INfluenza VaccInation To mitigate typE 1 Diabetes (INVITED): a study protocol for a randomised, double-blind, placebo-controlled clinical trial in children and adolescents with recent-onset type 1 diabetes.

INTRODUCTION: Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving ß-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer ß-cell protection. This study aims to assess the effect of influenza vaccination on preserving ß-cell function in children and adolescents with recent-onset T1D. METHODS AND ANALYSIS: The INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7-17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual ß-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D. ETHICS AND DISSEMINATION: Ethical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.

Effect of screening mammography on the risk of breast cancer deaths and of all-cause deaths: a systematic review with meta-analysis of cohort studies.

OBJECTIVES: Observational cohort studies are used to evaluate the effectiveness of screening mammography in women offered screening. Because screening mammography has no effect on causes of death other than breast cancer (BC), cohort studies should show reductions in the risk of BC death substantially greater than possible reductions in the risk of all-cause death. We assessed the risk of BC deaths and of all-cause (or of nonBC) deaths associated with screening mammography attendance reported in cohort studies. STUDY DESIGN AND SETTING: Cohort studies published from 2002 to 2022 on women invited to screening mammography were searched in PubMed, Web of Sciences, Scopus, and in review articles. Random effect meta-analyses were performed using relative risks (RRs) of death between women who attended screening compared to women who did not attend screening. RESULTS: Eighteen cohort studies were identified, nine that reported RRs of BC deaths only, five that reported RRs of all-cause deaths only, and four that reported RRs for both BC deaths and all-cause deaths. The latter four cohort studies reported 12-76 times more all-cause deaths than BC deaths. The random-effect summary of RR for BC mortality in screening attendees vs nonattendees was 0.55 (95% CI: 0.50-0.60) in 13 cohort studies. The summary of RR for all-cause mortality was 0.54 (0.50-0.58) in 10 cohort studies. In the four cohort studies that evaluated both outcomes, the summary of RRs were 0.63 (0.43-0.83) for BC mortality and of 0.54 (0.44-0.64) for all-cause mortality. CONCLUSION: The similar relative reductions in breast- and all-cause (or nonBC) mortality indicates that screening mammography attendance is an indicator of characteristics associated with a lower risk of dying from any cause, including from BC, which observational studies have falsely interpreted as a screening effect.

Danish Women Make Decisions about Participation in Breast Cancer Screening prior to Invitation Information: An Online Survey Using Experimental Methods.

INTRODUCTION: At mammography screening invitation, the Danish Health Authority recommends women aged 50 to 69 y make an informed decision about whether to be screened. Previous studies have shown that women have very positive attitudes about screening participation. Therefore, we hypothesized that Danish women may already have decided to participate in breast cancer screening prior to receiving their screening invitation at age 50 y. METHODS: We invited a random sample of 2,952 Danish women aged 44 to 49 y (prescreening age) to complete an online questionnaire about barriers to informed screening decision making using the official digital mailbox system in Denmark. We asked participants about their screening intentions using 3 different questions to which women were randomized: screening presented 1) as an opportunity, 2) as a choice, and 3) as an opportunity plus a question about women's stage of decision making. All women completed questions about background characteristics, intended participation in the screening program, use and impact of screening information, and preferences for the decision-making process. Data were linked to sociodemographic register data. RESULTS: A total of 790 (26.8%) women participated in the study. Herein, 97% (95% confidence interval: 96%-98%) reported that they wanted to participate in breast cancer screening when invited at age 50 y. When presented with the choice compared with the opportunity framing, more women rejected screening. When asked about their stage of decision making, most (87%) had already made a decision about screening participation and were unlikely to change their mind. CONCLUSION: In our study, almost all women of prescreening age wanted to participate in breast cancer screening, suggesting that providing information at the time of screening invitation may be too late to support informed decision making. HIGHLIGHTS: Almost all women of prescreening age (44-49 y) in our study wanted to participate in the Danish national mammography screening program starting at age 50 y.Early decision making represents a barrier for informed decision making as women in this study had intentions to participate in breast cancer screening prior to receiving an official screening invitation, and therefore, providing information at the time of screening invitation may be too late to support informed decision making.Very few women rejected screening participation; however, more women rejected screening when the information was framed as an active choice between having or declining breast cancer screening (continue with usual care) compared with presenting only the option of screening with no description of the alternative.Two-thirds of women reading the screening information in this study had unchanged attitudes toward screening after reading the presented information.

Trends in cause-specific mortality among people with type 2 and type 1 diabetes from 2002 to 2019: a Danish population-based study.

Background: Despite advances in primary and secondary prevention of cardiovascular disease, excess mortality persists within the diabetes population. This study explores the components of this excess mortality and their interaction with sex. Methods: Using Danish registries (2002-2019), we identified residents aged 18-99 years, their diabetes status, and recorded causes of death. Applying Lexis-based methods, we computed age-standardized mortality rates (asMRs), mortality relative risks (asMRRs), and log-linear trends for cause-specific mortality. Findings: From 2002 to 2019, 958,278 individuals died in Denmark (T2D: 148,620; T1D: 7830) during 84.4 M person-years. During the study period, overall asMRs declined, driven by reducing cardiovascular mortality, notably in men with T2D. Conversely, cancer mortality remained high, making cancer the leading cause of death in individuals with T2D. Individuals with T2D faced an elevated mortality risk from nearly all cancer types, ranging from 9% to 257% compared to their non-diabetic counterparts. Notably, obesity-related cancers exhibited the highest relative risks: liver cancer (Men: asMRR 3.58 (3.28; 3.91); Women: asMRR 2.49 (2.14; 2.89)), pancreatic cancer (Men: asMRR 3.50 (3.25; 3.77); Women: asMRR 3.57 (3.31; 3.85)), and kidney cancer (Men: asMRR 2.10 (1.84; 2.40); Women: asMRR 2.31 (1.92; 2.79)). In men with type 2 diabetes, excess mortality remained stable, except for dementia. In women, diabetes-related excess mortality increased by 6-17% per decade across all causes of death, except cardiovascular disease. Interpretation: In the last decade, cancer has emerged as the leading cause of death among individuals with T2D in Denmark, emphasizing the need for diabetes management strategies incorporating cancer prevention. A sex-specific approach is crucial to address persistently higher relative mortality in women with diabetes. Funding: Supported by Steno Diabetes Center Aarhus, which is partially funded by an unrestricted donation from the Novo Nordisk Foundation, and by The Danish Diabetes Academy.

Development of antibody levels and subsequent decline in individuals with vaccine induced and hybrid immunity to SARS-CoV-2.

OBJECTIVES: This study aimed to compare antibody trajectories among individuals with SARS-CoV-2 hybrid and vaccine-induced immunity. METHODS: Danish adults receiving three doses of BTN162b2 or mRNA-1237 were included prior to first vaccination (Day 0). SARS-CoV-2 anti-spike IgG levels were assessed before each vaccine dose, at Day 90, Day 180, 28 days after 3rd vaccination (Day 251), Day 365, and prior to 4th vaccination (Day 535). SARS-CoV-2 PCR results were extracted from the national microbiology database. Mixed-effect multivariable linear regression investigated the impact of hybrid-immunity (stratified into 4 groups: no hybrid immunity, PCR+ prior to 3rd dose, PCR+ after 3rd dose and before Day 365, PCR+ after Day 365) on anti-spike IgG trajectories. RESULTS: A total of 4,936 individuals were included, 47% developed hybrid-immunity. Anti-spike IgG increases were observed in all groups at Day 251, with the highest levels in those PCR+ prior to 3rd dose (Geometric Mean; 535,647AU/mL vs. 374,665AU/mL with no hybrid-immunity, P<0.0001). Further increases were observed in participants who developed hybrid immunity after their 3rd dose. Anti-spike IgG levels declined from Day 251-535 in individuals without hybrid-immunity and in those who developed hybrid-immunity prior to their 3rd dose, with lower rate of decline in those with hybrid-immunity. CONCLUSION: Hybrid-immunity results in higher and more durable antibody trajectories in vaccinated individuals.

Danish Diabetes Birth Registry 2: a study protocol of a national prospective cohort study to monitor outcomes of pregnancies of women with pre-existing diabetes.

INTRODUCTION: Despite technological developments and intensified care, pregnancies in women with pre-existing diabetes are still considered high-risk pregnancies. The rate of adverse outcomes in pregnancies affected by diabetes in Denmark is currently unknown, and there is a limited understanding of mechanisms contributing to this elevated risk. To address these gaps, the Danish Diabetes Birth Registry 2 (DDBR2) was established. The aims of this registry are to evaluate maternal and fetal-neonatal outcomes based on 5 years cohort data, and to identify pathophysiology and risk factors associated with short-term and long-term outcomes of pregnancies in women with pre-existing diabetes. METHODS AND ANALYSIS: The DDBR2 registry is a nationwide 5-year prospective cohort with an inclusion period from February 2023 to February 2028 of pregnancies in women with all types of pre-existing diabetes and includes registry, clinical and questionnaire data and biological samples of mother-partner-child trios. Eligible families (parents age ≥18 years and sufficient proficiency in Danish or English) can participate by either (1) basic level data obtained from medical records (mother and child) and questionnaires (partner) or (2) basic level data and additional data which includes questionnaires (mother and partner) and blood samples (all). The primary maternal outcome is Hemoglobin A1c (HbA1c) levels at the end of pregnancy and the primary offspring endpoint is the birth weight SD score. The DDBR2 registry will be complemented by genetic, epigenetic and metabolomic data as well as a biobank for future research, and the cohort will be followed through data from national databases to illuminate possible mechanisms that link maternal diabetes and other parental factors to a possible increased risk of adverse long-term child outcomes. ETHICS AND DISSEMINATION: Approval from the Ethical Committee is obtained (S-20220039). Findings will be sought published in international scientific journals and shared among the participating hospitals and policymakers. TRIAL REGISTRATION NUMBER: NCT05678543.

Treatment patterns and adherence to lipid-lowering drugs during eight-year follow-up after a coronary heart disease event.

BACKGROUND AND AIMS: Proper prescription and high adherence to intensive lipid lowering drugs (LLD) in patients with coronary heart disease (CHD) are crucial and strongly recommended. The aim of this study is to investigate long-term treatment patterns and adherence to LLD following hospitalization for a CHD event. METHODS: Patients admitted to two Norwegian hospitals with a CHD event from 2011 to 2014 (N = 1094) attended clinical examination and completed a questionnaire, median 16 months later. Clinical data were linked to pharmacy dispensing data from 2010 to 2020. The proportions using high-intensity statin therapy (atorvastatin 40/80 mg or rosuvastatin 20/40 mg) and non-statin LLD after the CHD event were assessed. Adherence was evaluated by proportion of days covered (PDC) and gaps in treatment. RESULTS: Median age at hospitalization was 63 (IQR 12) years, 21 % were female. Altogether, 1054 patients (96 %) were discharged with a statin prescription, while treatment was dispensed in 85 % within the following 90 days. During median 8 (SD 2.5) years follow-up, the proportion using high-intensity statin therapy ranged 62-68 %, whereas the use of ezetimibe increased from 4 to 26 %. PDC <0.8 was found in 22 % of statin users and 26 % of ezetimibe users. The proportions with a treatment gap exceeding 180 days were 22 % for statins and 28 % for ezetimibe. Smoking at hospitalization and negative affectivity were significantly associated with reduced statin adherence, regardless of adherence measure. CONCLUSIONS: In this long-term follow-up of patients with CHD, less than 70 % used high-intensity statin therapy with only small changes over time, and only 25 % used additional treatment with ezetimibe. We identified factors associated with reduced statin adherence that may be target for interventions.

Patients with repeated acute admissions to somatic departments: sociodemographic characteristics, disease burden, and contact with primary healthcare sector - a retrospective register-based case-control study.

BACKGROUND: Healthcare systems face escalating capacity challenges and patients with repeated acute admissions strain hospital resources disproportionately. However, studies investigating the characteristics of such patients across all public healthcare providers in a universal healthcare system are lacking. OBJECTIVE: To investigate characteristics of patients with repeated acute admissions (three or more acute admissions within a calendar year) in regard to sociodemographic characteristics, disease burden, and contact with the primary healthcare sector. METHODS: This matched register-based case-control study investigated repeated acute admissions from 1 January 2014 to 31 December 2018, among individuals, who resided in four Danish municipalities. The study included 6169 individuals with repeated acute admissions, matched 1:4 to individuals with no acute admissions and one to two acute admissions, respectively. Group comparisons were conducted using conditional logistic regression. RESULTS: Receiving social benefits increased the odds of repeated acute admissions 9.5-fold compared with no acute admissions (odds ratio (OR) 9.5; 95% confidence interval (CI) 8.5; 10.6) and 3.4-fold compared with one to two acute admissions (OR 3.4; 95% CI 3.1; 3.7). The odds of repeated acute admissions increased with the number of used medications and chronic diseases. Having a mental illness increased the odds of repeated acute admissions 5.8-fold when compared with no acute admissions (OR 5.7; 95% CI 5.2; 6.4) and 2.3-fold compared with one to two acute admissions (OR 2.3; 95% CI 2.1; 2.5). Also, high use of primary sector services (e.g. nursing care) increased the odds of repeated acute admissions when compared with no acute admissions and one to two acute admissions. CONCLUSIONS: This study pinpointed key factors encompassing social status, disease burden, and healthcare utilisation as pivotal markers of risk for repeated acute admissions, thus identifying high-risk patients and facilitating targeted intervention.

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial.

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

Whey Protein Premeal Lowers Postprandial Glucose Concentrations in Adults Compared with Water-The Effect of Timing, Dose, and Metabolic Status: a Systematic Review and Meta-analysis.

BACKGROUND: Serving whey protein before a meal in order to lower postprandial blood glucose concentrations is known as a premeal. The underlying mechanisms are only partly understood but may involve stimulation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and insulin secretion together with a slower gastric emptying rate. OBJECTIVES: The objective of this systematic review and meta-analysis was to review all randomized clinical trials investigating premeals with whey protein in comparison with a nonactive comparator (control) that evaluated plasma glucose, GLP-1, GIP, insulin, and/or gastric emptying rate. Secondary aims included subgroup analyses on the timing and dose of the premeal together with the metabolic state of the participants [lean, obese, and type 2 diabetes mellitus (T2DM)]. METHODS: We searched EMBASE, CENTRAL, PUBMED, and clinicaltrials.gov and found 16 randomized crossover trials with a total of 244 individuals. The last search was performed on 9 August, 2022. RESULTS: Whey protein premeals lowered peak glucose concentration by -1.4 mmol/L [-1.9 mmol/L; -0.9 mmol/L], and the area under the curve for glucose was -0.9 standard deviation (SD) [-1.2 SD; -0.6 SD] compared with controls (high certainty). In association with these findings, whey protein premeals elevated GLP-1 (low certainty) and peak insulin (high certainty) concentrations and slowed gastric emptying rate (high certainty) compared with controls. Subgroup analyses showed a more pronounced and prolonged glucose-lowering effect in individuals with T2DM compared with participants without T2DM. The available evidence did not elucidate the role of GIP. The protein dose used varied between 4 and 55 g, and meta-regression analysis showed that the protein dose correlated with the glucose-lowering effects. CONCLUSIONS: In conclusion, whey protein premeals lower postprandial blood glucose, reduce gastric emptying rate, and increase peak insulin. In addition, whey protein premeals may elevate plasma concentrations of GLP-1. Whey protein premeals may possess clinical potential, but the long-term effects await future clinical trials.

ChatGPT- versus human-generated answers to frequently asked questions about diabetes: A Turing test-inspired survey among employees of a Danish diabetes center.

Large language models have received enormous attention recently with some studies demonstrating their potential clinical value, despite not being trained specifically for this domain. We aimed to investigate whether ChatGPT, a language model optimized for dialogue, can answer frequently asked questions about diabetes. We conducted a closed e-survey among employees of a large Danish diabetes center. The study design was inspired by the Turing test and non-inferiority trials. Our survey included ten questions with two answers each. One of these was written by a human expert, while the other was generated by ChatGPT. Participants had the task to identify the ChatGPT-generated answer. Data was analyzed at the question-level using logistic regression with robust variance estimation with clustering at participant level. In secondary analyses, we investigated the effect of participant characteristics on the outcome. A 55% non-inferiority margin was pre-defined based on precision simulations and had been published as part of the study protocol before data collection began. Among 311 invited individuals, 183 participated in the survey (59% response rate). 64% had heard of ChatGPT before, and 19% had tried it. Overall, participants could identify ChatGPT-generated answers 59.5% (95% CI: 57.0, 62.0) of the time, which was outside of the non-inferiority zone. Among participant characteristics, previous ChatGPT use had the strongest association with the outcome (odds ratio: 1.52 (1.16, 2.00), p = 0.003). Previous users answered 67.4% (61.7, 72.7) of the questions correctly, versus non-users' 57.6% (54.9, 60.3). Participants could distinguish between ChatGPT-generated and human-written answers somewhat better than flipping a fair coin, which was against our initial hypothesis. Rigorously planned studies are needed to elucidate the risks and benefits of integrating such technologies in routine clinical practice.

Women's health literacy and attendance in breast cancer screening: a Danish population-based study combining survey and register data.

AIM: To investigate the association between women's health literacy and attendance in the Danish national breast cancer screening programme. METHODS: In a population-based cross-sectional study, information on two health literacy subscales, measured using the Health Literacy Questionnaire (HLQ), and sociodemographic factors was obtained from the 'How are you? 2017' survey in the Central Denmark Region. Information on screening attendance was obtained from register data from 2016-2017. Data were linked based on individual civil registration numbers. To account for missing data, multiple imputation by chained equations was implemented to fill in missing values on all variables. Unadjusted and adjusted logistic regression analyses were performed separately for two HLQ subscales to estimate odds ratio (OR) of screening attendance. Both multiple imputation analyses and complete case analyses were performed. RESULTS: A total of 6012 women were included in multiple imputed statistical analyses. Generally, women had high health literacy levels. In multiple imputed analyses, the unadjusted OR of the primary HLQ subscale, understanding, was 1.32 (95% confidence interval (CI): 1.10-1.59), indicating higher odds for screening attendance with higher health literacy level. However, after adjustment no significant association between the HLQ subscale of understanding and screening attendance was found (OR 1.09 (95% CI: 0.90-1.33)). Similar results were found for the secondary HLQ subscale of engaging (insignificant association in adjusted analysis). No effect modification from sociodemographic characteristics was found. Similar results were found in complete case analyses. CONCLUSIONS: No significant association was found between health literacy and attendance in the Danish breast cancer screening programme.

Quantifying the impact of unmeasured confounding in observational studies with the E value.

The E value method deals with unmeasured confounding, a key source of bias in observational studies. The E value method is described and its use is shown in a worked example of a meta-analysis examining the association between the use of antidepressants in pregnancy and the risk of miscarriage.

Scandinavian trial of uncomplicated aortic dissection therapy: study protocol for a randomized controlled trial.

BACKGROUND: Contemporary management of uncomplicated type B aortic dissections (uTBAD) is based on the acuity and various morphological features. Medical therapy is mandatory, while the risks of early thoracic endovascular aortic repair (TEVAR) are balanced against the potential for rupture, complex surgery, and death. Improved aortic morphology following TEVAR is documented, but evidence for improved overall survival is lacking. The costs and impact on quality of life are also needed. METHODS: The trial is a randomized, open-label, superiority clinical trial with parallel assignment of subjects at 23 clinical sites in Denmark, Norway, Sweden, Finland, and Iceland. Eligibility includes patients aged ≥ 18 with uTBAD of < 4 weeks duration. Recruited subjects will be randomized to either standard medical therapy (SMT) or SMT + TEVAR, where TEVAR must be performed between 2-12 weeks from the onset of symptoms. DISCUSSION: This trial will evaluate the primary question of whether early TEVAR improves survival at 5 years among uTBAD patients. Moreover, the costs and the impact on quality of life should provide sorely needed data on other factors that play a role in treatment strategy decisions. The common Nordic healthcare model, with inclusion of all aortic centers, provides a favorable setting for carrying out this trial, while the robust healthcare registries ensure data validity. TRIAL REGISTRATION: ClinicalTrials.gov NCT05215587. Registered on January 31, 2022.

Colon cancer diagnosed in patients with non-specific symptoms - comparisons between diagnostic paradigms.

Background In Denmark, the Cancer Patient Pathway for Non-Specific Signs and Symptoms (NSSC-CPP) has been implemented with variations: in some areas, general practitioners (GPs) do the initial diagnostic work-up (GP paradigm); in other areas, patients are referred directly to the hospital (hospital paradigm). There is no evidence to suggest the most beneficial organisation. Therefore, this study aims to compare the occurrence of colon cancer and the risk of non-localised cancer stage between the GP and hospital paradigms.Material and Methods In this registry-based case-control study, we applied multivariable binary logistic regression models to estimate the odds ratios (OR) of colon cancer and non-localised stage associated with the GP paradigm and hospital paradigm. All cases and controls were assigned to a paradigm based on their diagnostic activity (CT scan or CPP) six months before the index date. As not all CT scans in the control group were part of the cancer work-up as a sensitivity analysis, we investigated the impact of varying the fraction of these, which were randomly removed using a bootstrap approach for inference.Results The GP paradigm was more likely to result in a cancer diagnosis than the hospital paradigm; ORs ranged from 1.91-3.15 considering different fractions of CT scans as part of cancer work-up. No difference was found in the cancer stage between the two paradigms; ORs ranged from 1.08-1.10 and were not statistically significant.Conclusion Patients in the GP paradigm were diagnosed with colon cancer more often, but we cannot conclude that the distribution of respectively localised or non-localised extent of disease is different from that of patients in the hospital paradigm.

Methodology of the brodalumab assessment of hazards: a multicentre observational safety (BRAHMS) study.

INTRODUCTION: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections. METHODS AND ANALYSIS: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed. ETHICS AND DISSEMINATION: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS30280.

Danish Women Want to Participate in a Hypothetical Breast Cancer Screening with Harms and No Reduction in Mortality: A Cross-Sectional Survey.

INTRODUCTION: Informed decision making is recommended in breast cancer screening. Decision aids with balanced information on harms and benefits are recommended to support informed decision making. However, informed screening decision making may be challenged by overly positive attitudes toward cancer screening. We hypothesized that a substantial proportion of Danish women would want to participate in screening regardless of the presented information. Therefore, we aimed to estimate the prevalence of Danish women wanting to participate in a hypothetical breast cancer screening offering no reduction in breast cancer mortality but potential harms related to unnecessary treatment. METHODS: In a cross-sectional study, we invited a random sample of 751 women in the nonscreening population aged 44 to 49 y in the Central Denmark Region to an online questionnaire using the official digital mailbox system. The questionnaire included a description of a hypothetical screening and questions about thoughts on breast cancer, health literacy, and questions on the assessment of the hypothetical screening including intended participation, understanding, and belief in information. Data were linked to register data on sociodemographic factors. RESULTS: In total, 43.0% (323/751) responded to the questionnaire. Of these, 247 (82.3% [95% confidence interval: 77.5-86.5]) wanted to participate in the hypothetical breast cancer screening (participation group). More than two-thirds in both the participation group and nonparticipation group seemed to understand the presented information. Half of the women who understood the information disbelieved it. CONCLUSIONS: Exceeding our expectations, a majority of women wanted to participate in a hypothetical screening with potential harms but no reduction in breast cancer mortality. A large proportion understood but disbelieved the screening information. This could indicate that Danish women make their screening decisions based on beliefs rather than presented screening information. This study was registered at ClinicalTrials.gov (Identifier: NCT04509063). HIGHLIGHTS: The majority of Danish women wanted to participate in a hypothetical breast cancer screening with potential harms related to unnecessary treatment but no reduction in mortality.A large proportion of women understood but disbelieved the hypothetical screening information.Informed decision making may be challenging when women disbelieve the information they receive.Enthusiasm for cancer screening and potential disbelief in information are important factors when developing and improving screening information and invitation.

Cox regression using a calendar time scale was unbiased in simulations of COVID-19 vaccine effectiveness & safety.

BACKGROUND: Observational studies on corona virus disease 2019 (COVID-19) vaccines compare event rates in vaccinated and unvaccinated person time using Poisson or Cox regression. In Cox regression, the chosen time scale needs to account for the time-varying incidence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection and COVID-19 vaccination.We aimed to quantify bias in person-time based methods, with and without adjustment for calendar time, using simulations and empirical data analysis. METHODS: We simulated 500,000 individuals who were followed for 365 days, and a point exposure resembling COVID-19 vaccination (cumulative incidence 80%). We generated an effectiveness outcome, emulating the incidence of severe acute respiratory syndrome corona virus 2 infection in Denmark during 2021 (risk 10%), and a safety outcome with seasonal variation (myocarditis, risk 1/5,000). Incidence rate ratios (IRRs) were set to 0.1 for effectiveness and 5.0 for safety outcomes. IRRs and hazard ratios (HRs) were estimated using Poisson and Cox regression with a time under observation scale, and a calendar time scale. Bias was defined as estimated IRR or HR-true IRR. Further, we obtained estimates for both outcomes using data from the Danish health registries. RESULTS: Unadjusted IRRs (biaseffectivenes +0.16; biassafety -2.09) and HRs estimated using a time-under-observation scale (+0.28;-2.15) were biased. Adjustment for calendar time reduced bias in Cox (+0.03; +0.33) and Poisson regression (0.00; -0.28). Cox regression using a calendar time scale was least biased (0.00, +0.12). When analyzing empirical data, adjusted Poisson and Cox regression using a calendar time scale yielded estimates in accordance with existing evidence. CONCLUSION: Lack of adjustment for the time-varying incidence of COVID-19 related outcomes may severely bias estimates.

Incidence in pharmacoepidemiology: A conceptual framework for incidence of a single substance or group of substances with statins as an example.

A framework for analysing incidence in pharmacoepidemiology and drug statistics is suggested using statins as an example. A new case of statin use (first-ever use or recurrence of treatment) can be defined as new on the group (NoG), new on substance whether new on the group or not (NoS), new on substance and new on the group (NoS_and_NoG), new on substance and not new on the group (NoS_not_NoG). METHOD: Individual-level dispensations of statins 2006-2019 for 1 017 058 individuals with at least one dispensation 2019 in Sweden. RESULTS: With 12-month run-in, corresponding to at least 8 months without treatment, the incidence proportion of NoG was 13.39 new cases per 1000 inhabitants and 8.40 with 10-year run-in. Thus, 37% had first been treated with any statin between 12 months and 10 years before the index date. For atorvastatin, NoS was 10.69, NoS_and_NoG 9.99, and NoS_not_NoG 0.70 per 1000 inhabitants. 0.70 per 1000 inhabitants or 6.6% of new cases of atorvastatin represented a change from another statin during the run-in. CONCLUSION: It is essential to separate new cases that are new both on the substance and on the group from those that represent a change of therapy during the run-in.