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Background General practitioners encounter the vast majority of patients with Epstein-Barr virus-related disease, i.e. infectious mononucleosis in children and adolescents. With the expanding knowledge regarding the multifaceted role of Epstein-Barr virus in both benign and malignant disease we chose to focus this review on Epstein-Barr virus-related conditions with relevance to the general practitioners. A PubMed and Google Scholar literature search was performed using PubMed’s MeSH terms of relevance to Epstein-Barr virus/infectious mononucleosis in regard to complications and associated conditions. Main text In the present review, these included three early complications; hepatitis, splenic rupture and airway compromise, as well as possible late conditions; lymphoproliferative cancers, multiple sclerosis, rheumatoid arthritis, and chronic active Epstein-Barr virus infection. This review thus highlights recent advances in the understanding of Epstein-Barr virus pathogenesis, focusing on management, acute complications, referral indications and potentially associated conditions. Conclusions Hepatitis is a common and self-limiting early complication to infectious mononucleosis and should be monitored with liver tests in more symptomatic cases. Splenic rupture is rare. Most cases are seen within 3 weeks after diagnosis of infectious mononucleosis and may occur spontaneously. There is no consensus on the safe return to physical activities, and ultrasonic assessment of spleen size may provide the best estimate of risk. Airway compromise due to tonsil enlargement is encountered in a minority of patients and should be treated with systemic corticosteroids during hospitalization. Association between lymphoproliferative cancers, especially Hodgkin lymphoma and Burkitt lymphoma, and infectious mononucleosis are well-established. Epstein-Barr virus infection/infectious mononucleosis as a risk factor for multiple sclerosis has been documented and may be linked to genetic susceptibility. Chronic active Epstein-Barr virus infection is rare. However, a general practitioner should be aware of this as a differential diagnosis in patients with persisting symptoms of infectious mononucleosis for more than 3 months.

The diagnostic delay in celiac disease (CD) is currently a burden for individual and society. Biochemical tests may be used in risk-identification of CD to reduce the diagnostic delay, and we aimed to explore prediction models for CD antibody seropositivity. We developed two prediction models in a cohort study using data from primary care in greater Copenhagen (2006–2015). All patients with CD antibody tests were included. Two candidate sets of predictors were considered: (1) all blood tests measured, (2) tests deemed clinically relevant pre-study or previously studied. Both models assessed test results 5 years before CD-testing. We developed and evaluated prediction models in 10-fold cross-validation framework for each set of predictors. Four machine learning methods were combined in stacked models using SuperLearner. 54,877 patients were included, 672 CD antibody seropositive. Cross-validated estimated area under the curves were 0.68 and 0.63. Distributions of predicted probabilities overlapped substantially between patients with CD antibody seropositivity and seronegativity. Food allergen antibody and IgA were the most important predictors. Biochemical tests had low predictive power but provided methodological insights for future models. These may improve by combining biochemical tests with other clinical information but should preferably aim to stay clinically implementable.

It has been argued that persons with severe mental illness (SMI) receive poorer treatment for somatic comorbidities. This study assesses the treatment rates of glucose-lowering and cardiovascular medications among persons with incident type 2 diabetes (T2D) and SMI compared to persons with T2D without SMI. We identified persons ≥30 years old with incident diabetes (HbA 1c ≥ 48 mmol/mol and/or glucose ≥ 11.0 mmol/L) from 2001 through 2015 in the Copenhagen Primary Care Laboratory (CopLab) Database. The SMI group included persons with psychotic, affective, or personality disorders within five years preceding the T2D diagnosis. Using a Poisson regression model, we calculated the adjusted rate ratios (aRR) for the redemption of various glucose-lowering and cardiovascular medications up to ten years after T2D diagnosis. We identified 1,316 persons with T2D and SMI and 41,538 persons with T2D but no SMI. Despite similar glycemic control at diagnosis, persons with SMI redeemed a glucose-lowering medication more often than persons without SMI in the period 0.5–2 years after the T2D diagnosis; for example, the aRR was 1.05 (95% CI 1.00–1.11) in the period 1.5–2 years after the T2D diagnosis. This difference was mainly driven by metformin. In contrast, persons with SMI were less often treated with cardiovascular medications during the first 3 years after T2D diagnosis, e.g., in the period 1.5–2 years after T2D diagnosis, the aRR was 0.96 (95% CI 0.92–0.99). For people with SMI in addition to T2D, metformin is more likely to be used in the initial years after T2D diagnosis, while our results suggest potential room for improvement regarding the use of cardiovascular medications.

The Copenhagen General Practice Laboratory (CGPL) was founded in 1922 to provide paraclinical analyses to the primary health-care sector in Copenhagen. At the end of 2015, CGPL was closed and the CopLab database was established to make CGPL data available for research. We isolated tests performed at the CGPL with clinically relevant test results. The database was linked to national registers containing health, social, and demographic information. Results are presented with descriptive statistics showing counts, percentages, medians, and interquartile ranges (IQR). The CopLab database includes 1,373,643 unique individuals from primary care with test results from laboratory analyses of blood/urine/semen as well as cardiac and lung function tests collected by CGPL from greater Copenhagen from 2000 to 2015. The CopLab database holds nearly all test results requested by general practitioners throughout years 2000 to 2015 for residents in the greater Copenhagen area. The median age of the individuals was 51 years and 59.7% were females. Each individual has a median of 4 requisitions. More than 1 million participants are currently alive and living in Denmark and may be followed in national registries such as the Danish National Patient Registry, Laboratory Database, National Prescription Database etc.

Background The prevalence of chronic kidney disease (CKD) is increasing globally. Early diagnosis in primary care may have a role in ensuring proper intervention. We aimed to determine the prevalence and outcome of CKD in primary care. Methods We performed an observational cohort study in primary care in Copenhagen (2001–2015). Outcomes were stroke, myocardial infarction (MI), heart failure (HF), peripheral artery disease (PAD), all-cause- and cardiovascular mortality. We combined individuals with normal kidney function and CKD stage 2 as reference. We conducted cause-specific Cox proportional regressions to calculate the hazard ratios for outcomes according to CKD group. We explored the associations between kidney function and the outcomes examined using eGFR as a continuous variable modelled with penalised splines. All models were adjusted for age, gender, diabetes, hypertension, existing CVD, heart failure, LDL cholesterol and use of antihypertensive treatment. Results We included 171,133 individuals with at least two eGFR measurements of which the majority (n = 157,002) had eGFR > 60 ml/min/1.73m 2 at index date, and 0.05% were in CKD stage 5. Event rates were low in eGFR > 60 ml/min/1.73m 2 but increased in those with higher stages of CKD. In adjusted analyses we observed an increase in hazard rates for every outcome with every increment in CKD stage. Compared to the reference group, individuals in CKD stage 4 had double the hazard rate of PAD, MI, cardiovascular and all-cause mortality. Conclusions Our data from a large primary care cohort demonstrate an early increase in the risk of adverse outcomes already at CKD stage 3. This underlines the importance of studying early intervention in primary care.

To investigate possible biochemical abnormalities associated with celiac disease (CD) antibody positivity in a primary health care setting and thereby identify predictors that could potentially reduce diagnostic delay and underdiagnosis of CD. This observational cohort study included measurements of CD antibodies in the Copenhagen Primary Care Laboratory (CopLab) database from 2000 to 2015; CD antibody positivity was defined as tissue transglutaminase antibody IgA or IgG ≥ 7 kU/L and/or deamidated gliadin peptide antibody IgG ≥ 10 kU/L. Individuals with a prior diagnosis of CD were excluded. We examined differences between individuals with positive and negative CD antibody tests regarding the results of biochemical tests performed six months before and one month after the date of the CD antibody test. We identified 76,265 measurements of CD antibodies during 2000–2015, and 57,061 individuals met the inclusion criteria (706 antibody-positive and 56,355 antibody-negative). We found lower ferritin, hemoglobin, cobalamin and folic acid levels and higher levels of transferrin, ALAT (alanine transaminase), and alkaline phosphate among individuals with a positive CD antibody test. Furthermore, we illustrated more measurements below the sex-specific reference intervals for hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), ferritin, cobalamin and folic acid among individuals with a positive CD antibody test. This study identified several biochemical abnormalities associated with CD antibody positivity among individuals referred to CD antibody testing. The pattern of abnormalities suggested that micronutrient deficiencies were prevalent among CD antibody-positive individuals, confirming malabsorption as a sign of CD. These findings illustrate the possibility of reducing diagnostic delay and underdiagnosis of CD.

Purpose The quality of patient-reported outcome (PRO) data can be compromised by non-response (NR) to scheduled questionnaires, particularly if reasons for NR are related to health problems, which may lead to unintended bias. The aim was to investigate whether electronic reminders and real-time monitoring improve PRO completion rate. Methods The population-based study “Quality of life in Danish multiple myeloma patients” is a longitudinal, multicentre study with consecutive inclusion of treatment-demanding newly diagnosed or relapsed patients with multiple myeloma. Education of study nurses in the avoidance of NR, electronic reminders, 7-day response windows and real-time monitoring of NR were integrated in the study. Patients complete PRO assessments at study entry and at 12 follow-up time points using electronic or paper questionnaires. The effect of the electronic reminders and real-time monitoring were investigated by comparison of proportions of completed questionnaires before and after each intervention. Results The first 271 included patients were analysed; of those, 249 (85%) chose electronic questionnaires. Eighty-four percent of the 1441 scheduled PRO assessments were completed within the 7-day response window and 11% after real-time monitoring, achieving a final PRO completion rate of 95%. A significant higher proportion of uncompleted questionnaires were completed after the patients had received the electronic reminder and after real-time monitoring. Conclusions Electronic reminders and real-time monitoring contributed to a very high completion rate in the study. To increase the quality of PRO data, we propose integrating these strategies in PRO studies, however highlighting that an increase in staff resources is required for implementation.

To examine whether education level influences screening, monitoring, and treatment of hypercholesterolemia. Epidemiological cohort study. Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre. Cholesterol blood test results ordered by general practitioners in Greater Copenhagen were retrieved from 2000-2018. Using the International Standard Classification of Education classification, the population was categorized by length of education in three groups (basic education; up to 10 years, intermediate education; 11-12 years, advanced education; 13 years or more). The database comprised 13,019,486 blood sample results from 653,903 patients. Frequency of lipid measurement, prevalence of statin treatment, age and comorbidity at treatment initiation, total cholesterol threshold for statin treatment initiation, and achievement of treatment goal. The basic education group was measured more frequently (1.46% absolute percentage difference of total population measured [95% CI 0.86%-2.05%] in 2000 and 9.67% [95% CI 9.20%-10.15%] in 2018) over the period compared to the intermediate education group. The advanced education group was younger when receiving first statin prescription (1.87 years younger [95% CI 1.02-2.72] in 2000 and 1.06 years younger [95% CI 0.54-1.58 in 2018) compared to the intermediate education group. All education groups reached the treatment goals equally well when statin treatment was initiated. Higher education was associated with earlier statin prescription, although the higher educated group was monitored less frequently. There was no difference in reaching treatment goal between the three education groups. These findings suggest patients with higher education level achieve an earlier dyslipidemia prevention intervention with an equally satisfying result compared to lower education patients. Key Points Little is known about the role of social inequality as a possible barrier for managing hypercholesterolemia in general practice. Increasing education level was associated to less frequent measurement and less frequent statin treatment. Patients with higher education level were younger, and less comorbidity at first statin prescription. Education level had no effect on frequency of statin treatment-initiated patients reaching the treatment goal was found.

Background Assessment of cancer patients´ quality of life (QoL) through patient-reported outcomes (PRO) during and after treatment is gaining ground. The HM-PRO is the first generic Haematological Malignancy specific PRO measure for use in clinical practice and clinical trials. Such generic tools are needed in Denmark. The study aim was to translate and cross-culturally adapt the HM-PRO into Danish and evaluate the psychometric properties. Methods Translation and cross-cultural adaptation of the original English HM-PRO into Danish followed established guidelines. After cognitive debriefing interviews, it underwent psychometric testing with a variety of hematologic malignancies. Construct validity, internal consistency, dimensionality, item response theory (IRT) and differential item functioning were investigated. Results 295 patients were included for psychometric evaluation; confirmatory factor and bifactor analyses for both HM-PRO parts provided good evidence to support the suggested factor structure (Cronbach’s-α Part-A = 0.81, Part-B = 0.84; Part-A CFA CFI = 0.922, TLI = 0.912; bi-factor CFI = 0.989, TLI = 0.978). IRT showed good item-fit and factor loadings and absence of local dependency. Conclusion The HM-PRO has demonstrated favourable psychometric properties and can be used broadly within the Danish Healthcare system to monitor symptoms as well as QoL impact of patients with haematological cancer and optimize patient engagement during routine cancer care. What is the new aspect of your work? In response to the intention of the Danish Health Authority to systematically collect PRO data on health-related QoL in Danish cancer patients, this study investigates the translation and cross-cultural adaptation of the original English HM-PRO into Danish. What is the central finding of your work? Few issues were met with the translation and adaptation of HM-PRO into Danish. What is (or could be) the specific clinical relevance of your work? The HM-PRO has demonstrated favourable psychometric properties and can be used broadly within the Danish Healthcare system to monitor symptoms as well as QoL impact of patients with haematological cancer and optimize patient engagement during routine cancer care.

Background The dynamics of pre-diagnostic lymphocytosis in patients with ensuing chronic lymphocytic leukemia (CLL) need to be explored as a better understanding of disease progression may improve treatment options and even lead to disease avoidance approaches. Our aim was to investigate the development of lymphocytosis prior to diagnosis in a population-based cohort of patients with CLL and to assess the prognostic information in these pre-diagnostic measurements. Methods All patients diagnosed with CLL in the Greater Copenhagen area between 2008 and 2016 were included in the study. Pre-diagnostic blood test results were obtained from the Copenhagen Primary Care Laboratory Database encompassing all blood tests requested by Copenhagen general practitioners. Using pre-diagnostic measurements, we developed a model to assess the prognosis following diagnosis. Our model accounts for known prognostic factors and corresponds to lymphocyte dynamics after diagnosis. Results We explore trajectories of lymphocytosis, associated with known recurrent mutations. We show that the pre-diagnostic trajectories are an independent predictor of time to treatment. The implementation of pre-diagnostic lymphocytosis slope groups improved the model predictions (compared to CLL-IPI alone) for treatment throughout the period. The model can manage the heterogeneous data that are to be expected from the real-world setting and adds further prognostic information. Conclusions Our findings further knowledge of the development of CLL and may eventually make prophylactic measures possible. Plain language summary While clinicians largely agree that patients with chronic lymphocytic leukemia (CLL) have increased levels of white blood cells in the years preceding their diagnosis, there is less certainty as to how and when this increase occurs. A better understanding of how white blood cell levels change during this period might help us to predict who will become ill and require treatment. In this work, we explore patterns of white blood cell growth and develop a tool to predict the time to treatment for CLL based on these growth rates. Using our tool in the clinic might help clinicians to decide who needs treatment for CLL and when, potentially leading to better outcomes for patients. Andersen et al. evaluate lymphocyte dynamics in chronic lymphocytic leukemia (CLL) patients prior to diagnosis. The authors develop a model to predict risk of requiring CLL treatment or death based on pre-diagnostic lymphocyte growth rates.