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Aims/hypothesisA head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin.MethodsThis randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.ResultsOf the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300.Conclusions/interpretationThere was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.Trial registrationClinicalTrials.gov NCT03078478FundingThis trial was funded by Novo Nordisk (Bagsvaerd, Denmark)

Introduction The Apgar score is routinely given at childbirth worldwide. A low Apgar score at 5 minutes is a strong predictor for neonatal death. Scores below 7 have been associated with higher risks of later neurologic disability. Few studies have assessed the association between Apgar score and school performance and intelligence. The existing literature points towards a possible association between Apgar score and later cognitive function, but the contradictions call for further investigation to fully understand the potential association. This study aimed to examine the possible association between Apgar score at 5 minutes and academic performance and intelligence in youth. Material and methods The study is a cohort study. The cohort consists of all Danish liveborn children in 1978–2000 (n = 1 450 681). Data regarding pregnancies, births, parents, school grades, and intelligence of the children were retrieved from different Danish registers. Multiple imputations were performed to avoid discarding data. After exclusion, the final cohort consisted of 1 005 241 children. Associations between Apgar score at 5 minutes and school graduation, grades and attendance, and intelligence scores from conscription were analyzed using univariate and multivariate logistic and linear regressions. Results No association was found between Apgar score and graduating primary school. Adjusted odds ratio (aOR) of graduating upper secondary education and attending conscription were significantly lower for children with scores below 7 compared with 7–10: graduating upper secondary education: Apgar 0–3: aOR 0.79 (95% CI 0.67–0.93), Apgar 4–6: aOR 0.86 (95% CI 0.81–0.93), attending conscription: Apgar 0–3: aOR 0.73 (95% CI 0.59–0.91), Apgar 4–6: aOR 0.73 (95% CI 0.66–0.80). The Apgar 4–6 group had significantly lower total mean primary school grade average: −0.13 (95% CI −0.21 to −0.054) and lower mean intelligence scores at conscription: −0.57 (95% CI −1.09 to −0.058). All other differences remained insignificant. Conclusions Performances when graduating school and attending conscription were overall equal regardless of Apgar score at 5 minutes. Chances of graduating primary school were the same irrespective of the score, but chances of graduating upper secondary education and attending conscription were significantly lower with scores below 7. The results suggest that children with scores below 7 may fail to appear at upper secondary education and conscription, but if they do, they perform equally to anyone else.

Introduction It is suggested that birth by elective cesarean section (CS) reduces the risk of birth‐related infant mortality and injury. Other studies suggest an increased risk of somatic immune‐related diseases among children born by CS such as asthma, type 1 diabetes, and inflammatory bowel disease. The WHO Statement on Cesarean Section Rates 2015 described an increase in CS globally. The statement concluded that the effects of CS on social and psychological outcomes remain unclear and that more research is needed to fully understand the effects of CS, including effects on cognition and intelligence in the child. Therefore, we aimed to investigate the association between delivery by CS (elective and acute) and school performance and intelligence in youth. Material and methods This cohort study included all Danish live‐born children in 1978–2000. We retrieved data regarding pregnancies, births, parents, school grades, and intelligence of the children from Danish registers and performed multiple imputations to avoid discarding data. The final cohort after exclusion comprised 1 408 230 children. Associations between CS and school graduation, grades, conscription attendance, and conscription intelligence scores were analyzed using univariate and multivariate logistic and linear regressions. Results Adjusted odds ratio with 95% CI of graduating from lower (LSE) and upper (USE) secondary education and of attending conscription were significantly lower in the CS group: LSE graduation: 0.87 (0.84–0.89), USE graduation: 0.93 (0.92–0.94), attending conscription: 0.95 (0.93–0.98). The CS group had significantly lower grade point averages (GPA) in LSE with adjusted differences in mean total GPA of −0.090 (−0.10 to −0.007), and mean core subject GPA of −0.098 (−0.11 to −0.08), in USE with total GPA difference of −0.091 (−0.11 to −0.075) and lower mean intelligence scores of −0.36 (−0.46 to −0.27) in adjusted linear models. A sub‐analysis revealed lower chances of graduating LSE and USE when born by acute rather than elective CS. Conclusions Chances of LSE and USE graduation and of attending conscription were significantly lower for children born by CS. However, even significant differences in mean GPAs and intelligence scores were very small, so performances when graduating school and attending conscription were comparable regardless of delivery mode. Delivery by cesarean section was associated with lower odds ratio of passing lower and upper secondary education (0.87 [0.84–0.89] and 0.93 [0.92–0.94], respectively) and attending conscription 0.95 (0.93–0.97) but not with poorer results when passing or attending.

This multicenter cohort study on embryo assessment and outcome data from 11,744 IVF/ICSI cycles with 104,830 oocytes and 42,074 embryos, presents the effect of women's age on oocyte, zygote, embryo morphology and cleavage parameters, as well as cycle outcome measures corrected for confounding factors as center, partner's age and referral diagnosis. Cycle outcome data confirmed the well-known effect of women's age. Oocyte nuclear maturation and proportion of 2 pro-nuclear (2PN) zygotes were not affected by age, while a significant increase in 3PN zygotes was observed in both IVF and ICSI (p<0.0001) with increasing age. Maternal age had no effect on cleavage parameters or on the morphology of the embryo day 2 post insemination. Interestingly, initial hCG value after single embryo transfer followed by ongoing pregnancy was increased with age in both IVF (p = 0.007) and ICSI (p = 0.001) cycles. For the first time, we show that a woman's age does impose a significant footprint on early embryo morphological development (3PN). In addition, the developmentally competent embryos were associated with increased initial hCG values as the age of the women increased. Further studies are needed to elucidate, if this increase in initial hCG value with advancing maternal age is connected to the embryo or the uterus.

ObjectiveSoluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker associated with presence and progression of disease and with increased risk of mortality. We aimed to evaluate the unspecific biomarker suPAR as a prognostic marker in patients admitted to acute care.MethodsThis registry-based retrospective cohort study included 4343 consecutively admitted patients from the Acute Medical Unit at a large Danish university hospital. Time to readmission and death were analysed by multiple Cox regression. Results were reported as HRs for 30-day and 90-day follow-up.ResultsDuring 30-day follow-up, 782 patients (18.0%) were readmitted and 224 patients (5.2%) died. Comparing 30-day readmission and mortality between patients in the highest and lowest suPAR quartiles yielded HRs of 2.11 (95% CI 1.70 to 2.62) and 4.11 (95% CI 2.46 to 6.85), respectively, when adjusting for age, sex, Charlson score and C reactive protein. Area under the curve for receiver operating characteristics curve analysis of suPAR for 30-day mortality was 0.84 (95% CI 0.81 to 0.86). Furthermore, in the entire cohort, women had slightly higher suPAR compared with men, and suPAR was associated with age, admission time, admission to intensive care unit and Charlson score.ConclusionsIn this large unselected population of acute medical patients, suPAR is strongly associated with disease severity, readmission and mortality after adjusting for all other risk factors, indicating that suPAR adds information to established prognostic indicators. While patients with low suPAR levels have low risk of readmission and mortality, patients with high suPAR levels have a high risk of adverse events.

Background The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is a strong predictor of disease development and premature mortality in the general population. Unhealthy lifestyle habits such as smoking or unhealthy eating is known to elevate the suPAR level. We aimed to investigate whether change in lifestyle habits impact on the suPAR level, and whether the resultant levels are associated with mortality. Results Paired suPAR measurements from baseline- and the 5-year visit of the population-based Inter99 study were compared with the habits of diet, smoking, alcohol consumption, and physical activity. Paired suPAR measurements for 3225 individuals were analyzed by linear regression, adjusted for demographics and lifestyle habits. Compared to individuals with a healthy lifestyle, an unhealthy diet, low physical activity, and daily smoking were associated with a 5.9, 12.8, and 17.6% higher 5-year suPAR, respectively. During 6.1 years of follow-up after the 5-year visit, 1.6% of those with a low suPAR (mean 2.93 ng/ml) died compared with 3.8% of individuals with a high suPAR (mean 4.73 ng/ml), P  <  0.001. In Cox regression analysis, adjusted for demographics and lifestyle, the hazard ratio for mortality per 5-year suPAR doubling was 2.03 (95% CI: 1.22–3.37). Conclusion Lifestyle has a considerable impact on suPAR levels; the combination of unhealthy habits was associated with 44% higher 5-year suPAR values and the 5-year suPAR was a strong predictor of mortality. We propose suPAR as a candidate biomarker for lifestyle changes as well as the subsequent risk of mortality.

Background Women living with HIV (WLWH) have high rates of persistent high-risk human papillomavirus (hrHPV) infections and cervical cancer. We aimed to assess the distribution of hrHPV genotypes, risk factors of type-specific hrHPV persistence, and high-grade squamous intraepithelial lesions or worse (≥HSIL) in WLWH in Denmark. Methods From the prospective Study on HIV, cervical Abnormalities and infections in women in Denmark (SHADE) we identified WLWH with a positive hrHPV test during the study period; 2011–2014. HIV demographics were retrieved from the Danish HIV Cohort Study and pathology results from the The Danish Pathology Data Bank. Logistic regression was used to identify risk factors associated with persistent hrHPV infection (positivity of the same hrHPV type in two samples one-two years after the first hrHPV positive date) and ≥ HSIL. Results Of 71 WLWH, 31 (43.7%) had persistent hrHPV infection. Predominant hrHPV genotypes were HPV58, 52, 51, and 35 and most frequently observed persistent genotypes were HPV52, 33 and 31. CD4 < 350 cells/μL predicted genotype-specific hrHPV persistence (adjusted OR 4.36 (95%CI: 1.18–16.04)) and ≥ HSIL was predicted by prior AIDS (adjusted OR 8.55 (95% CI 1.21–60.28)). Conclusions This prospective cohort study of well-treated WLWH in Denmark found a high rate of persistent hrHPV infections with predominantly non-16/18 hrHPV genotypes. CD4 count < 350 cells/μL predicted hrHPV persistence, while prior AIDS predicted ≥HSIL.

To estimate the incidence of incisional hernias requiring surgical repair after cesarean delivery over a 10-year period. This population- and register-based cohort study identified all women in Denmark with no history of previous abdominal surgery who had a cesarean delivery between 1991 and 2000. The cohort was followed from their first until 10 years after their last cesarean delivery within the inclusion period or until the first of the following events: hernia repair, death, emigration, abdominal surgery, or cesarean delivery after the inclusion period. For women who had a hernia repair, hospital records regarding the surgery and previous cesarean deliveries were tracked and manually analyzed to validate the relationship between hernia repair and cesarean delivery. Data were analyzed with a competing risk analysis that included each cesarean delivery. We identified 57,564 women who had had 68,271 cesarean deliveries during the inclusion period. During follow-up, 134 of these women had a hernia requiring repair. Of these 68 (51% [95% CI 42-60%]) were in a midline incision although the transverse incision was the primary approach at cesarean delivery during the inclusion period. The cumulated incidence of a hernia repair within 10 years after a cesarean delivery was 0.197% (95% CI 0.164-0.234%). The risk of a hernia repair was higher during the first 3 years after a cesarean delivery, with an incidence after 3 years of 0.157% (95% CI 0.127-0.187%). The overall risk of an incisional hernia requiring surgical repair within 10 years after a cesarean delivery was 2 per 1000 deliveries in a population in which the transverse incision was the primary approach at cesarean delivery.

The soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of mortality risk in various patient populations. However, little is known about the implications of lifestyle for suPAR levels in the general population. Lifestyle, demographic, and cardiovascular disease (CVD) risk factor data were collected from 5,538 participants in the Danish population-based Inter99 study. Their suPAR levels were measured using a sandwich enzyme-linked immunosorbent assay. In the final adjusted model, smoking and morbid obesity were strongly associated with higher suPAR levels (P < 0.001). An unhealthy diet and alcohol abstinence in men were also associated with higher suPAR levels. Physical activity in leisure time had a modest impact on suPAR levels in univariate analysis, but not in the final adjusted model. In conclusion, smoking and morbid obesity were strongly associated with higher serum suPAR levels in this general population. Diet and alcohol consumption also seemed to impact suPAR levels. Lifestyle changes are likely to affect suPAR since ex-smokers had suPAR levels comparable to those of never-smokers.

Chronic hepatitis C (CHC) causes liver cirrhosis in 5%-20% of patients, leading to increased morbidity and mortality. This study aimed to estimate liver-related morbidity and mortality among patients with CHC and cirrhosis in Denmark with and without antiviral treatment and sustained virologic response (SVR). Furthermore we aimed to estimate the rate of hepatocellular carcinoma (HCC) and decompensation associated with certain prognostic factors. Patients with CHC and cirrhosis registered in the Danish Database for Hepatitis B and C were eligible. Cirrhosis was based on liver biopsy, transient elastography, and clinical cirrhosis. Data were extracted from nationwide registries. The study period was from 2002 until 2013. Of 1,038 patients included, 716 (69%) were male and the median age was 52 years. Median follow-up was 3.8 years, 360 patients died, and 233 of 519 treated patients achieved SVR. Alcohol overuse and hepatitis C virus genotype 3 were associated with an increased incidence rate (IR) of HCC, whereas diabetes and alcohol overuse were associated with increased IRs of decompensation. Achieving SVR reduced all-cause mortality (adjusted mortality rate ratio 0.68 [95% CI 0.43-1.09]) and liver-related mortality (mortality rate ratio 0.6 [95% CI 0.36-1]), as well as liver-related morbidity with adjusted IR ratios of 0.37 (95% CI 0.22-0.62) for HCC and 0.31 (95% CI 0.17-0.57) for decompensation. The IRs of HCC and decompensation remained elevated in patients with alcohol overuse after SVR. Alcohol overuse, hepatitis C genotype 3, and diabetes were associated with liver-related morbidity in patients with CHC and cirrhosis. SVR markedly reduced liver-related morbidity and mortality; however, special attention to patients with alcohol overuse should continue after SVR.