Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight.

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.

Remote ischemic postconditioning has a detrimental effect and remote ischemic preconditioning seems to have no effect on small intestinal anastomotic strength.

BACKGROUND: The effect of remote pre- and postconditioning on anastomotic healing has been sparsely studied. The aim of our study was to investigate whether remote ischemic conditioning (RIC) applied before and after the creation of a small bowel anastomosis had an effect on anastomotic healing on postoperative day five evaluated by a tensile strength test and histological analysis. MATERIALS AND METHODS: Twenty-two female piglets were randomized into two groups. The intervention group (n = 12) received RIC on the forelimbs consisting of 15 min of ischemia followed by 30 min of reperfusion before the first end-to-end ileal anastomosis was created. The RIC procedure was repeated and the second and more distal anastomosis was performed. The control group (n = 10) had two similar anastomoses with similar time intervals but without RIC. On postoperative day five, the anastomoses were subjected to macroscopic evaluation, tensile strength test and histological examination. RESULTS: Mean tensile strength when the first transmural rupture appeared (MATS-2) was significantly lower in the first anastomosis in the intervention group compared to the control group (11.4 N vs 14.7 N, p < .05). Similar result was found by the maximal strength (MATS-3) as defined by a drop in the load curve (12.3 N vs 15.9 N, p < .05). Histologically, a significantly higher necrosis score was found in the anastomosis in the intervention group (1.4 vs 0.8, p < .05). No other significant differences were found. CONCLUSIONS: In conclusion, post-anastomotic remote ischemic conditioning had a detrimental effect and pre-anastomotic conditioning seems to have no effect on small intestinal anastomotic strength.

Hepatitis C time trends in reported cases and estimates of the hidden population born before 1965, Denmark and Sweden, 1990 to 2020.

BackgroundAccording to the World Health Organization, hepatitis C virus (HCV) infection should be under control by 2030.AimOur aim was to describe the size and temporal changes in reported cases of chronic HCV infection in Denmark and Sweden and to estimate the size of the hidden (undiagnosed) population born before 1965.MethodsWe extracted all HCV infections reported to national surveillance systems in Denmark and Sweden from 1990 to 2020. Prediction of the size of the hidden HCV-infected population was restricted to the cohort born before 1965 and cases reported up to 2017. We applied a model based on removal sampling from binomial distributions, estimated the yearly probability of diagnosis, and deducted the original HCV-infected population size.ResultsDenmark (clinician-based) reported 10 times fewer hepatitis C cases annually than Sweden (laboratory and clinician-based), peaking in 2007 (n = 425) and 1992 (n = 4,537), respectively. In Denmark, the birth year distribution was monophasic with little change over time. In recent years, Sweden has had a bimodal birth year distribution, suggesting ongoing infection in the young population. In 2017, the total HCV-infected population born before 1965 was estimated at 10,737 living persons (95% confidence interval (CI): 9,744-11,806), including 5,054 undiagnosed, in Denmark and 16,124 (95% CI: 13,639-18,978), including 10,580 undiagnosed, in Sweden.ConclusionsThe reporting of HCV cases in Denmark and Sweden was different. For Denmark, the estimated hidden population was larger than the current national estimate, whereas in Sweden the estimate was in line with the latest published numbers.

Sample size determination in method comparison and observer variability studies.

The comparison of two quantitative measuring devices is often performed with the Limits of Agreement proposed by Bland and Altman in their seminal Lancet paper back in 1986. Sample size considerations were rare for such agreement analyses in the past, but recently several proposals have been made depending on how agreement is to be assessed and the number of replicates to be used. We have summarized recent developments and recommendations in various situations including a distinction between method comparison and observer variability studies. These include current state-of-the-art analysis of and reporting guidelines for agreement studies. General recommendations close the paper.

Alemtuzumab treatment in Denmark: A national study based on the Danish Multiple Sclerosis Registry.

OBJECTIVE: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark. METHODS: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits. RESULTS: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab (p < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88, p < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95, p = 0.001). CONCLUSION: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.

Embolization of the middle meningeal artery in patients with chronic subdural hematoma-a systematic review and meta-analysis.

BACKGROUND: Chronic subdural hematoma (CSDH) remains a neurosurgical condition with high recurrence rate after surgical treatment. The primary pathological mechanism is considered to be repeated microbleedings from fragile neo-vessels within the outer hematoma membrane. The neo-vessels are supplied from peripheral branches of the middle meningeal artery, and embolization of MMA (eMMA) has been performed to prevent re-bleeding episodes and thereby CSDH recurrence. OBJECTIVE: To evaluate the published evidence for the effect of eMMA in patients with recurrent CSDH. Secondarily, to investigate the effect of eMMA as an alternative to surgery for primary treatment of CSDH. METHOD: A systematic review of the literature on eMMA in patients with recurrent CSDH was conducted. PubMed, Embase, and Cochrane databases were reviewed using the search terms: Embolization, Medial Meningeal Artery, Chronic Subdural Haematoma, and Recurrence. Furthermore, the following mesh terms were used: Chronic Subdural Haematoma AND embolization AND medial meningeal artery AND recurrence. Eighteen papers were found and included. No papers were excluded. The number of patients with primary CSDH and the number of patients with recurrent CSDH treated with eMMA were listed. Furthermore, the number of recurrences in both categories was registered. RESULTS: Eighteen papers with a total of 191 included patients diagnosed with CSDH treated with eMMA for primary and recurrent CSDH were identified. Recurrence rate for patients treated with eMMA for recurrent CSDH was found to be 2.4%, 95% CI (0.5%; 11.0%), whereas the recurrence rate for patients treated with eMMA for primary CSDH was 4.1%, 95% CI (1.4%; 11.4%). CONCLUSION: eMMA is a minimally invasive procedure for treatment of CSDH. Although this study is limited by publication bias, it seems that this procedure may reduce recurrence rates compared with burr hole craniostomy for both primary and recurrent hematomas. A controlled study is warranted.

Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength.

Hand grip strength is a measure of muscular strength and is used to study age-related loss of physical capacity. In order to explore the biological mechanisms that influence hand grip strength variation, an epigenome-wide association study (EWAS) of hand grip strength in 672 middle-aged and elderly monozygotic twins (age 55-90 years) was performed, using both individual and twin pair level analyses, the latter controlling the influence of genetic variation. Moreover, as measurements of hand grip strength performed over 8 years were available in the elderly twins (age 73-90 at intake), a longitudinal EWAS was conducted for this subsample. No genome-wide significant CpG sites or pathways were found, however two of the suggestive top CpG sites were mapped to the COL6A1 and CACNA1B genes, known to be related to muscular dysfunction. By investigating genomic regions using the comb-p algorithm, several differentially methylated regions in regulatory domains were identified as significantly associated to hand grip strength, and pathway analyses of these regions revealed significant pathways related to the immune system, autoimmune disorders, including diabetes type 1 and viral myocarditis, as well as negative regulation of cell differentiation. The genes contributing to the immunological pathways were HLA-B, HLA-C, HLA-DMA, HLA-DPB1, MYH10, ERAP1 and IRF8, while the genes implicated in the negative regulation of cell differentiation were IRF8, CEBPD, ID2 and BRCA1. In conclusion, this exploratory study suggests hand grip strength to associate with differentially methylated regions enriched in immunological and cell differentiation pathways, and hence merits further investigations.

The Danish chronic subdural hematoma study-predicting recurrence of chronic subdural hematoma.

BACKGROUND: An increasing incidence of chronic subdural hematoma (CSDH) and an unchanging high recurrence rate of 10-20% call for individualized treatment. The aim of this study was to establish individualized prediction models for the risk of recurrence treating death as a competing risk. METHODS: A retrospective national cohort of unilateral CSDH was included for analysis. Using competing risk survival analysis, we tested whether available covariates were associated with the risk of recurrence. We further established a pre- and a postoperative prediction model, where predictors were chosen using a LASSO approach. The models were visualized in nomograms. Predictive performance was evaluated by c index and calibrations plots. RESULTS: A total of 763 patients with surgically evacuated unilateral CSDH were included for analysis. The recurrence rate was 14% while 12% of patients died during follow-up (1 year). In our association model, hematoma size, drain type, drainage time, presence of complications, and Glasgow Coma Score were significantly associated to recurrence. Subdural drain was associated with a lower recurrence risk than subgaleal drain. The preoperative model included hematoma size, hematoma density, and history of hypertension. The postoperative model included further drain type, drainage time, and surgical complications. CONCLUSION: The nomograms allow easy assessment of the recurrence risk for the individual patient, providing a better possibility for individual adjustment of treatment and follow-up. The predictive performance indicates that significant unaccounted or unknown factors still remain. The association test found passive subdural drain superior to passive subgaleal drain in minimizing the risk of CSDH recurrence.

The null hypothesis of GSEA, and a novel statistical model for competitive gene set analysis.

Motivation: Competitive gene set analysis intends to assess whether a specific set of genes is more associated with a trait than the remaining genes. However, the statistical models assumed to date to underly these methods do not enable a clear cut formulation of the competitive null hypothesis. This is a major handicap to the interpretation of results obtained from a gene set analysis. Results: This work presents a hierarchical statistical model based on the notion of dependence measures, which overcomes this problem. The two levels of the model naturally reflect the modular structure of many gene set analysis methods. We apply the model to show that the popular GSEA method, which recently has been claimed to test the self-contained null hypothesis, actually tests the competitive null if the weight parameter is zero. However, for this result to hold strictly, the choice of the dependence measures underlying GSEA and the estimators used for it is crucial. Contact: bdebrabant@health.sdu.dk. Supplementary information: Supplementary material is available at Bioinformatics online.

The role of personality, disability and physical activity in the development of medication-overuse headache: a prospective observational study.

BACKGROUND: Factors associated with development of medication-overuse headache (MOH) in migraine patients are not fully understood, but with respect to prevention, the ability to predict the onset of MOH is clinically important. The aims were to examine if personality characteristics, disability and physical activity level are associated with the onset of MOH in a group of migraine patients and explore to which extend these factors combined can predict the onset of MOH. METHODS: The study was a single-center prospective observational study of migraine patients. At inclusion, all patients completed questionnaires evaluating 1) personality (NEO Five-Factor Inventory), 2) disability (Migraine Disability Assessment), and 3) physical activity level (Physical Activity Scale 2.1). Diagnostic codes from patients' electronic health records confirmed if they had developed MOH during the study period of 20 months. Analyses of associations were performed and to identify which of the variables predict onset MOH, a multivariable least absolute shrinkage and selection operator (LASSO) logistic regression model was fitted to predict presence or absence of MOH. RESULTS: Out of 131 participants, 12 % (n=16) developed MOH. Migraine disability score (OR=1.02, 95 % CI: 1.00 to 1.04), intensity of headache (OR=1.49, 95 % CI: 1.03 to 2.15) and headache frequency (OR=1.02, 95 % CI: 1.00 to 1.04) were associated with the onset of MOH adjusting for age and gender. To identify which of the variables predict onset MOH, we used a LASSO regression model, and evaluating the predictive performance of the LASSO-mode (containing the predictors MIDAS score, MIDAS-intensity and -frequency, neuroticism score, time with moderate physical activity, educational level, hours of sleep daily and number of contacts to the headache clinic) in terms of area under the curve (AUC) was weak (apparent AUC=0.62, 95% CI: 0.41-0.82). CONCLUSION: Disability, headache intensity and frequency were associated with the onset of MOH whereas personality and the level of physical activity were not. The multivariable LASSO model based on personality, disability and physical activity is applicable despite moderate study size, however it can be considered as a weak classifier for discriminating between absence and presence of MOH.

Gene set analysis for GWAS: assessing the use of modified Kolmogorov-Smirnov statistics.

We discuss the use of modified Kolmogorov-Smirnov (KS) statistics in the context of gene set analysis and review corresponding null and alternative hypotheses. Especially, we show that, when enhancing the impact of highly significant genes in the calculation of the test statistic, the corresponding test can be considered to infer the classical self-contained null hypothesis. We use simulations to estimate the power for different kinds of alternatives, and to assess the impact of the weight parameter of the modified KS statistic on the power. Finally, we show the analogy between the weight parameter and the genesis and distribution of the gene-level statistics, and illustrate the effects of differential weighting in a real-life example.

Early Dynamics of P-selectin and Interleukin 6 Predicts Outcomes in Ischemic Stroke.

BACKGROUND: Thromboinflammatory molecules connect the prothrombotic state, endothelial dysfunction, and systemic/local inflammation in the acute phase of ischemic stroke. METHODS: We prospectively investigated (1) serial changes in the levels of thromboinflammatory biomarkers in 76 patients with acute ischemic stroke (6, 24, and 72 hours after onset); (2) compared with 44 patients with asymptomatic severe (≥70%) carotid stenosis and 66 patients with Parkinson disease; and (3) we applied multiple regression methods, relating biological biomarkers combined with demographic data and comorbidities to poststroke infection, death, and functional outcome, and assessed the ability of the models to predict each outcome. RESULTS: Interleukin 6 (IL-6) levels and change of IL-6 concentrations by 72 hours correlated with the size of tissue damage indicated by S100B titers. Levels of IL-6 and P-selectin at 72 hours were higher in patients with large-artery versus lacunar stroke. High concentration of IL-6, monocyte chemotactic protein 1, and S100B at 6 hours were associated with poststroke infections; high concentration of IL-6, S100B, and high-sensitivity C-reactive protein (hsCRP) correlated with death. Change of P-selectin from 6 to 72 hours by 1 unit increased the incidence of poststroke infections with an odds ratio of 22.7; each 100 units of IL-6 at baseline increased the odds of death by 9‰, and at 72 hours, the odds of poststroke infections by 4‰. Each unit of baseline hsCRP elevated the odds of death by 7%. CONCLUSIONS: In regression models, in which biological, demographic, and comorbid factors were combined, those biological biomarkers predicted poor outcome with high accuracy, which were characterized by an increasing concentration by 72 hours. Two particular biomarkers emerged to predict outcomes besides hsCRP: early dynamic changes in the systemic levels of P-selectin and IL-6.

Optimal drainage time after evacuation of chronic subdural haematoma (DRAIN TIME 2): a multicentre, randomised, multiarm and multistage non-inferiority trial in Denmark.

BACKGROUND: Postoperative drainage after surgical evacuation of chronic subdural haematoma reduces the risk of recurrence, but the optimum drainage time is uncertain. We aimed to investigate the shortest possible drainage time without increasing the haematoma recurrence rate. METHODS: We conducted a randomised, multi-arm and multistage non-inferiority trial at four neurosurgical centres in Denmark. We enrolled adult patients (aged ≥18 years) with symptomatic chronic subdural haematoma. All patients were treated according to the national standard practice with a burr hole above the maximum width of the haematoma. Patients were randomly assigned in a 1:1:1 ratio via a centralised web server to receive 6 h, 12 h, or 24 h of postoperative passive subdural drainage. Randomisation was done by an independent on-call neurosurgeon and was masked until 6 h after surgery. The primary outcome was symptomatic haematoma recurrence at 3 months after surgery; the rate of recurrence was assessed in a regression model for non-inferiority testing, with no missing data. Personnel assessing the primary outcome were masked to group allocation. Non-inferiority was assessed with a prespecified margin of 7%, in a modified intention-to-treat population-defined as patients with randomly assigned treatment excluding those withdrawing from study participation after randomisation, or experiencing acute rebleedings or accidental drain removal. This trial is registered with ISRCTN (number 15186366); the trial was stopped after the first interim analysis on the advice of an independent safety advisory committee. FINDINGS: Between March 1, 2021, and June 30, 2022, 347 patients were enrolled and 331 were followed up to 3 months, 105 were assigned to 6 h of drainage, 111 to 12 h of drainage, and 115 to 24 h of drainage. At admission, 83 (25%) participants were women and 248 (75%) were men, mean age was 75·7 years (SD 10·5), median modified Rankin Scale score was 4 (IQR 3-5), and median Glasgow Coma Scale score was 15 (IQR 14-15). At 3 months after surgery, haematoma recurrence was reported in 28 (27%) of 105 patients who were assigned to 6 h drainage (predicted haematoma recurrence rate 27·0%, 95% CI 18·5 to 35·4), 22 (20%) of 111 assigned to 12 h drainage (19·5%, 12·0 to 27·0), and 12 (10%) of 115 assigned to 24 h drainage (10·4%, 4·8 to 16·0). The risk of haematoma recurrence was increased by 16·5 percentage points (95% CI 6·5 to 26·6) in patients drained for 6 h compared with 24 h, and by 9·1 percentage points (-0·4 to 18·5) in patients drained for 12 h compared with 24 h. Therefore, non-inferiority of 6 h and 12 h of drainage to 24 h of drainage was not established. 20 patients had died by 3 months, seven in the 6 h group, eight in the 12 h group, and five in the 24 h group. The most frequent known causes of death were haematoma recurrence (three in 12 h group), comorbidity (three in 12 h group), and pneumonia (one each in 6 h and 12 h groups, two in 24 h group). The most frequent complication was postoperative infection, reported in 20 (20%) patients in the 6 h group, 25 (23%) in the 12 h group, and 19 (17%) in the 24 h group. The most common infection source was the urinary tract. INTERPRETATION: Patients surgically treated for symptomatic chronic subdural haematoma and postoperatively drained for 6 h or 12 h had higher rates of haematoma recurrence than did patients drained for 24 h. The findings from this non-inferiority trial provide evidence to support 24 h of postoperative drainage as the standard drain time when a fixed drain time approach is used. To provide solid evidence of generalisability of the results to countries other than Denmark, a multinational randomised controlled trial will be needed. FUNDING: None.

Descriptive registry study on outcome and complications of external ventricular drainage treatment of intraventricular haemorrhage in a Danish cohort: a study protocol.

INTRODUCTION: Intraventricular haemorrhage (IVH) is associated with high morbidity and mortality. External ventricular drainage (EVD) has been shown to decrease mortality. Although EVD is widely used, outcome and complication rates in EVD-treated patients with IVH are not fully elucidated. This study aims to describe EVD complication rates and outcomes in patients with primary and secondary IVH at two university hospitals in Denmark. The study will provide a historical reference of relevant endpoints for use in future clinical trials involving patients with IVH. METHODS AND ANALYSIS: This descriptive, multicentre registry study included adult patients (age 18+) with primary or secondary IVH and treated with at least one EVD between 2017 and 2021 at Aarhus University Hospital or Odense University Hospital. Patients are identified using the Danish National Patient Register. Data are collected and recorded from patient medical records. Relevant descriptive statistics and correlation analyses will be applied. ETHICS AND DISSEMINATION: Ethical approval and authorisation to access, store and analyse data have been obtained (Central Denmark Region Committee on Health Research Ethics). The research lead will present the results of the study. Data will be reported according to the Strengthening the Reporting of Observational Studies in Epidemiology and results submitted for publication in peer-reviewed journals.

Impact of a nationwide school policy on body mass index in Danish school children: An interrupted time series analysis.

Objectives: A new school policy mandating 45 min physical activity daily during school was introduced in Denmark in 2014. We aimed to evaluate the effect of this policy on BMI in school-aged children. It was hypothesized that the school policy would decrease BMI, especially in the obese fraction of the population (90th percentile BMI). Study design: This register-based study was conducted as a natural experiment. Methods: Analyses were based on data from The National Child Health Register that contains nationwide data on height and weight from mandatory preventive health examinations completed by school nurses or medical doctors during pre-preparatory classes (0th-3rd grade) and lower secondary education (7th-9th grade). A total of 401,517 children were included in the analyses with annual repeated cross-sectional data covering the period from 2012 to 2018. The effect of the school policy was evaluated using an interrupted time series approach comparing pre- and post-policy slopes in BMI, stratified by sex and age-group. Results: In boys, no significant differences were observed in mean BMI slopes from pre-to post-policy in either age-group. In girls, post-policy slopes were significantly higher compared to pre-policy in both age-groups (0th-3rd grade: ß:0·034 kg/m2, 95%-CI: (0·024; 0·043), p-value: <0·001; 7th-9th grade: ß:0·066 kg/m2, 95%-CI: (0·028; 0·103), p-value: 0·001). No significant differences in slopes were observed in BMI at the 90th percentile from pre-to post-policy for both sexes and across both age-groups. Adjustment for leisure-time physical activity as a potential time-varying confounder did not alter the findings. Conclusions: In conclusion, we did not detect a significant decrease in BMI levels among school-aged children following the introduction of a nationwide school policy specifying daily physical activity in school. If anything, a small positive change in BMI was observed in girls. More research is needed to understand whether structural changes similar to this requirement are able to prevent overweight and obesity in children and adolescents.

Treatment of Intraventricular Hemorrhage with External Ventricular Drainage and Fibrinolysis: A Comprehensive Systematic Review and Meta-Analysis of Complications and Outcome.

BACKGROUND: External ventricular drainage (EVD) is a key factor in the treatment of intraventricular hemorrhage (IVH) but associated with risks and complications. Intraventricular fibrinolysis (IVF) has been proposed to improve clinical outcome and reduce complications of EVD treatment. The following review and metaanalysis provides a comprehensive evaluation of IVH treatment with external ventricular drainage (EVD) and intraventricular fibrinolysis (IVF) with regards to complications and clinical outcomes. METHODS: The PRISMA guidelines were followed preparing this review. Studies included in the meta-analysis were compared using forest plots and the related odds ratios. RESULTS: After a literature search, 980 articles were identified and 65 and underwent full-text review. Forty-two articles were included in the review and meta-analysis. We found that bolted and antibiotic-coated catheters were superior to tunnelled/uncoated catheters (P < 0.001) and antibiotic- vs. silver-impregnated catheters (P < 0.001]) in preventing infection. Shunt dependency was related to the volume of blood in the ventricles but unaffected by IVF (P = 0.98). IVF promoted hematoma clearance, decreased mortality (22.4% vs. 40.9% with IVF vs. no IVF, respectively, P < 0.00001), improved good functional outcomes (47.2% [IVF] vs. 38.3% [no IVF], P = 0.03), and reduced the rate of catheter occlusion from 37.3% without IVF to 10.6% with IVF (P = 0.0003). CONCLUSIONS: We present evidence and best practice recommendations for the treatment of IVH with EVD and intraventricular fibrinolysis. Our analysis further provides a comprehensive quantitative reference of the most relevant clinical endpoints for future studies on novel IVH technologies and treatments.

Effect of nationwide school policy on device-measured physical activity in Danish children and adolescents: a natural experiment.

Background: A new Danish school policy with a requirement for 45 min physical activity daily during school hours was introduced in 2014. The objective of this natural experiment was to evaluate the effect of this nationwide school policy on physical activity in Danish children and adolescents. Methods: Four historical studies completed between 2009 and 2012 comprised the pre-policy study population. Post-policy data were collected in 2017/18. All post-policy schools were represented in the four pre-policy studies. Age-groups and seasons were matched. In total, 4816 children and adolescents aged 6-17 were included in the analyses (2346 pre-policy and 2470 post-policy). Children and adolescents were eligible if they had accelerometer measurements and did not have any physical disabilities preventing activity. Physical activity was measured by accelerometry. Main outcome was any bodily movement. Secondary outcomes were moderate to vigorous physical activity and overall movement volume (mean counts per minute). Findings: The school policy interrupted a linear decreasing pre-policy trend in physical activity during school hours. All activity outcomes increased post-policy during a standardized school day (8:10 am-1 pm). Increases were more pronounced in the youngest children. Specifically, we observed a daily increase during a standardized school day in 2017/2018 of 14.2 min of movement (95% CI: 11.4-17.0, p < 0.001), 6.5 min of moderate to vigorous physical activity (95% CI: 4.7-8.3, P < 0.001), and 141.8 counts per minute (95% CI: 108.5-175.2, P < 0.001). Interpretation: A national school policy may be an important strategy to increase physical activity during school hours among children and adolescents. Funding: The Danish Foundation TrygFonden has funded the PHASAR project (ID 115606).

Postoperative drainage for 6, 12, or 24 h after burr-hole evacuation of chronic subdural hematoma in symptomatic patients (DRAIN-TIME 2): study protocol for a nationwide randomized controlled trial.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common acute or subacute neurosurgical condition, typically treated by burr-hole evacuation and drainage. Recurrent CSDH occurs in 5-20% of cases and requires reoperation in symptomatic patients, sometimes repeatedly. Postoperative subdural drainage of maximal 48 h is effective in reducing recurrent hematomas. However, the shortest possible drainage time without increasing the recurrence rate is unknown. METHODS: DRAIN-TIME 2 is a Danish multi-center, randomized controlled trial of postoperative drainage time including all four neurosurgical departments in Denmark. Both incapacitated and mentally competent patients are enrolled. Patients older than 18 years, free of other intracranial pathologies or history of previous brain surgery, are recruited at the time of admission or no later than 6 h after surgery. Each patient is randomized to either 6, 12, or 24 h of passive subdural drainage following single burr-hole evacuation of a CSDH. Mentally competent patients are asked to complete the SF-36 questionnaire. The primary endpoint is CSDH recurrence rate at 90 days. Secondary outcome measures include SF-36 at 90 days, length of hospital stay, drain-related complications, and complications related to immobilization and mortality. DISCUSSION: This multi-center trial will provide evidence regarding the shortest possible drainage time without increasing the recurrence rate. The potential impact of this study is significant as we believe that a shorter drainage period may be associated with fewer drain-related complications, fewer complications related to immobilization, and shorter hospital stays-thus reducing the overall health service burden from this condition. The expected benefits for patients' lives and health costs will increase as the CSDH patient population grows. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15186366 . Registered in December 2020 and updated in October 2021. This protocol was developed in accordance with the SPIRIT Checklist and by use of the structured study protocol template provided by BMC Trials.

Integrative analysis of clinical and epigenetic biomarkers of mortality.

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.