Temporal trends and regional variability in BRAF and KRAS genetic testing in Denmark (2010-2022): Implications for precision medicine.

OBJECTIVE: This study aims to evaluate the developments in the testing of Kirsten Rat Sarcoma viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations across different cancer types and regions in Denmark from 2010 to 2022. STUDY DESIGN AND SETTING: Using comprehensive data from the Danish health registries, we linked molecular test results from the Danish Pathology Registry with cancer diagnoses from the Danish National Patient Registry between 2010 and 2022. We assessed the frequency and distribution of KRAS and BRAF mutations across all cancer types, years of testing, and the five Danish regions. RESULTS: The study included records of KRAS testing for 30 671 patients and BRAF testing for 30 860 patients. Most KRAS testing was performed in colorectal (78%) and lung cancer (18%), and BRAF testing in malignant melanoma (13%), colorectal cancer (67%), and lung cancer (12%). Testing rates and documentation mutational subtypes increased over time. Reporting of wildtype results varied between lung and colorectal cancer, with underreporting in lung cancer. Regional variations in testing and reporting were observed. CONCLUSION: Our study highlights substantial progress in KRAS and BRAF testing in Denmark from 2010 to 2022, evidenced by increased and more specific reporting of mutational test results, thereby improving the precision of cancer diagnosis and treatment. However, persistent regional variations and limited testing for cancer types beyond melanoma, colorectal, and lung cancer highlight the necessity for a nationwide assessment of the optimal testing approach.

The impact of type 2 diabetes and glycaemic control on mortality and clinical outcomes in hospitalized patients with COVID-19 in the capital region of Denmark.

AIM: To explore the impact of type 2 diabetes (T2D), glycaemic control and use of glucose-lowering medication on clinical outcomes in hospitalized patients with COVID-19. MATERIALS AND METHODS: For all patients admitted to a hospital in the Capital Region of Denmark (1 March 2020 to 1 December 2021) with confirmed COVID-19, we extracted data on mortality, admission to intensive care unit (ICU), demographics, comorbidities, medication use and laboratory tests from the electronic health record system. We compared patients with T2D to patients without diabetes using Cox proportional hazards models adjusted for available confounding variables. Outcomes were 30-day mortality and admission to an ICU. For patients with T2D, we also analysed the association of baseline haemoglobin A1c (HbA1c) levels and use of specific glucose-lowering medications with the outcomes. RESULTS: In total, 4430 patients were analysed, 1236 with T2D and 2194 without diabetes. The overall 30-day mortality was 19% (n = 850) and 10% (n = 421) were admitted to an ICU. Crude analyses showed that patients with T2D both had increased mortality [hazard ratio (HR) 1.37; 95% CI 1.19-1.58] and increased risk of ICU admission (HR 1.28; 95% CI 1.04-1.57). When adjusted for available confounders, this discrepancy was attenuated for both mortality (adjusted HR 1.13; 95% CI 0.95-1.33) and risk of ICU admission (adjusted HR 1.01; 95% CI 0.79-1.29). Neither baseline haemoglobin A1c nor specific glucose-lowering medication use were significantly associated with the outcomes. CONCLUSION: Among those hospitalized for COVID-19, patients with T2D did not have a higher risk of death and ICU admission, when adjusting for confounders.

Discontinuation of antipsychotics in individuals with first-episode schizophrenia and its association to functional outcomes, hospitalization and death: a register-based nationwide follow-up study.

BACKGROUND: Discontinuation of antipsychotic medication may be linked to high risk of relapse, hospitalization and mortality. This study investigated the use and discontinuation of antipsychotics in individuals with first-episode schizophrenia in relation to cohabitation, living with children, employment, hospital admission and death. METHODS: Danish registers were used to establish a nationwide cohort of individuals ⩾18 years with schizophrenia included at the time of diagnosis in1995-2013. Exposure was antipsychotic medication calculated using defined daily dose and redeemed prescriptions year 2-5. Outcomes year 5-6 were analysed using binary logistic, negative binomial and Cox proportional hazard regression. RESULTS: Among 21 351, 9.3% took antipsychotics continuously year 2-5, 38.6% took no antipsychotics, 3.4% sustained discontinuation and 48.7% discontinued and resumed treatment. At follow-up year 6, living with children or employment was significantly higher in individuals with sustained discontinuation (OR 1.98, 95% CI 1.53-2.56 and OR 2.60, 95% CI 1.91-3.54), non-sustained discontinuation (OR 1.25, 95% CI 1.05-1.48 and 2.04, 95% CI 1.64-2.53) and no antipsychotics (OR 2.00, 95% CI 1.69-2.38 and 5.64, 95% CI 4.56-6.97) compared to continuous users. Individuals with non-sustained discontinuation had more psychiatric hospital admissions (IRR 1.27, 95% CI 1.10-1.47) and longer admissions (IRR 1.68, 95% CI 1.30-2.16) year 5-6 compared to continuous users. Mortality during year 5-6 did not differ between groups. CONCLUSION: Most individuals with first-episode schizophrenia discontinued or took no antipsychotics the first years after diagnosis and had better functional outcomes. Non-sustained discontinuers had more, and longer admissions compared to continuous users. However, associations found could be either cause or effect.

Association of maternal psoriasis and small for gestational age or preterm birth: a nationwide matched cohort study in 69 080 singleton infants.

BACKGROUND: Women with certain inflammatory diseases have an increased risk of giving birth to infants who are small for gestational age (SGA) or preterm birth (PTB), with maternal disease activity being the most important risk factor. However, previous studies investigating an association between psoriasis and SGA are scarce and have shown conflicting results. AIM: To investigate the association between maternal psoriasis and risk of SGA infants and PTB, respectively, both overall and stratified by psoriasis severity. METHODS: This was a nationwide register-based matched cohort study of women with psoriasis matched 1 : 10 to women without psoriasis on age at delivery, body mass index and smoking status and with their first singleton infant born during the period 2004-2017. Odds ratio (OR) and 95% CI were calculated in conditional logistic regression models adjusted for known risk factors. RESULTS: From 516 063 deliveries, we identified 6282 women with psoriasis and 62 798 matched women without psoriasis. The risk of SGA and PTB was similar in women with psoriasis and matched controls: adjusted OR (aOR) = 1.07 (95% CI 0.98-1.17) and aOR = 1.05 (95% CI 0.93-1.19), respectively. The risk of term SGA was increased in women with psoriasis (aOR 1.11; 95% CI 1.01-1.22) compared with matched controls. CONCLUSION: Maternal psoriasis was not associated with increased risk of SGA or PTB. Risk of term SGA was slightly increased in women with a history of psoriasis compared with matched controls, however; these infants are likely to be constitutionally small with no increased risk of perinatal morbidity and mortality.

Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden.

BACKGROUND: The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths. METHODS AND FINDINGS: A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates. CONCLUSIONS: Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy.

Use of tramadol and other analgesics following media attention and risk minimization actions from regulators: a Danish nationwide drug utilization study.

PURPOSE: To describe the use of tramadol and other analgesics in Denmark focusing on the impact of media attention (June and December 2017) and regulatory actions (September 2017 and January 2018) on the use of tramadol. METHODS: Using nationwide registries, we identified all adults who filled a prescription for tramadol and other analgesics from 2014 to 2019. We described incidence rates, prevalence proportions, and total use of tramadol and other analgesics over time. We also described switching between analgesics, treatment duration, skewness in drug use, and doctor-shopping. RESULTS: From early 2017 until the end of 2019, total tramadol use decreased markedly while the use of morphine and oxycodone decreased slightly. The quarterly prevalence of tramadol use decreased from 32/1000 individuals in 2014 to 18/1000 at the end of 2019, dropping mainly at the time of media attention. Concomitantly, the quarterly prevalence increased for oxycodone (from 5.1 to 8.2) and morphine (from 8.5 to 9.8), mainly due to more short-term and sporadic users, and decreased for codeine (14 to 9.6). From 2014 to mid-2017, the incidence of tramadol use was stable (around 2.2/1000 person-months) but dropped in June 2017 to 1.7/1000, coinciding with the media attention. The incidence of tramadol use continued to decrease (to 1.1/1000 at the end of 2019). CONCLUSION: We identified a decline in tramadol use coinciding with the media attention in 2017 and continuing during regulatory actions. There was generally no evidence of unintended effects on the utilization of opioids related to the media attention and regulatory actions.

Fatal outcome and intensive care unit admission after total hip and knee arthroplasty: An analytic of preoperative frailty and comorbidities.

BACKGROUND: With increasing demand for total hip arthroplasty (THA) and total knee arthroplasty (TKA), a higher percentage of patients are identified with comorbidities that might increase the risk of complications. We aimed to elucidate the preoperative characteristics of patients with a fatal outcome or admission to the Intensive Care Unit (ICU) within 90 days after THA or TKA. We arbitrarily hypothesized that more than 50% of those patients would be frail. METHODS: This is a register based, explorative study including patients undergoing elective, unilateral, primary THA or TKA in the Capital Region of Denmark from 2010 to 2017, and who subsequently died or were admitted to the ICU within 90 days. The modified Frailty Index (mFI) was calculated from the medical records, and a score of ≥0.36 defined frailty. RESULTS: A total of 33,758 patients underwent THA or TKA, and 284 patients (0.8%) died or were admitted to the ICU within 90 days. Fifty-seven patients (20%) were frail (95% CI 16.2-25.7%). The most common comorbidities were hypertension (63%) and pulmonary diseases (32%), and 56% used walking aids. Two or more comorbidities were present in 65% of patients, and 14% had no comorbidities at all. CONCLUSION: Only 20% of patients with a fatal outcome or ICU admission after elective THA or TKA could be categorized as frail based on the mFI. Further studies with a prospective design are needed to clarify the mFI as a risk stratification tool in elderly multimorbid patients undergoing elective arthroplasty surgery.

Content and validation of the Electronic Patient Medication module (EPM)-the administrative in-hospital drug use database in the Capital Region of Denmark.

Aims: Registries on in-hospital drug use are sparse, especially those that can be linked to nationwide registries. In this study, we present and validate the Electronic Patient Medication module (EPM)-the electronic administrative database on in-hospital drug use covering the Capital Region of Denmark. Methods: The research database (EPM-research) is an adaptation of the database underlying the electronic administrative database for in-hospital drug use (EPM-clinic). The validation study was comprised of two sub-studies. Sub-study 1: Accordance of registration between EPM-clinic and EPM-research was investigated by analyzing randomly chosen retrospective patient records. Sub-study 2: Workflows and real-life registration practices were investigated through visits to three different (two medical and one emergency) departments. An observer followed a nurse while dispensing and administering drugs. This information was compared with EPM-research. The primary endpoint for both sub-studies was accordance of generic name between registrations. Secondary endpoints were exact brand name, dose, and time of each administration. Accordance (proportions) with 95% confidence intervals (CI) using the Clopper-Pearson method were calculated. The study was approved by the Danish Data Protection Agency (BFH-2016-058-04906) and the Danish Patient Safety Authority (3-3013-1884/1/). Results: In sub-study 1 227 retrospective drug administrations were reviewed. Accordance of generic name was 100.0% (CI 98.4%-100.0%). In sub-study 2 176 drug administrations were observed of which 173 were recorded with identical generic name, resulting in 98.3% (CI 95.1%-99.6%) accordance of data. Conclusions: Our validation of the EPM-research showed very high accordance. With detailed information on in-hospital drug use, the EPM-research may be a useful tool in pharmacoepidemiological research.

Long term treatment with stimulant laxatives - clinical evidence for effectiveness and safety?

OBJECTIVES: Bisacodyl and sodium picosulfate are classified both as stimulant laxatives, approved for short-term treatment of constipation and sold without prescription (OTC). Stimulant laxatives are associated with harmful long-term colonic effects and possible carcinogenic risk - and evidence support that these agents are used for longer periods. We aimed to compile and review the clinical trial evidence describing the effectiveness and safety of long-term treatment (>14 continuous days) with stimulant laxatives. METHODS: The PubMed database was searched for all randomised clinical trials (RCTs) examining the effect of bisacodyl or sodium picosulfate in adult patients diagnosed with constipation. RESULTS: Five RCTs (one open-label and four double-blinded) with intervention periods of four weeks duration were eligible. These included 1008 patients, whereof 26% dropped out. A positive global assessment of efficacy was obtained in 78-99% of the patients treated with bisacodyl or sodium picosulfate. Notably, the same global assessment was obtained in 46-54% of the placebo-treated patients. Compared to placebo, an improvement in stool consistency and a significant increase in number of bowel movements peer week were seen in favor of bisacodyl and sodium picosulfate. However, for pyridostigmine, a significant difference was seen compared to bisacodyl. AEs were generally mild, but frequent (up to 72%) mostly diarrhea and abdominal pain. CONCLUSION: The evidence base does not support use of stimulant laxatives for more than four weeks. Due to the substantial use of stimulant laxatives including sold OTC, longer term RCTs and epidemiological studies investigating effects and safety on the longer term are warranted.

The Use and Safety of TNF Inhibitors during Pregnancy in Women with Psoriasis: A Review.

Psoriasis is a chronic immune-mediated inflammatory disease affecting women of childbearing potential. Biologic agents, notably Tumor Necrosis Factor inhibitors (TNFi), are the only current non-contraindicated systemic treatment option during pregnancy. TNFi comprised of complete immunoglobulin G (IgG) antibodies antibodies (adalimumab, golimumab, and infliximab) actively cross the placenta from the second trimester and are detectable in the child up to one year postpartum. Data on safety of TNFi are conflicting; however a trend towards drug-specific harm has been reported, with increased risk of congenital malformations and preterm birth. TNFi exposure may alter the immune system of the infant towards hypersensitivity and reduced response to intracellular infections. Confounding by indication should be considered, as chronic inflammatory disease itself may pose a risk of adverse pregnancy outcomes. The quality of the current evidence is very low and no studies specifically address TNFi safety in women with psoriasis. Nonetheless, risks associated with TNFi treatment must be balanced against the as-yet uncertain risk of adverse outcomes in infants born to women with severe psoriasis. We searched PubMed using Medical Subject Headings (MeSH) terms and identified relevant studies and guidelines. Herein, we present the current knowledge of the use and safety of TNFi during pregnancy in women with psoriasis.

Clarithromycin, trimethoprim, and penicillin and oxidative nucleic acid modifications in humans: randomised, controlled trials.

AIMS: In vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not restricted to bacteria, but also occurs in mammalian cells. Oxidative stress is linked to several diseases. This study investigates whether antibiotic drugs induce oxidative stress in healthy humans as a possible mechanism for adverse reactions to the antibiotic drugs. METHODS: This study contains information from two randomised, controlled trials. Participants underwent 1 week treatment with clarithromycin, trimethoprim, phenoxymethylpenicillin (penicillin V), or placebo. Oxidative modifications were measured as 24-h urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and plasma levels of malondialdehyde before and after treatment as a measurement of DNA oxidation, RNA oxidation, and lipid peroxidation, respectively. RESULTS: Clarithromycin significantly increased urinary excretion of 8-oxodG by 22.0% (95% confidence interval (CI): 3.6-40.4%) and 8-oxoGuo by 14.9% (95% CI: 3.7-26.1%). Further, we demonstrated that trimethoprim significantly lowered urinary excretion of 8-oxodG by 21.7% (95% CI: 5.8-37.6%), but did not influence urinary excretion of 8-oxoGuo. Penicillin V did not influence urinary excretion of 8-oxodG or 8-oxoGuo. None of the antibiotic drugs influenced plasma levels of malondialdehyde. CONCLUSION: Clarithromycin significantly increases oxidative nucleic acid modifications. Increased oxidative modifications might explain some of clarithromycin's known adverse reactions. Trimethoprim significantly lowers DNA oxidation but not RNA oxidation. Penicillin V had no effect on oxidative nucleic acid modifications.

The Effect of Trimethoprim on Serum Folate Levels in Humans: A Randomized, Double-Blind, Placebo-Controlled Trial.

Trimethoprim antagonize the actions of folate by inhibition of dihydrofolate reductase. This could diminish serum folate levels in humans and causes folate deficiency in some patients. We conducted a randomized, double-blind, placebo-controlled trial, to investigate the effect of trimethoprim on serum folate levels in healthy participants after a 7-day trial period. Thirty young, healthy males were randomly allocated to receive trimethoprim, 200 mg twice daily, and 30 were randomly allocated to placebo. Before trial initiation, participant numbers were given randomly generated treatment allocations within sealed opaque envelopes. Participants and all staff were kept blinded to treatment allocations during the trial. Serum folate was measured at baseline and at end of trial. In the 58 participants analyzed (30 in the trimethoprim group and 28 in the placebo group), 8 had folate deficiency at baseline. Within the trimethoprim group, serum folate was significantly decreased (P = 0.018) after the trial. We found a mean decrease in serum folate among trimethoprim exposed of 1.95 nmol/L, compared with a 0.21 nmol/L mean increase in the placebo group (P = 0.040). The proportion of folate-deficient participants increased significantly within the trimethoprim group (P = 0.034). No serious adverse events were observed. In conclusion, we found that a daily dose of 400 mg trimethoprim for 7 days significantly lowered serum folate levels in healthy study participants.

Diclofenac/misoprostol during early pregnancy and the risk of miscarriage: a Danish nationwide cohort study.

INTRODUCTION: Misoprostol can be used in the prevention of gastric ulcer in treatment with diclofenac and is used in rheumatic diseases. Since misoprostol causes contractions of the uterus, it can also be used to induce abortions when administrated vaginally. The aim of the study was to investigate if early pregnancy exposure to oral diclofenac/misoprostol was associated with miscarriage. METHOD: We conducted a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2011. All births were identified using the Medical Birth Registry, and all records of induced abortion and miscarriage were from the National Hospital Register. Data on drug use were from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women exposed to diclofenac/misoprostol in early pregnancy. RESULT: We identified 1,338,824 pregnancies (970,491 births, 142,147 miscarriages, 226,145 induced abortions). One hundred sixty-six were exposed to diclofenac/misoprostol in the early pregnancy of which 28.3 % (47) ended up in a miscarriage compared to 10.6 % among unexposed. The adjusted hazard ratio of having a miscarriage after exposure to diclofenac/misoprostol in the first trimester was 3.6 (CI 95 % 2.6-4.9). CONCLUSION: We found an increased risk of miscarriage after exposure to diclofenac/misoprostol during the early pregnancy. Women in the fertile age should not be treated with the combination of diclofenac/misoprostol if other options were available.

Birth outcomes after exposure to mebendazole and pyrvinium during pregnancy - A Danish nationwide cohort study.

Mebendazole and pyrvinium are anthelmintics used to treat infections with pinworms, a common infection in children. Other indications for treatment with mebendazole are infections with soil-transmitted helminths. These infections are rare in Denmark, but affect more than 1.5 billion people worldwide. Limited safety data of anthelmintics during pregnancy exists and the purpose of this study was to investigate the association between exposure to mebendazole or pyrvinium during pregnancy and the adverse pregnancy outcomes: congenital malformations, stillbirths, neonatal mortality and small for gestational age. The Danish Fertility Database was used to identify all births in Denmark from 1997 to 2007. Maternal exposure to anthelmintics was identified through The Danish Prescription Registry. Of 713667 births, 2567 mothers redeemed a prescription for mebendazole; 1588 for pyrvinium. Logistic regression analysis adjusted for potential confounders. We found no association between exposure to mebendazole and major congenital malformations (OR = 0.7 (CI 95% 0.5-1.1)) or other negative birth outcomes and we found no association between exposure to pyrvinium and major congenital malformations (OR = 0.8 (CI 95% 0.4-1.5)) or other negative birth outcomes. No increased risk was found of having negative birth outcomes after exposure at any trimester during pregnancy.

Use of thyroid hormones in relation to pregnancy: a Danish nationwide cohort study.

OBJECTIVE: To determine the rate of exposure of pregnant women to levothyroxine and to assess changes in these rates before, during and after pregnancy. DESIGN: Register-based cohort study. SETTING: Danish nationwide registers. POPULATION: All women having a live birth in Denmark between 1 January 1997 and 31 December 2010 (n = 912 342). METHODS: All pregnant women in the study period were identified from the Danish Medical Birth Register. Exposed women were identified from the Danish National Prescription Register, based on redemption of levothyroxine prescriptions before, during or after pregnancy. MAIN OUTCOME MEASURES: The rate of pregnant women redeeming levothyroxine prescriptions and maternal characteristics. RESULTS: We identified a fourfold increase in levothyroxine prescription redemption during the study period, from 0.34% in 1997 to 1.39% by 2010. A mean of 0.79% of our cohort received levothyroxine. Most of the women who were using levothyroxine before pregnancy continued the therapy during their pregnancy, but 9.4% stopped redeeming their prescriptions. Overall, 0.28% of our cohort received a levothyroxine prescription for the first time within 9 months after pregnancy. CONCLUSIONS: Fewer women than expected received levothyroxine treatment during pregnancy even though a fourfold increase was observed during the study period. Furthermore, one of 10 discontinued treatments during pregnancy. These findings all indicate that too few women are treated for hypothyroidism during pregnancy. Further research is needed to determine whether hypothyroid pregnant women are suboptimally treated and the possible consequences for the mother and fetus.

Diurnal variation of urinary markers of nucleic acid oxidation.

AIMS: Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) are biomarkers of oxidative stress with clinical potential in a variety of diseases. As part of their clinical validation, this study aimed to investigate whether the urinary excretion of 8-oxodG and 8-oxoGuo undergoes diurnal variation and to evaluate the validity of 6-hour sampling as well as creatinine corrected spot urine sampling. METHODS: A total of 23 healthy study subjects collecting their 24-h urine in four fractions covering 6 hours each. Urinary 8-oxodG and 8-oxoGuo levels were quantified using a modified version of UPLC-MS/MS. RESULTS: No significant difference in excretion levels between the 12-h diurnal and 12-h nocturnal state or between the four 6-h periods during the day was found for either biomarker. A strong linear relationship between the excretion levels in each of the 6-h periods and the 24-h excretion level was shown for both biomarkers. Creatinine correction of the 6-h levels reduced the biological variation of the excretion levels and weakened the linear relationship with the uncorrected 24-h excretion level for both biomarkers. The correlations were strengthened when the 24-h excretion level was expressed per kg body weight. CONCLUSION: The results showed that 8-oxodG and 8-oxoGuo did not undergo diurnal variation in the study population overall and hence that the time of sampling is not crucial. Furthermore, 6-h sampling can be used as a substitute for 24-h sampling, and creatinine corrected sampling may be rational due to the reduction in biological variation of the biomarkers and the reasonable correlation with body weight-adjusted 24-h levels.

Increasing Medication Use and Polypharmacy in Type 2 Diabetes: The Danish Experience From 2000 to 2020.

OBJECTIVE: Type 2 diabetes often coexists with other conditions that are amenable to pharmacological treatment. We hypothesized that polypharmacy among individuals with type 2 diabetes has increased since 2000. RESEARCH DESIGN AND METHODS: Using Danish national registries, we established a cohort of all Danish individuals (aged ≥18 years) with type 2 diabetes between 2000 and 2020. We analyzed their medication use and prevalence of varying degrees of polypharmacy (≥5 or ≥10 medications), stratifying by age, sex, number of chronic diseases, and socioeconomic status. RESULTS: The cohort grew from 84,917 patients in 2000 to 307,011 in 2020, totaling 461,849 unique patients. The number of daily medications used per patient increased from (mean ± SD) 3.7 ± 2.8 (in 2000) to 5.3 ± 3.2 (in 2020). The lifetime risk of polypharmacy was substantial, with 89% (n = 409,062 of 461,849) being exposed to ≥5 medications at some point and 47% (n = 217,467of 461,849) to ≥10 medications. The increases were driven by an expanding group of medications, with analgesics, antihypertensives, proton pump inhibitors, and statins having the largest net increase. Advanced age, male sex, lower socioeconomic status, and Danish ethnicity positively correlated with polypharmacy but could not explain the overall increase in polypharmacy. CONCLUSIONS: Medication use and polypharmacy have increased among patients with type 2 diabetes. Although the implications and appropriateness of this increased medication use are uncertain, the results stress the increasing need for health care personnel to understand the potential risks associated with polypharmacy, including medication interactions, adverse effects, and over- and underprescribing.

Adverse Pregnancy Outcomes and Subsequent First-Time Use of Psychiatric Treatment Among Fathers in Denmark.

Importance: Becoming a first-time parent is a major life-changing event and can be challenging regardless of the pregnancy outcome. However, little is known how different adverse pregnancy outcomes affect the father's risk of psychiatric treatment post partum. Objective: To examine the associations of adverse pregnancy outcomes with first-time psychiatric treatment in first-time fathers. Design, Setting, and Participants: This nationwide cohort study covered January 1, 2008, to December 31, 2017, with a 1-year follow-up completed December 31, 2018. Data were gathered from Danish, nationwide registers. Participants included first-time fathers with no history of psychiatric treatment. Data were analyzed from August 1, 2022, to February 20, 2024. Exposures: Adverse pregnancy outcomes including induced abortion, spontaneous abortion, stillbirth, small for gestational age (SGA) and not preterm, preterm with or without SGA, minor congenital malformation, major congenital malformation, and congenital malformation combined with SGA or preterm compared with a full-term healthy offspring. Main Outcomes and Measures: Prescription of psychotropic drugs, nonpharmacological psychiatric treatment, or having a psychiatric hospital contact up to 1 year after the end of the pregnancy. Results: Of the 192 455 fathers included (median age, 30.0 [IQR, 27.0-34.0] years), 31.1% experienced an adverse pregnancy outcome. Most of the fathers in the study had a vocational educational level (37.1%). Fathers experiencing a stillbirth had a significantly increased risk of initiating nonpharmacological psychiatric treatment (adjusted hazard ratio [AHR], 23.10 [95% CI, 18.30-29.20]) and treatment with hypnotics (AHR, 9.08 [95% CI, 5.52-14.90]). Moreover, fathers experiencing an early induced abortion (≤12 wk) had an increased risk of initiating treatment with hypnotics (AHR, 1.74 [95% CI, 1.33-2.29]) and anxiolytics (AHR, 1.79 [95% CI, 1.18-2.73]). Additionally, late induced abortion (>12 wk) (AHR, 4.46 [95% CI, 3.13-6.38]) and major congenital malformation (AHR, 1.36 [95% CI, 1.05-1.74]) were associated with increased risk of nonpharmacological treatment. In contrast, fathers having an offspring being born preterm, SGA, or with a minor congenital malformation did not have a significantly increased risk of any of the outcomes. Conclusions and Relevance: The findings of this Danish cohort study suggest that first-time fathers who experience stillbirths or induced abortions or having an offspring with major congenital malformation had an increased risk of initiating pharmacological or nonpharmacological psychiatric treatment. These findings further suggest a need for increased awareness around the psychological state of fathers following the experience of adverse pregnancy outcomes.

Association Between First-time Neurologic Events and Metronidazole Treatment: A Case-time Control Study.

PURPOSE: Metronidazole, a widely used antimicrobial medication, has been linked to neurologic adverse drug reactions. This study investigates the association between metronidazole use and first-time neurologic events. METHODS: We conducted a case-time-control study using data from the Danish National Patient Register and the National Prescription Register in years 2013 to 2021. Patients with a first-time diagnosis of encephalopathy, cerebellar dysfunction, or peripheral neuropathy were included. Conditional logistic regression analyses were performed to estimate the risk of neurologic events associated with metronidazole use. FINDINGS: Out of 476,066 first-time metronidazole prescriptions, the 100-day cumulative incidence of peripheral neuropathy was 0.016%, and 0.002% for cerebellar dysfunction or encephalopathy. In the case-time control study, we identified 17,667 persons with a first-time neurologic event and were included for the analysis. The estimated odds ratio for the combined neurologic events was 0.98 (95% CI, 0.59-1.64, P = 0.95) with no statistically significant association across different subgroups and time windows. IMPLICATIONS: Our findings suggest that metronidazole-induced neurologic events may be rarer than previously described, and we did not find any consistent or statistically significant association between metronidazole exposure. Nonetheless, clinicians should remain vigilant to potential neurologic risks in patients receiving metronidazole, to ensure its safe and effective use.