae colonizing humans in a representative sample of a general population in a community setting. Altogether, 2,975 participants (54% women) >40 y in the population-based Tromsø Study: Tromsø7, Norway (2015-2016) were included. Fecal samples were screened for K. pneumoniae, which were characterized using whole-genome sequencing. Risk factors for carriage were analyzed using multivariable logistic regression on data from questionnaires and the Norwegian Prescription Database. Prevalence of K. pneumoniae gastrointestinal carriage was 16.3% (95% CI 15.0-17.7, no gender difference). Risk factors associated with carriage included age ≥60 y, travel to Greece or Asia past 12 months (adjusted odds ratio 1.49, 95% CI 1.11-2.00), Crohn's disease/ulcerative colitis (2.26, 1.20-4.27), use of proton pump inhibitors (1.62, 1.18-2.22) and non-steroidal anti-inflammatory drugs past 6 months (1.38, 1.04-1.84), and antibiotic use the last month (1.73, 1.05-2.86). Prevalence was higher among those having used combinations of drug classes and decreased over time with respect to preceding antibiotic use. The K. pneumoniae population was diverse with 300 sequence types among 484 isolates distributed across four phylogroups. Only 5.2% of isolates harbored acquired resistance and 11.6% had virulence factors. Identification of risk factors for gastrointestinal carriage allows for identification of individuals that may have higher risk of extraintestinal infection during hospitalization. The findings that specific diseases and drugs used were associated with carriage show an impact of these possibly through modulating the human gut microbiota promoting colonization. The diverse population structure of carriage isolates reflects the ecologically adaptive capacity of the bacterium and challenges for vaccine prospects and the identification of reservoirs as a potential source for human colonization.

Circulating sex-steroids and Staphylococcus aureus nasal carriage in a general female population.

OBJECTIVE: Staphylococcus aureus is a major human pathogen, and nasal carriers have an increased risk for infection and disease. The exploration of host determinants for nasal carriage is relevant to decrease infection burden. Former studies demonstrate lower carriage prevalence in women and among users of progestin-only contraceptives. The aim of this study was to investigate the possible associations between circulating sex-steroid hormones and nasal carriage of Staphylococcus aureus in a general population. METHODS: In the population-based sixth Tromsø study (2007-2008) nurses collected nasal swab samples from 724 women aged 30-87 not using any exogenous hormones, and 700 of the women had a repeated nasal swab taken (median interval 28 days). We analysed a panel of serum sex-steroids by liquid chromatography tandem mass spectrometry, and collected information about lifestyle, health and anthropometric measures. Multivariable logistic regression was used to study the association between circulating sex-steroids and Staphylococcus aureus carriage (one swab) and persistent carriage (two swabs), while adjusting for potential confounding factors. Women in luteal phase were excluded in the analysis of androgens. RESULTS: Staphylococcus aureus persistent nasal carriage prevalence was 22%. One standard deviation increase in testosterone and bioavailable testosterone was associated with lower odds of persistent nasal carriage, (OR = 0.57; 95% CI = 0.35-0.92 and OR = 0.52, 95% CI = 0.30-0.92) respectively. Analysis stratified by menopause gave similar findings. Persistent carriers had lower average levels of androstenedione and DHEA, however, not statistically significant. CONCLUSION: This large population-based study supports that women with lower levels of circulating testosterone may have increased probability of Staphylococcus aureus persistent carriage.

No change in the consumption of thyroid hormones after starting low dose naltrexone (LDN): a quasi-experimental before-after study.

BACKGROUND: Low dose naltrexone (LDN) is reported to have beneficial effects in several autoimmune diseases. The purpose of this study was to examine whether starting LDN was followed by changes in the dispensing of thyroid hormones to patients with hypothyroidism. METHODS: We performed a quasi-experimental before-after study based on the Norwegian Prescription Database. Study participants were identified by using reimbursement codes for hypothyroidism. Cumulative dispensed Defined Daily Doses and the number of users of triiodothyronine (T3) and levothyroxine (LT4) 1 year before and after the first LDN prescription was compared in three groups based on LDN exposure. RESULTS: We identified 898 patients that met the inclusion criteria. There was no association between starting LDN and the subsequent dispensing of thyroid hormones. If anything, there was a tendency towards increasing LT4 consumption with increasing LDN exposure. CONCLUSION: The results of this study do not support claims of efficacy of LDN in hypothyroidism.

Empirical prescribing of penicillin G/V reduces risk of readmission of hospitalized patients with community-acquired pneumonia in Norway: a retrospective observational study.

BACKGROUND: Norwegian guideline recommendations on first-line empirical antibiotic prescribing in hospitalised patients with community-acquired pneumonia (CAP) are penicillin G/V in monotherapy, or penicillin G in combination with gentamicin (or cefotaxime) in severely ill patients. The aim of this study was to explore how different empirical antibiotic treatments impact on length of hospital stay (LOS) and 30-day hospital readmission. A secondary aim was to describe median intravenous- and total treatment duration. METHODS: We included CAP patients (≥18 years age) hospitalised in North Norway during 2010 and 2012 in a retrospective study. Patients with negative chest x-ray, malignancies or immunosuppression or frequent readmissions were excluded. We collected data on patient characteristics, empirical antibiotic prescribing, treatment duration and clinical outcomes from electronic patient records and the hospital administrative system. We used directed acyclic graphs for statistical model selection, and analysed data with mulitvariable logistic and linear regression. RESULTS: We included 651 patients. Median age was 77 years [IQR; 64-84] and 46.5% were female. Median LOS was 4 days [IQR; 3-6], 30-day readmission rate was 14.4% and 30-day mortality rate was 6.9%. Penicillin G/V were empirically prescribed in monotherapy in 51.5% of patients, penicillin G and gentamicin in combination in 22.9% and other antibiotics in 25.6% of patients. Prescribing other antibiotics than penicillin G/V monotherapy was associated with increased risk of readmission [OR 1.9, 95% CI; 1.08-3.42]. Empirical antibiotic prescribing was not associated with LOS. Median intravenous- and total treatment duration was 3.0 [IQR; 2-5] and 11.0 [IQR; 9.8-13] days. CONCLUSIONS: Our findings show that empirical prescribing with penicillin G/V in monotherapy in hospitalised non-severe CAP-patients, without complicating factors such as malignancy, immunosuppression and frequent readmission, is associated with lower risk of 30-day readmission compared to other antibiotic treatments. Median total treatment duration exceeds treatment recommendations.

Non-prescription purchase of antibiotics during travel abroad among a general adult population in Norway: Findings from the seventh Tromsø Study.

BACKGROUND: Non-prescription purchase of antibiotics is undesirable and has not recently been investigated in a representative population in a high-income low-use country during travel abroad. This study examined self-reported prevalence of antibiotic purchase abroad with and without prescription among participants reporting international travel in a general adult population in Norway, and the associations with socio-demographic, lifestyle and health factors. METHODS: We analysed questionnaire-data from 19995 participants (10470 women) ≥40 years in the population-based Tromsø Study 7, 2015-2016. Data from the Norwegian Prescription Database were used to examine antibiotic use in Norway. We calculated adjusted odds ratios (AOR) for "travel abroad", "any antibiotic purchase abroad", and "antibiotic purchase abroad with" and "without prescription" using multivariable logistic regression. RESULTS: Over half (55.0%, 95%CI 54.3-55.7%) participants reported travel abroad of >1 week duration in the past year. Travelers were more likely than non-travelers to be women (AOR = 2.02, 95%CI 1.42-2.88%) and report high education/income, childhood mostly lived abroad, healthy lifestyle, and good/excellent self-rated health. In total, 17904 travel episodes to 148 countries were reported. Altogether, 3.7% (95% CI 3.4%-4.1%) of travelers had purchased antibiotic abroad in the past year. Non-prescription purchase (1.5%, 95% CI 1.3-1.7) was associated with younger age, being female (AOR 1.41, 1.0-1.97), number of travels (reference: one episode, two: AOR = 1.82, 1.25-2.67, three: 2.60, 1.58-4.28, four: 3.10, 1.40-6.36 and ≥five: 4.70, 2.30-9.62), occurrences of diarrhoea (one: 2.42, 1.50-3.93 and ≥two: 3.08, 1.29-7.35), and antibiotic use in Norway in the past year (1.84, 1.29-2.62), whereas purchase with prescription (2.4%, 2.1-2.7) was associated with low income, growing-up abroad, recent hospital admission, additionally including number of travels/diarrhoea, and antibiotic use in Norway. Thailand (10.7%, 95% CI 7.8-14.3), Turkey (5.5%, 3.8-7.8) and Spain (3.6%, 3.0-4.3) were the countries most commonly associated with any antibiotic purchase. About two in five travelers who bought antibiotics in Thailand had done so without prescription, three in five in Turkey, and less than one in three in Spain. CONCLUSION: Overall, a small proportion of travelers had bought antibiotics abroad in the past year. Low prevalence of non-prescription purchase may be explained by awareness of the risks associated with self-medication, cultural views, unawareness of the non-prescription availability, and/or few infections. Divergent predictors for purchase abroad with versus without prescription may suggest different reasons for these practices.

Efficacy of mecillinam against clinical multidrug-resistant Escherichia coli in a murine urinary tract infection model.

Pivmecillinam, a pro-drug of mecillinam, has been used extensively in Scandinavia for the treatment of acute lower urinary tract infections (UTIs) caused by Enterobacterales. It is still an attractive first-line drug for the empirical treatment of UTIs owing to the low prevalence of resistance as well as its favourable impact on the intestinal microbiota as a pro-drug and good in vitro efficacy against extended-spectrum ß-lactamase (ESBL)- and plasmid-mediated AmpC ß-lactamase-producing Escherichia coli. However, optimal dosing of pivmecillinam as well as its in vivo efficacy against UTIs caused by multidrug-resistant (MDR) broad-spectrum ß-lactamase-producing E. coli has not been thoroughly studied. In this study, the efficacy of two mimicked human dosing regimens of pivmecillinam (200 mg and 400 mg three times daily) against clinical E. coli strains, including isolates producing ESBLs (CTX-M-14 and CTX-M-15), plasmid-mediated AmpCs (CMY-4 and CMY-6) and carbapenemases (NDM-1 and VIM-29), in a murine UTI model was compared. Both dosing regimens reduced the number of CFU/mL in urine for all strains, including mecillinam-resistant strains. Combining the effect for all six strains showed no significant differences in effect between doses for all three fluids/organs, but for each dose there was a highly significant effect in urine, kidney and bladder compared with vehicle-treated mice. Overall, this highlights the need for further studies to elucidate the role of mecillinam in the treatment of infections caused by MDR E. coli producing broad-spectrum ß-lactamases, including specific carbapenemases.

Correction: Low dose naltrexone: Effects on medication in rheumatoid and seropositive arthritis. A nationwide register-based controlled quasi-experimental before-after study.

[This corrects the article DOI: 10.1371/journal.pone.0212460.].

Changes in the consumption of antiepileptics and psychotropic medicines after starting low dose naltrexone: A nation-wide register-based controlled before-after study.

In this controlled before-after study based on data from the Norwegian Prescription Database, we examine whether starting off-label use of Low Dose Naltrexone (LDN) is followed by changes in the consumption of psychotropic medicines including antiepileptics. Patients that collected LDN for the first time in 2013 (N = 11247) were included and stratified into three groups based on LDN exposure. We compared differences in means of cumulative number of defined daily doses (DDD) as well as changes in the number of users one year before and one year after starting LDN. There was a dose-response association between increasing LDN exposure and reductions in the number of users of antiepileptics, antipsychotics and antidepressants. There were significant difference-in-differences in DDDs between the groups with the lowest and highest LDN exposure of antipsychotics (1.4 DDD, 95% CI 0.4 to 2.3, p = 0.007), and in number of users of antiepileptics (3.1% points, 95% CI 1.6% to 4.6%, p < 0.001), antipsychotics (2.1% points, 95% CI 1.2% to 3%, p < 0.001), and antidepressants (2.8% points, 95% CI 1.1% to 4.4%, p = 0.001). The findings show an association between the initiation of persistent LDN use and reduced consumption of several psychotropic medicines and antiepileptics. Beneficial effects of LDN in the treatment of psychiatric diseases cannot be ruled out.