The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF): Rationale and design.

AIMS: Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a unique pragmatic registry-based randomized controlled trial. METHODS: SPIRRIT-HFpEF is a multicentre, prospective, randomized, open-label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N-terminal pro-B-type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre-specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event-driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients. CONCLUSION: SPIRRIT-HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry-based trials in heart failure and other chronic conditions.

Congenital heart defects in children born after assisted reproductive technology: a CoNARTaS study.

BACKGROUND AND AIMS: Children born after assisted reproductive technology (ART) have worse perinatal outcomes compared with spontaneously conceived children. This study investigates whether children conceived after ART have a higher risk of congenital heart defects (CHDs) compared with children born after spontaneous conception (SC). METHODS: All 7 747 637 liveborn children in Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1987-2015), where 171 735 children were conceived after ART, were included. National ART and medical birth registry data were cross-linked with data from other health and population registries. Outcomes were major CHDs, severe CHDs, 6 hierarchical CHD lesion groups, and 10 selected major CHDs, diagnosed prenatally or up to 1 year of age (Denmark, Finland, and Sweden) and prenatally or at birth (Norway). The association between ART and CHDs was assessed with multivariable logistic regression analysis, with adjustment for available confounders. RESULTS: Major CHDs were detected in 3159 children born after ART (1.84%) and in 86 824 children born after SC [1.15%; adjusted odds ratio (AOR) 1.36; 95% confidence interval (CI) 1.31-1.41]. Risk was highest in multiples, regardless of conception method. Severe CHDs were detected in 594 children born after ART (0.35%) and in 19 375 children born after SC (0.26%; AOR 1.30; 95% CI 1.20-1.42). Risk was similar between ICSI and IVF and between frozen and fresh embryo transfer. CONCLUSIONS: Assisted reproductive technology-conceived children have a higher prevalence of major CHDs, being rare, but severe conditions. The absolute risks are, however, modest and partly associated with multiple pregnancies, more prevalent in ART.

A guide to large data sets for population-based cancer research: Strengths, limitations, and pitfalls.

With the proliferation of cancer research based on large databases, misalignment of research questions and data set capabilities is inevitable. Nationally maintained databases are appealing to cancer researchers because of the ease of access to large amounts of patient data available for analysis and risk estimation. Data sets that are commonly used in cancer research include the National Cancer Database, the SEER (Surveillance, Epidemiology, and End Results) program of the National Cancer Institute, the SEER-Medicare database, the American College of Surgeons National Surgical Quality Improvement Program, and the Healthcare Cost and Utilization Project databases, among others. Each data set has pros and cons with respect to variable availability and the ability to analyze cancer-specific outcomes. It is critical for researchers to understand the strengths and limitations of each database. Changing variable definitions, the length of postoperative data collection, and the availability of patient-reported outcomes or social determinants of health data are examples of factors that researchers must consider when selecting a data set for research purposes. For the current review, the authors summarized the advantages and disadvantages of various national data sets for cohort studies in cancer populations.

Education and employment among patients with childhood-onset epilepsy in adulthood: A population-based cohort study.

OBJECTIVE: This study explored the association of childhood-onset epilepsy (COE) with educational attainment, adulthood employment, and income. METHODS: A population-based cohort of 312 children with COE was identified from Tampere University Hospital, Finland. Population Register Center formed a matched random population sample of 1248 children without COE as a reference cohort. The two cohorts were linked to the Statistics Finland database to obtain information on educational attainment, employment status, and income. Fisher's exact test was used to compare employment and graduation. Independent samples t-test was used for analyzing graduation grades and the Mann-Whitney test was used for analyzing yearly income. Results were stratified by sex and disability. RESULTS: During a follow-up of 25 years, a substantially higher proportion of the patients never entered the workforce, 37 % (109/312) compared with 4 % (44/1248) for the referents without COE (p < 0.001). A two-fold difference was observed for COE patients without other disabilities (7.7 %, 13/169, p = 0.01). No clear difference was found in long-term employment between the COE without disabilities and the referents (67 %, 114/169 versus 74 %, 920/1248, p = 0.087). The patients with COE had worse lower secondary school graduation grade averages (7.36 vs 7.6, p = 0.004) and graduation rates (64 % vs 98 %, p < 0.001), the patients without disabilities had similar results to referents (7.43, p = 0.07, 98 %). Of the patients with COE, 18 % graduated from college compared to 38 % of the referents (p < 0.001). The median income was lower in males and females with COE of all ages compared to the referents. The COE patients without additional mental or physical disabilities had income comparable to the healthy referents. 143 patients (46 %) had additional disabilities. SIGNIFICANCE: Patients with COE have lower educational attainment, stable employment, and income. Patients without disabilities also have an increased risk of unemployment, but those capable of entering the workforce have stable careers with earnings comparable to the rest of the population.

Health map for HealthGap: Defining a geographical catchment to examine cardiovascular risk in Victoria, Australia.

The HealthGap study aimed to understand cardiovascular risk among Indigenous Australians in Victoria using linked administrative data. A key challenge was differing spatial coverages of sources: state-level data for risk factors but cardiovascular outcomes for three hospitals. Catchments were defined based on hospital postcodes to estimate denominator populations for risk modelling: first- and second-order neighbours, and spatial distribution of outcomes ('spatial event distribution'). Catchment coverage was assessed through proportions of patients presenting to study hospitals from catchment postcodes. The spatial event distribution performed best, capturing 82% events overall (first-order:40%; second-order:64%) and 65% Indigenous (27% and 45%). No approach excluded proximal non-study hospitals. Spatial event distributions could help define denominator populations when geographic information on outcome data is available but may not avoid potential misclassification.

Healthcare-seeking behaviour preceding diagnosis of Lyme neuroborreliosis: population-based nationwide matched nested case-control study.

OBJECTIVES: To identify diagnostic opportunities, we investigated healthcare-seeking behaviour among patients with Lyme neuroborreliosis (LNB) within 28 weeks before diagnosis. METHODS: We conducted a population-based, nationwide matched nested case-control study (Denmark, 2009-2021). As cases, we included all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis). We randomly selected controls from the general population and matched 10:1 on date of birth and sex. Exposures were assignment of diagnostic codes for symptoms, contact to medical specialties, medical wandering, and undergoing diagnostic procedures. We calculated the weekly and 3-month proportions of individuals with exposures and calculated absolute risk differences with corresponding 95% CI. RESULTS: We included 1056 cases with LNB and 10 560 controls. Within 3 months before diagnosis, the most frequent assigned symptoms were pain (difference: 13.0%, 95% CI: 10.9-15.1). Cases with LNB exhibited increased contact with most specialties, particularly general practitioners (difference: 48.7%, 95% CI: 46.0-51.4), neurology (difference: 14.3%, 95% CI: 11.7-16.8), and internal medicine (difference: 11.1%, 95% CI: 8.7-13.5), and medical wandering (difference: 17.1%, 95% CI: 14.3-20.0). Common diagnostic procedures included imaging of the brain (difference: 10.2, 95% CI: 8.3-12.1), the spine (difference: 8.8%, 85% CI: 7.0-10.6), and the abdomen (difference: 7.2%, 95% CI: 5.4-9.1). The increase in healthcare-seeking behaviour was observed ≤12 weeks preceding diagnosis. DISCUSSION: Pain appears to be an ambiguous symptom of LNB, potentially contributing to delays in establishing the correct diagnosis. It would be difficult to identify patients with LNB more effectively as the increased healthcare-seeking behaviour preceding diagnosis is distributed across many medical specialties.

Prescription medication use in the 10 years prior to diagnosis of young onset Alzheimer's disease: a nationwide nested case-control study.

BACKGROUND: Patients with young onset Alzheimer's disease (YOAD) face long diagnostic delays. Prescription medication use may provide insights into early signs and symptoms, which may help facilitate timely diagnosis. METHODS: In a register-based nested case-control study, we examined medication use for everyone diagnosed with YOAD in a Danish memory clinic during 2016-2020 compared to cognitively healthy controls. Prescription medication use were grouped into 13 overall categories (alimentary tract and metabolism, blood and blood forming organs, cardiovascular system, dermatologicals, genitourinary system and sex hormones, systemic hormonal preparations, antiinfectives for systemic use, antineoplastic and immunomodulating agents, musculo-skeletal system, nervous system, antiparasitic products, respiratory system, and sensory organs). Further stratifications were done for predetermined subcategories with a use-prevalence of at least 5% in the study population. Conditional logistic regression produced odds ratios, which given the use of incidence-density matching is interpretable as incidence rate ratios (IRRs). The association between prescription medication use and subsequent YOAD diagnosis was examined in the entire 10-year study period and in three time-intervals. RESULTS: The study included 1745 YOAD cases and 5235 controls. In the main analysis, several overall categories showed significant associations with YOAD in one or more time-intervals, namely blood and blood forming organs and nervous system. Prescription medication use in the nervous system category was increased for YOAD cases compared to controls already 10->5 years prior to diagnosis (IRR 1.17, 95% CI 1.05-1.31), increasing to 1.57 (95% CI 1.39-1.78) in the year preceding diagnosis. This was largely driven by antidepressant and antipsychotic use, and especially prominent for first-time users. CONCLUSIONS: In this study, medication use in several categories was associated with YOAD. Onset of treatment-requiring psychiatric symptoms such as depression or psychosis in mid-life may serve as potential early indicators of YOAD.

Registry-based randomised controlled trials: conduct, advantages and challenges-a systematic review.

BACKGROUND: Registry-based randomised controlled trials (rRCTs) have been described as pragmatic studies utilising patient data embedded in large-scale registries to facilitate key clinical trial procedures including recruitment, randomisation and the collection of outcome data. Whilst the practice of utilising registries to support the conduct of randomised trials is increasing, the use of the registries within rRCTs is inconsistent. The purpose of this systematic review is to explore the conduct of rRCTs using a patient registry to facilitate trial recruitment and the collection of outcome data, and to discuss the advantages and challenges of rRCTs. METHODS: A systematic search of the literature was conducted using five databases from inception to June 2020: PubMed, Embase (through Ovid), CINAHL, Scopus and the Cochrane Controlled Register of Trials (CENTRAL). The search strategy comprised of MESH terms and key words related to rRCTs. Study selection was performed independently by two reviewers. A risk of bias for each study was completed. A narrative synthesis was conducted. RESULTS: A total 47,862 titles were screened and 24 rRCTs were included. Eleven rRCTs (45.8%) used more than one registry to facilitate trial conduct. Six rRCTs (25%) randomised participants via a specific randomisation module embedded within a registry. Recruitment ranged between 209 to 106,000 participants. Advantages of rRCTs are recruitment efficiency, shorter trial times, cost effectiveness, outcome data completeness, smaller carbon footprint, lower participant burden and the ability to conduct multiple trials from the same registry. Challenges are data collection/management, quality assurance issues and the timing of informed consent. CONCLUSIONS: Optimising the design of rRCTs is dependent on the capabilities of the registry. New registries should be designed and existing registries reviewed to enable the conduct of rRCTs. At all times, data management and quality assurance of all registry data should be given key consideration. We suggest the inclusion of the term 'registry-based' in the title of all rRCT manuscripts and a clear simple breakdown of the registry-based conduct of the trial in the abstract to facilitate indexing in the major databases.

Educational gradient in hip fracture incidence in Norway. The Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

Examining fracture dynamics by socioeconomic status may inform healthcare and prevention. We found a higher risk of hip fracture in men and women with lower educational level in Norway. However, by age 90 + years, the cumulative incidence was higher in those with higher education, due to their higher life expectancy. PURPOSE: Socioeconomic gradients are seen for several health outcomes in high-income countries. We aimed to examine possible educational gradients in risk of hip fracture in Norway and to describe the cumulative incidence of hip fracture by educational level. METHODS: In a population-wide cohort of Norwegians aged ≥ 50 years, information on attained education from Statistics Norway was linked to hospital-treated hip fractures and deaths during 2002-2019. We estimated relative fracture risk by educational level (primary, secondary or tertiary) in Cox proportional hazards regression. We also examined the cumulative incidence over attained age by gender and educational level in competing risk regression. RESULTS: The population included N = 1,389,858 individuals with 135,938 incident hip fractures. Compared with men who had attained tertiary education, hazard ratios (95% confidence intervals) for hip fracture were 1.44 (1.40, 1.49) in men with primary education only and 1.26 (1.22, 1.29) in men with secondary education. In women, the corresponding estimates were 1.28 (1.25, 1.31) and 1.16 (1.13, 1.19). In the age range 50 to 90 years, the highest cumulative incidence of hip fracture was seen in those with primary education. The gradient gradually diminished with advancing age and was reversed in the oldest (> 90 years) in both genders. CONCLUSIONS: There was a clear educational gradient in hip fracture incidence in both men and women in Norway, with a higher risk in people with lower education. Despite this, the cumulative incidence of hip fracture in old age was highest among people with higher education, due to their higher life expectancy.

Long-term survival following out-of-hospital cardiac arrest in women and men: Influence of comorbidities, social characteristics, and resuscitation characteristics.

AIM: We aimed to study sex differences in long-term survival following out-of-hospital cardiac arrest (OHCA) compared to the general population, and determined associations for comorbidities, social characteristics, and resuscitation characteristics with survival in women and men separately. METHODS: We followed 2,452 Danish (530 women and 1,922 men) and 1,255 Dutch (259 women and 996 men) individuals aged ≥25 years, who survived 30 days post-OHCA in 2009-2015, until 2019. Using Poisson regression analyses we assessed sex differences in long-term survival and sex-specific associations of characteristics mutually adjusted, and compared survival with an age- and sex-matched general population. The potential predictive value was assessed with the Concordance-index. RESULTS: Post-OHCA survival was longer in women than men (adjusted incidence rate ratio (IRR) for mortality 0.74, 95%CI 0.61-0.89 in Denmark; 0.86, 95%CI 0.65-1.15 in the Netherlands). Both sexes had a shorter survival than the general population (e.g., IRR for mortality 3.07, 95%CI 2.55-3.70 and IRR 2.15, 95%CI 1.95-2.37 in Danish women and men). Higher age, glucose lowering medication, no dyslipidaemia medication, unemployment, and a non-shockable initial rhythm were associated with shorter survival in both sexes. Cardiovascular medication, depression/anxiety medication, living alone, low household income, and residential OHCA location were associated with shorter survival in men. Not living with children and bystander cardiopulmonary resuscitation provision were associated with shorter survival in women. The Concordance-indexes ranged from 0.51 to 0.63. CONCLUSIONS: Women survived longer than men post-OHCA. Several characteristics were associated with long-term post-OHCA survival, with some sex-specific characteristics. In both sexes, these characteristics had low predictive potential.

The risk of Type 1 diabetes in children born after ART: a Nordic cohort study from the CoNARTaS group.

STUDY QUESTION: Do children born after ART have a higher risk of developing Type 1 diabetes (DM1) than children conceived without ART? SUMMARY ANSWER: The risk of DM1 was similar for children conceived with and without ART, and there were no clear differences in risk according to method of fertility treatment. WHAT IS KNOWN ALREADY: ART is associated with a higher risk of adverse perinatal outcomes, and the risk depends on the method of ART. The Developmental Origins of Health and Disease theory proposes that prenatal stress can provoke changes in endocrine processes which impact health later in life. STUDY DESIGN SIZE DURATION: A Nordic register-based cohort study was carried out, including all children born in Denmark (birth years 1994-2014), Finland (1990-2014), and Norway (1984-2015). The study included 76 184 liveborn singletons born after ART and 4 403 419 born without ART. Median follow-up was 8.3 and 13.7 years in the ART and non-ART group, respectively. PARTICIPANTS/MATERIALS SETTING METHODS: The cohort, initiated by the Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS), was established by linking national registry data from the medical birth registries and national patient registries available in the Nordic countries. We performed multivariable logistic regression analyses for the birth year intervals 1984-1990, 1991-1995, 1996-2000, 2001-2005, 2006-2010, and 2011-2015, while adjusting for year of birth within each interval, sex of the child, parity, maternal age, maternal diabetes, and maternal smoking during pregnancy as potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 259 (3.4‰) children born after ART were diagnosed with DM1, while this was the case for 22 209 (5.0‰) born without ART, corresponding to an adjusted odds ratio of 0.98 (95% CI: 0.861.11). Within the different birth year intervals, no significant difference in risk of DM1 between the two groups was found, except for the youngest cohort of children born 2011-2015 where ART was associated with a higher risk of DM1. We found no significant differences in risk of DM1 when comparing children born after IVF versus ICSI or fresh versus frozen embryo transfer, but with only few cases in each group. LIMITATIONS REASONS FOR CAUTION: The main limitation of the study is the relatively short follow-up time. The incidence rate of DM1 peaks during ages 10-14 years, hence a longer follow-up would benefit all analyses and, in particular, the subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Overall, our findings are reassuring especially considering the concomitantly increasing number of children born from ART and the increasing incidence of DM1 globally. STUDY FUNDING/COMPETING INTERESTS: This Nordic registry study has been supported by the Nordic Trial Alliance/NORDFORSK and Rigshospitalets Research Foundation. The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. None of the authors has any conflicts of interest to declare regarding this study. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Presence and development of diabetic retinopathy in 16 999 patients with type 1 diabetes in the Danish Registry of Diabetic Retinopathy.

PURPOSE: To evaluate the five-year incidence of diabetic retinopathy (DR) and associated risk markers in patients with type 1 diabetes in the national Danish DR-screening programme. METHODS: Based on national data, we included all 16 999 patients with type 1 diabetes in the Danish Registry of Diabetic Retinopathy, who attended the national screening programme in the period 2013-2018. According to the worse eye at first screening, DR was classified (levels 0-4) and linked with various national health registries to retrieve information on diabetes duration, systemic comorbidity, and medication. RESULTS: At first screening, median age and duration of diabetes were 45.0 and 16.7 years, and 57.5% were males. The prevalence and five-year incidences for DR and progression to proliferative DR (PDR) were 44.2%, 8.9% and 2.0%, respectively. In multivariable Cox models, the incidence endpoints were associated with duration of diabetes (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.63-1.89, and HR 2.04, 95% CI 1.73-2.40 per 10 years), moderately low Charlson Comorbidity Index score (HR 1.27, 95% CI 1.10-1.47, and HR 2.80, 95% CI 2.23-3.51), and use of blood pressure lowering medication (HR 1.20, 95% CI 1.05-1.36, and HR 1.98, 95% CI 1.53-2.57). CONCLUSION: In a study of all patients with type 1 diabetes from the Danish DR-screening programme, we identified duration of diabetes, systemic disease and use of anti-hypertensive treatment as consistent risk markers for incident and progressive DR.

Exploring dual diagnosis in opioid agonist treatment patients: a registry-linkage study in Czechia and Norway.

BACKGROUND: Knowledge of co-occurring mental disorders (termed 'dual diagnosis') among patients receiving opioid agonist treatment (OAT) is scarce. This study aimed (1) to estimate the prevalence and structure of dual diagnoses in two national cohorts of OAT patients and (2) to compare mental disorders between OAT patients and the general populations stratified on sex and standardized by age. METHODS: A registry-linkage study of OAT patients from Czechia (N = 4,280) and Norway (N = 11,389) during 2010-2019 was conducted. Data on mental disorders (F00-F99; ICD-10) recorded in nationwide health registers were linked to the individuals registered in OAT. Dual diagnoses were defined as any mental disorder excluding substance use disorders (SUDs, F10-F19; ICD-10). Sex-specific age-standardized morbidity ratios (SMR) were calculated for 2019 to compare OAT patients and the general populations. RESULTS: The prevalence of dual diagnosis was 57.3% for Czechia and 78.3% for Norway. In Czechia, anxiety (31.1%) and personality disorders (25.7%) were the most prevalent, whereas anxiety (33.8%) and depression (20.8%) were the most prevalent in Norway. Large country-specific variations were observed, e.g., in ADHD (0.5% in Czechia, 15.8% in Norway), implying differences in screening and diagnostic practices. The SMR estimates for any mental disorders were 3.1 (females) and 5.1 (males) in Czechia and 5.6 (females) and 8.2 (males) in Norway. OAT females had a significantly higher prevalence of co-occurring mental disorders, whereas SMRs were higher in OAT males. In addition to opioid use disorder (OUD), other substance use disorders (SUDs) were frequently recorded in both countries. CONCLUSIONS: Results indicate an excess of mental health problems in OAT patients compared to the general population of the same sex and age in both countries, requiring appropriate clinical attention. Country-specific differences may stem from variations in diagnostics and care, reporting to registers, OAT provision, or substance use patterns.

Considerations for the use of biochemical laboratory registry data in clinical and public health research.

OBJECTIVES: To inform researchers of central considerations and limitations when applying biochemical laboratory-generated registry data in clinical and public health research. STUDY DESIGN AND SETTING: After review of literature on registry-based studies and the utilization of clinical laboratory registry data, relevant paragraphs and their applicability toward the creation of considerations for the use of biochemical registry data in research were evaluated. This led to the creation of an initial ten considerations. These were elaborated, edited, and merged after several read-throughs by all authors and discussed thoroughly under influence by the authors' personal experiences with laboratory databases and research registries in Denmark, leading to the formulation of five central considerations with corresponding items and illustrative examples. RESULTS: We recommend that the following considerations should be addressed in studies relying on biochemical laboratory-generated registry data: why are biochemical laboratory data relevant to examine the hypothesis, and how were the variable(s) utilized in the study? What were the primary indications for specimen collection in the study population of interest? Were there any pre-analytical circumstances that could influence the test results? Are data comparable between producing laboratories and within the single laboratory over time? Is the database representative in terms of completeness of study populations and key variables? CONCLUSION: It is crucial to address key errors in laboratory registry data and acknowledge potential limitations.

Incidence of ADHD medication use among Finnish children and adolescents in 2008-2019: a need for practice changes?

AIMS: This study examined the incidence of attention-deficit/hyperactivity disorder medication among children and adolescents by sex and age group in Finland during 2008-2019. METHODS: The data on children and adolescents aged 6-18 years receiving reimbursement for any attention-deficit/hyperactivity disorder medication was collected from the nationwide register on reimbursed purchases. The incidence was calculated as a ratio of the number of new users and the number of age and sex-matched population at risk. Negative binomial models were used to calculate rate ratios (RRs). RESULTS: In 2019, the incidence of attention-deficit/hyperactivity disorder medication was 13.4 per 1000 boys and 4.8 per 1000 girls. Among boys, the incidence became 3.7 times greater during the observed years (RR 95% confidence interval (CI) 2.0, 6.5, P<0.0001), whereas in girls it was 7.6 times greater (RR 95% CI 2.1, 27.4, P=0.0019). The boys had 2.8 times the incidence rate compared with the girls (RR 95% CI 2.2, 3.6, P<0.0001). The increase was associated with age only among boys (P=0.0001). The highest incidence rate 23.4 per 1000 individuals (95% CI 22.5, 24.4) was found in 2019 among 6-8-year-old boys. CONCLUSIONS: The incidence of attention-deficit/hyperactivity disorder medication use among children and adolescents increased significantly in Finland during the study period. Incidence was higher among boys, but the increase was greater among girls. The most common group to start attention-deficit/hyperactivity disorder medication was 6-8-year-old boys. These findings warrant critical evaluation of the diagnostic and treatment policies currently available in Finland for the treatment of attention-deficit/hyperactivity disorder and related symptoms.

Characteristics and critical care interventions in drowning patients treated by the Danish Air Ambulance from 2016 to 2021: a nationwide registry-based study with 30-day follow-up.

BACKGROUND: Improving oxygenation and ventilation in drowning patients early in the field is critical and may be lifesaving. The critical care interventions performed by physicians in drowning management are poorly described. The aim was to describe patient characteristics and critical care interventions with 30-day mortality as the primary outcome in drowning patients treated by the Danish Air Ambulance. METHODS: This retrospective cohort study with 30-day follow-up identified drowning patients treated by the Danish Air Ambulance from January 1, 2016, through December 31, 2021. Drowning patients were identified using a text-search algorithm (Danish Drowning Formula) followed by manual review and validation. Operational and medical data were extracted from the Danish Air Ambulance database. Descriptive analyses were performed comparing non-fatal and fatal drowning incidents with 30-day mortality as the primary outcome. RESULTS: Of 16,841 dispatches resulting in a patient encounter in the six years, the Danish Drowning Formula identified 138 potential drowning patients. After manual validation, 98 drowning patients were included in the analyses, and 82 completed 30-day follow-up. The prehospital and 30-day mortality rates were 33% and 67%, respectively. The National Advisory Committee for Aeronautics severity scores from 4 to 7, indicating a critical emergency, were observed in 90% of the total population. They were significantly higher in the fatal versus non-fatal group (p < 0.01). At least one critical care intervention was performed in 68% of all drowning patients, with endotracheal intubation (60%), use of an automated chest compression device (39%), and intraosseous cannulation (38%) as the most frequently performed interventions. More interventions were generally performed in the fatal group (p = 0.01), including intraosseous cannulation and automated chest compressions. CONCLUSIONS: The Danish Air Ambulance rarely treated drowning patients, but those treated were severely ill, with a 30-day mortality rate of 67% and frequently required critical care interventions. The most frequent interventions were endotracheal intubation, automated chest compressions, and intraosseous cannulation.

Diabetic retinopathy as an independent marker of cardiovascular disease in type 1 diabetes: Results from a nationwide longitudinal matched case-cohort study.

PURPOSE: To investigate diabetic retinopathy (DR) as a potential marker of cardiovascular disease (CVD) in adults with type 1 diabetes attending the Danish DR-screening programme and non-diabetes adults. METHODS: In this registry-based matched case-cohort study, we identified 16 547 adults with type 1 diabetes, who were registered in the Danish Registry of Diabetic Retinopathy (DiaBase). Each case was age- and sex-matched by five non-diabetes individuals (n = 82 399), and odds ratios (ORs) and hazard ratios (HRs) were estimated for incident and upcoming CVD in multivariable models. RESULTS: Adults with type 1 diabetes (median age 44.5 years, 57.6% male) were more likely to have prevalent CVD (OR 1.29; 95% CI, 1.20-1.38) and to develop CVD within 5 years (HR 1.19; 95% CI, 1.08-1.30) as compared to non-diabetes control. However, adults without DR were less likely to develop CVD (HR 0.84; 95% CI, 0.72-0.97) compared to the reference population. For adults with type 1 diabetes, there was an increasing risk for incident CVD for increasing levels of DR (HR 1.33, 1.95, 1.71 and 2.39 for DR-levels 1-4, respectively). Patients with CVD at the time of the first screening had a higher risk to develop DR during follow-up (HR 1.23; 95% CI, 1.02-1.49). CONCLUSION: In a nationwide matched case-cohort study adjusted for potential confounders, DR was identified as an independent marker of prevalent and incident CVD in type 1 diabetes with increasing risk demonstrated for higher levels of DR. Likewise, CVD also independently predicted the risk of incident DR.

SARS-CoV-2 infection during pregnancy and the risk of adverse maternal outcomes in the Republic of Georgia: a national birth registry-based cohort study.

BACKGROUND: Georgia experienced an increase in maternal deaths (MD) during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which warrants further investigation. This study aimed to assess associations between timing of SARS-CoV-2 infection during pregnancy and MD, post-delivery intensive care unit (ICU) admission, and caesarean section (CS) delivery. METHODS: We performed a national birth registry-based cohort study of pregnant women who had completed 22 weeks of gestation and delivered between February 28, 2020, and August 31, 2022. The data were linked to coronavirus disease 2019 (COVID-19) testing, vital, and immunization registries. Pregnant women were classified into three groups: confirmed SARS-CoV-2 infection from conception through 31 days before delivery; confirmed infection within 30 days before or at delivery; and women negative for SARS-CoV-2 infection or without any test results (reference group). Multivariable logistic regression was used to calculate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Among 111,493 pregnant women, 16,751 had confirmed infection during pregnancy, and 7,332 were fully vaccinated against COVID-19 before delivery. Compared to the reference group, those with confirmed infection within 30 days before or at delivery experienced increased odds of MD (aOR: 43.11, 95% CI, 21.99-84.55), post-delivery ICU admission (aOR: 5.20, 95% CI, 4.05-6.67), and CS delivery (aOR: 1.11, 95% CI, 1.03-1.20). CONCLUSIONS: Pregnant women in Georgia with confirmed SARS-CoV-2 infection within 30 days before or at delivery experienced a considerably higher risk of MD and post-delivery ICU admission and a slightly higher risk for CS delivery. Additionally, the results highlighted that most pregnant women were not vaccinated against COVID-19. These findings should alert stakeholders that adherence to public health preventive measures needs to be improved.

Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Mapping morbidity 10 years prior to a diagnosis of young onset Alzheimer's disease.

INTRODUCTION: Early symptoms in young onset Alzheimer's disease (YOAD) may be misinterpreted, causing delayed diagnosis. This population-based study aimed to map morbidity prior to YOAD diagnosis. METHODS: In a register-based incidence density matched nested case-control study, we examined hospital-diagnosed morbidity for people diagnosed with YOAD in Danish memory clinics during 2016-2020 compared to controls in a 10-year period. Conditional logistic regression produced incidence rate ratios (IRRs). RESULTS: The study included 1745 cases and 5235 controls. YOAD patients had a higher morbidity burden in the year immediately before dementia diagnosis, for certain disorders up to 10 years before. This was especially evident for psychiatric morbidity with the highest increased IRRs throughout the entire period and IRR 1.43 (95% confidence interval 1.14-1.79) in the 5-10-years before dementia diagnosis. DISCUSSION: YOAD patients display a different pattern of morbidity up to 10 years prior to diagnosis. Awareness of specific alterations in morbidity may improve efforts toward a timely diagnosis. HIGHLIGHTS: Retrospective, nested case-control study of young onset Alzheimer's disease (YOAD). YOAD cases had a higher morbidity burden than controls. YOAD cases had a higher psychiatric morbidity burden up to 10 years before diagnosis. Altered morbidity patterns could serve as an early warning sign of YOAD.