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Long-term allograft survival remains a challenge in kidney transplantation. In this study, we aimed to identify biomarkers for potentially modifiable pathways involved in the outcome of kidney transplantation. We tested the hypothesis that a pre-existing systemic environment with endothelial cell activation in the recipient is associated with the outcome after kidney transplantation. In a retrospective study cohort of 611 kidney transplanted patients, we investigated associations between serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) before transplantation and delayed graft function, acute rejection, graft loss and mortality after transplantation. We adjusted associations for age, sex, preformed donor-specific antibodies (DSA), pretransplant diabetes, cardiovascular disease and dialysis. Additionally, we investigated if associations between endothelial cell activation markers and outcomes differed in recipients with and without preformed DSA. Serum levels of endothelial cell activation markers were associated with delayed graft function and mortality but not with rejection. Additionally, high levels of sICAM-1 were associated with graft loss. Associations were most pronounced in recipients without DSA, adjusted for potential confounders. Data suggest that endothelial cell activation at the time of transplantation is associated with graft loss and mortality after kidney transplantation, especially in transplant candidates without preformed DSA.

Objectives: Elevated soluble urokinase-type plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein (hsCRP) have been associated with increased mortality in patients with cardiovascular disease. The aim of the present study was to explore the relationship between suPAR and hsCRP values and associated mortality after elective cardiac surgery. A secondary aim was to assess whether a combined risk model of European System for Cardiac Operative Risk Evaluation (EuroSCORE II), suPAR, and/or hsCRP would improve the prognostic accuracy compared with EuroSCORE II alone. Design: Retrospective observational study. Setting: Single-center, university hospital. Participants: Adult patients admitted for elective on-pump cardiac surgery were included. Biobank blood samples were obtained from previous research projects at a tertiary heart center from 2012 to 2018. Interventions: None. Measurements and Main Results: A total of 931 patients were included. Kaplan-Meier and Cox proportional hazard analyses were used to explore a potential association between preoperative suPAR and hsCRP values and all-cause mortality up to one year after surgery. Thirty-day mortality was predicted from suPAR, hsCRP, and EuroSCORE II by logistic regression and compared using area under the receiver operating characteristics curve and Brier scores. After adjustment for known confounders, a doubling of suPAR and hsCRP corresponded to a hazard ratio for all-cause mortality of 2.27 (95% confidence interval 1.65-3.11; p < 0.001) and 1.26 (95% confidence interval 1.07-1.49; p = 0.005), respectively. However, adding the biomarkers to EuroSCORE II did not improve prediction/discrimination with respect to 30-day mortality. Conclusions: Elevated preoperative levels of suPAR and hsCRP were associated with all-cause mortality in elective cardiac surgery patients. However, inclusion of biomarkers did not improve the prognostic accuracy of EuroSCORE II.

Supplemental Digital Content is available in the text., Background: Available studies on the prevalence of infertility have proved to have certain limitations, with a scarcity of population-based studies and inconsistent reporting from surveys in countries at all income levels. We wanted to test the applicability of the current duration approach to data from the important Demographic and Health Surveys (DHS) program, funded by USAID since its inception in 1985, https://dhsprogram.com/. Methods: The current duration approach assumes that there is a well-defined time of initiation of attempts to get pregnant and defines the current duration of a still ongoing pregnancy attempt as the time interval from initiation to interview. The DHS interviews do not have an explicit question about initiation. We focused on nullipari and substituted date of “establishment of relationship with current partner” for initiation. Our study used the current duration approach on 15 datasets from DHS during 2002–2016 in eight different countries from sub-Saharan Africa, Asia, and Latin America. Results: Well-established statistical techniques for current duration data yielded results that for some countries postulated surprisingly long median times to pregnancy and surprisingly high estimates of infertility prevalence. Further study of the data structures revealed serious deviations from expected patterns, in contrast to our earlier experience from surveys in France and the United States where participants were asked explicitly about time of initiation of attempts to become pregnant. Conclusions: Using cohabitation as a proxy for the initiation of attempts to get pregnant is too crude. Using the current duration approach with DHS data will require more explicit questions during the DHS interviews about initiation of pregnancy attempt.

We investigated risks and hazard rates of developing chronic ocular graft-versus-host disease (oGVHD) in a large nationwide, single centre study by using the criteria proposed by “The International Chronic oGVHD Consensus Group”. This retrospective study included 1407 consecutive adults who underwent allogeneic haematopoietic stem cell transplantation (HSCT). Patients were examined by an ophthalmologist according to the hospital’s guidelines: baseline examination before HSCT, annually up to 5 years after HSCT. The 186 (13%) had dry eye disease before HSCT. The 5-year cumulative incidence of oGVHD was 18% (95% CI: 15–21) after myeloablative (MA) and 35% (95% CI: 30–39) after non-myeloablative conditioning (NMA). Factors associated with the rate of oGVHD were assessed separately according to conditioning regimen by using multiple Cox regression analyses. Factors that increased the rate in the MA group: Malignant disease, Schirmer’s test≤10 mm/5 min before transplantation, use of female donor, matched unrelated donor, peripheral blood as stem cell source, and grade III-IV acute GVHD. Factors that increased the rate in the NMA group: Schirmer’s test≤10 mm/5 min before transplantation and higher recipient age. We recommend a baseline ophthalmological examination before HSCT since many of the patients have signs of dry eyes before transplantation which increased the risk and rate of developing oGVHD.

Chronic diseases in children can impact their parents; this may be overlooked in a clinical setting. Our aim was to investigate associations of chronic diseases in children with their parents’ employment, health care utilization, mental health, and mortality. In a matched cohort study using nationwide and population-based data in Denmark, we included parents to children (< 18 years) with acute disseminated encephalomyelitis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis/juvenile idiopathic arthritis during 2008–2015. The reference group was parents to unaffected children. Outcomes were parental employment (early retirement, cash benefits, income), health care utilization (e.g., general practitioner, or hospital visits), mental health (visits to psychiatry/psychology clinics, antidepressant drug redemptions), and mortality. We included 13,769 parents with a chronically ill child and 138,606 control parents. Annual income was unaffected for two-parent families after the child’s disease onset, but two-parent families had increased hazard of early retirement of 25% (95% CI = 1.01–1.54; p = 0.04). Parents with a chronically ill child had (a) increased rate of antidepressant drug redemptions or psychology/psychiatry visits (hazard ratio 1.37; 95% CI = 1.28–1.46 at 1-year follow-up); (b) increased health care utilization, with an increased marginal mean in primary care of 1% (95% CI = 1.00–1.02; p = 0.005), hospital-affiliated visits of 19% (95% CI = 1.14–1.24; p < 0.0001), and hospital admissions of 14% (95% CI = 1.09–1.20; p < 0.0001); and (c) 69% increased mortality hazard (95% CI = 1.30–2.18; p < 0.0001) in parents younger than 50 years with no comorbidities, albeit small in absolute numbers. Conclusion: Pediatric chronic diseases were negatively associated with parental employment, mental health, and mortality, and increased health care utilization.What is Known:• Studies on the impact of pediatric chronic diseases on parental health are qualitative.• Knowledge is unavailable regarding the impact on parental work, health care utilization, and mortality.What is New:• Among 13,769 parents with a chronically ill child and 138,606 control parents, parents with a chronically ill child had 37% increased antidepressant drug redemptions, and these parents

The aim of the study was to investigate (1) the 30-day, 3-month, and 12-month cumulative mortalities for patients who underwent aneurysm occlusion, and (2) the causes of death, and (3) the potential risk factors for death.All patients who underwent surgical clipping or endovascular treatment of a ruptured aneurysm at Copenhagen University Hospital, during the period of January 1, 2017-December 31, 2019, were included and followed up for 12 months. Data regarding vital status, causes of death, comorbidities, treatment, and clinical presentations on admission was collected. The absolute mortality risk was estimated as a function of time with a 95% confidence interval. The associations between potential risk factors and death were estimated as odds ratios with 95% confidence intervals using logistic regression models.A total of 317 patients were included. The overall cumulative mortalities after 30 days, 3 months, and 12 months were 10.7%, 12.9%, and 16.1%, respectively. The most common cause of death was severe primary hemorrhage (52.9%), followed by infections (15.7%) and rebleeding (11.8%). WFNS score 3 and Fisher score 3 on admission, preprocedural hydrocephalus, and preprocedural rebleeding were found significantly associated with higher risk of death.Considerable mortality was seen. Possible preventable causes accounted for approximately 22% of the deaths. The occurrence of both pre- and postprocedural rebleeding's indicates an opportunity of further improvement of the mortality by (1) further reduction of time from aSAH to aneurysm occlusion and (2) continuous efforts in improving methods of aneurysm occlusion.

Summary Recurrent events in the presence of a terminal event are often encountered in a biomedical setting. The marginal mean of the number of recurrent events in a specified time period is a useful non-parametric summary of recurrent events data also in the presence of a terminal event. Other useful non-parametric summaries, that are simple to compute, are the distribution function of the number of recurrent events for each point in time and the variance of the number of recurrent events. For bivariate recurrent events, still in the presence of a terminal event, we suggest a simple non-parametric estimator of the covariance or correlation of the marginal number of events for both processes. When there is no terminal event the correlation is useful, but when there is an important terminal event we suggest an adjustment for correlation induced by the terminal event to obtain a measure that reflects the dependence in the recurrent event processes among survivors only. Our estimators can be used for deciding whether the two recurrent events are correlated and in what way. We provide large sample properties of our estimators and show their performance in small samples by simulations. The estimators are applied in a study of catheter complications among patients receiving home parenteral nutrition through a central venous catheter, and we show a positive correlation between the number of infections and the number of occlusion defects.

We investigated possible clinical and histopathological prognostic factors in a malignant meningioma cohort with comprehensive long-term population-based follow-up data. Twenty-four consecutive patients treated surgically for malignant meningioma at the Department of Neurosurgery and the Department of Pathology, Rigshospitalet, Copenhagen, Denmark, from December 2000 to March 2014 were retrospectively evaluated regarding progression-free survival (PFS) and overall survival (OS). Clinical parameters were recorded. All specimens underwent immunohistochemical analysis for Ki-67 and phosphohistone-H3 (PHH3). Prognostication was assessed with Cox proportional hazard regression analysis. The median follow-up was 46.1 months (range 0.7–150.7). The median progression-free survival was 16.5 months (95% CI 11.4–43.0) and the median overall survival was 46.6 months (95% CI 20.4–NA). Six patients were alive at the end of follow-up; two of these had not experienced a recurrence. No clinical parameter showed significant association with PFS or OS. Mitotic index (MI) was significantly associated with PFS and OS, and PHH3 MI with PFS. Immunohistochemical reactivity of Ki-67 > 10% was a negative predictor of PFS (HR 3.92, 95% CI 1.47–10.4, p = 0.0063) and OS (HR 3.35, 95% CI 1.12–10.1, p = 0.0313). The histological subgrouping of grade III meningioma into anaplastic and non-anaplastic revealed increased PFS for the latter (HR 4.57, CI 95% 1.32–15.7, p = 0.0164). We could not verify previous clinical parameters as prognostic factors in malignant meningioma. MI and the PHH3 MI were prognostic within WHO grade III meningiomas for PFS. An overall tumor staining of Ki-67 > 10% correlated with PFS and OS within grade III tumors.

The aim of the study was to determine the effects of a multi-component community-based health promotion intervention on body mass index (BMI) z-scores and waist circumference (WC) in three- to eight-year-old children. A quasi-experimental design was adopted to evaluate the effects of the SoL intervention involving three intervention and three control communities. The 19-month intervention was based on the supersetting approach and was designed to promote healthier eating and physical activity among children and their families. BMI z-scores and WC were measured at baseline and follow-up. At baseline, 238 (54%) and 214 (51%) of all eligible children were measured from intervention and control, respectively. The change over time in the BMI z-scores of children from the intervention group was significantly different from that of the control group (p = 0.001). BMI z-scores increased over time in the intervention group in contrast to the control group, whose BMI z-scores decreased (difference in change between groups 0.19 z-scores 95% CI 0.08, 0.30). No significant differences were observed for WC. The results showed no favourable effects of the intervention of Project SoL on BMI z-scores and WC in children. Further studies based on a larger sample size and a longer intervention duration are needed.

Background: Pediatric multiple sclerosis (MS) may hamper educational achievements due to psychiatric comorbidity and cognitive impairment. Our aims were to investigate school performance, psychiatric comorbidity, and healthcare utilization following pediatric MS and to differentiate between disability in MS and that arising from a non-brain-related chronic disease. Methods: We included all children (Results: Cohorts were children with MS ( n = 92), control children matched to children with MS ( n = 920), children with non-brain-related chronic diseases ( n = 9108), and “healthy” children with neither MS nor brain-related chronic disease ( n = 811,464). School performance in grades 9–12 was similar, but children with MS compared to those with non-brain-related chronic disease had an almost doubled hazard for psychiatric comorbidity (hazard ratio = 1.87; 95% confidence interval = 1.38–2.53; p Conclusion: Children with MS have a seemingly standard school performance but increased psychiatric comorbidity and a high rate of healthcare utilization.

Background: Chronic diseases in children can impact their parents; this may be overlooked in a clinical setting. Our objective was to investigate associations of chronic diseases in children with their parents’ employment, health care utilization, mental health, and mortality. Methods: In a matched cohort study using nationwide and population-based data in Denmark we included parents to children (

Meningiomas with inherently high mitotic indices and poor prognosis, such as WHO grade III meningiomas, have not been investigated separately to establish interchangeability between conventional mitotic index counted on H&amp, E stained slides (MI) and mitotic index counted on phosphohistone-H3 stained slides (PHH3 MI). This study investigates the agreement of MI and PHH3 MI and to analyze the association of progression-free survival (PFS) and MI, PHH3 MI, and the proliferative index (PI, Ki-67) in WHO grade III meningioma. Tumor specimens from 24 consecutive patients were analyzed for expression of Ki-67, PHH3 MI, and MI. Quantification was performed independently by two observers who made replicate counts in hot spots and overall tumor staining. Repeatability in replicate counts from MI and PHH3 MI was low in both observers. Consequently, we could not report the agreement. MI, PHH3 MI and hot spot counts of Ki-67 were associated with PFS (MI hot spot HR = 1.61, 95% CI 1.12&ndash, 2.31, p = 0.010, PHH3 MI hot spot HR = 1.59, 95% CI 1.15&ndash, 2.21, p = 0.006, Ki-67 hot spot HR = 1.06, 95% CI 1.02&ndash, 1.11. p = 0.004). We found markedly low repeatability of manually counted MI and PHH3 MI in WHO grade III meningioma, and we could not conclude that the two methods agreed. Subsequently, quantification with better repeatability should be sought. All three biomarkers were associated with PFS.

The importance of the human leukocyte antigen (HLA) system in kidney transplantation is well-known, but it remains unexplored if patient HLA antigens constitute independent risk factors in complications after transplantation. We hypothesized that specific HLA class II phenotypes associated with immune-mediated disease (HLA-IMD) predispose to immunological activity and/or complications after kidney transplantation. Based on the literature we defined HLA-DR2-DQ6; -DR3-DQ2 and -DR4-DQ8 as HLA-IMD phenotypes. We investigated associations between HLA-IMD phenotypes in patients, biomarkers of systemic chronic inflammation at the time of transplantation, and the outcome after kidney transplantation in a retrospective cohort study of 611 kidney transplanted patients. The HLA-IMD phenotypes were associated with higher levels of biomarkers of systemic inflammation. The HLA-DR4-DQ8 phenotype was associated with mortality after transplantation in Cox analyses with adjustments for confounders. Data support the hypothesis that specific HLA class II phenotypes affects immunological pathways that determine the midterm clinical outcome of kidney transplantation.

Introduction Elevated levels of soluble urokinase-type plasminogen activating receptor (suPAR) and high-sensitivity C-Reactive Protein (hs-CRP) have in previous studies been associated with increased mortality in selected cardiac surgery populations1 2. Aim of this study was to explore the relationship between suPAR and hsCRP-values and mortality in 30 days and during 1st year from surgery in patients admitted for elective cardiac surgery. Further, to assess whether a combined risk model of EuroSCORE II, suPAR and/or hs-CRP would improve the prognostic accuracy compared to EuroSCORE II alone. Methods Adult patients admitted for elective on-pump cardiac surgery, from August 2012 to June 2018, were included (n=931). Biobank blood samples were analysed for suPAR and hs-CRP levels. Biomarkers and clinical data were explored in relation to quartiles of the two biomarkers. Kaplan-Meier and Cox proportional hazard analysis were used to explore any association between preoperative suPAR and hs-CRP-values and all-cause mortality up to 1-year after surgery. Thirty-day mortality was predicted from suPAR, hsCRP and EuroSCORE II by logistic regression and compared using area under the ROC curve and Brier scores. Results A doubling of suPAR and hsCRP corresponded to a hazard ratio (HR) for all-cause mortality of 2.27 (95% CI 1.65-3.11, p Discussion In conclusion, elevated levels of the proinflammatory biomarkers, suPAR and hs-CRP, can be used as preoperative risk assessment for all-cause mortality in a population of all-comers to elective on-pump cardiac surgery. However, combination of either or both biomarkers to EuroSCORE II did not improve the prognostic accuracy compared to EuroSCORE II alone. In future studies, preoperative assessment of proinflammatory biomarkers may be used to establish personalised rehabilitation programs and follow-up on high-risk patients.

Incomplete information on explanatory variables is commonly encountered in studies of possibly censored event times. A popular approach to deal with partially observed covariates is multiple imputation, where a number of completed data sets, that can be analyzed by standard complete data methods, are obtained by imputing missing values from an appropriate distribution. We show how the combination of multiple imputations from a compatible model with suitably estimated parameters and the usual Cox regression estimators leads to consistent and asymptotically Gaussian estimators of both the finite-dimensional regression parameter and the infinite-dimensional cumulative baseline hazard parameter. We also derive a consistent estimator of the covariance operator. Simulation studies and an application to a study on survival after treatment for liver cirrhosis show that the estimators perform well with moderate sample sizes and indicate that iterating the multiple-imputation estimator increases the precision.

Self-poisoning with non-opioid analgesics presents a growing challenge to health care providers. We aimed to assess the impact of an 18-year age restriction of OTC sales and a pack size restriction of non-opioid analgesics sold OTC in pharmacies on hospital-treated poisonings and poisoning severity measured using biomarkers.We applied a before and after design using interrupted time series analysis. Data on all poisonings recorded as hospital admissions were obtained during 2002-2015 and biochemical parameters from laboratory databases during 2011-2015, both covering the entire Danish population.The age restriction was followed by a 17% level reduction in admissions for non-opioid analgesic poisoning among young people age 10-17 years (RR 0.830; 95% CI 0.697-0.988; p 0.036). After the pack size restriction, an instant level reduction of 18.5% (RR 0.815; 95% CI 0.729-0.912; p 0.001) was observed for the entire population. A 27% decrease in the number of poisonings with alanine transaminase levels (ALT) ≥ 210 U/L was observed (RR 0.734; 95% CI 0.579-0.931; p = 0.011) followed by 40% decrease in biomarkers indicative of liver failure (RR 0.597; 95% CI 0.421-0.847; p = 0.004). We also observed similar reductions for other poisonings such as psychotropics.Although declines in poisonings were observed after implementation of means restrictive measures, a causal link cannot be inferred.Age and pack size restriction were assiociated with a reduction in the numbers of poisonings. This was also observed for pharmaceutical poisonings in general, which might suggest a non-specific or spill-over effect.

We investigated risks and hazard rates of developing chronic ocular graft-versus-host disease (oGVHD) in a large nationwide, single centre study by using the criteria proposed by "The International Chronic oGVHD Consensus Group". This retrospective study included 1407 consecutive adults who underwent allogeneic haematopoietic stem cell transplantation (HSCT). Patients were examined by an ophthalmologist according to the hospital's guidelines: baseline examination before HSCT, annually up to 5 years after HSCT. The 186 (13%) had dry eye disease before HSCT. The 5-year cumulative incidence of oGVHD was 18% (95% CI: 15-21) after myeloablative (MA) and 35% (95% CI: 30-39) after non-myeloablative conditioning (NMA). Factors associated with the rate of oGVHD were assessed separately according to conditioning regimen by using multiple Cox regression analyses. Factors that increased the rate in the MA group: Malignant disease, Schirmer's test≤10 mm/5 min before transplantation, use of female donor, matched unrelated donor, peripheral blood as stem cell source, and grade III-IV acute GVHD. Factors that increased the rate in the NMA group: Schirmer's test≤10 mm/5 min before transplantation and higher recipient age. We recommend a baseline ophthalmological examination before HSCT since many of the patients have signs of dry eyes before transplantation which increased the risk and rate of developing oGVHD.

Background: Acute disseminated encephalomyelitis (ADEM) can cause cognitive impairment in children. However, long-term consequences for school performance and psychiatric morbidity have never been characterized. Our aim was to investigate long-term school performance and psychiatric morbidity after pediatric ADEM (

OBJECTIVE Primary ciliary dyskinesia (PCD) is a congenital lung disease that leads to recurrent and chronic lung infection. The resulting inflammation causes lung damage and declines in lung function. Mannose-binding lectin (MBL) is a first line host defense protein of importance for the innate immunity. Polymorphisms in the MBL gene named MBL2 result in unstable and low functional levels MBL proteins. MBL insufficiency is linked to an increased risk of lung infection and to declines in lung function in patients with cystic fibrosis. We investigated whether there is a similar link in patients with PCD. METHODS This retrospective longitudinal study included 85 patients with PCD. Diagnostics and age at diagnosis were recorded, complete spirometry data starting at diagnosis, and Pseudomonas aeruginosa infection status over the last 2 years were collected, and the patients were grouped according to MBL2 genotype status (MBL2-sufficient or MBL2-deficient). RESULTS MBL-deficient patients were diagnosed almost 3 years earlier than MBL-sufficient patients (median 6.1 vs 8.9 years, P

BACKGROUND: Children and adolescents are more prone to develop adverse effects during antipsychotic treatment than adults. The purpose of this paper iso investigate cardiometabolic effects and its predictors in youth with first-episode psychosis (FEP) treated with quetiapine-extended release (ER) vs. aripiprazole. METHODS: Youths with FEP aged 12–17 years were randomized to quetiapine-ER or aripiprazole in the 12-week, double-blinded, Tolerability and Efficacy of Antipsychotics (TEA) trial. Primary outcome was change in body weight; secondary outcomes were changes in body mass index (BMI) and waist circumference (WC), blood pressure (BP), heart rate, and lipid and glucose metabolism parameters. Possible predictors of cardiometabolic changes were examined. RESULTS: Altogether, 113 patients (schizophrenia-spectrum disorders=93%, age (mean±SD): 15.7±1.4 years, males=30.1%), were randomized to quetiapine-ER (n=55) or aripiprazole (n=58). Quetiapine-ER was associated with significantly larger increases in body weight, BMI z-score and WC z-score than aripiprazole (all between-group p-values p

Background Unfavorable conditions associated with cesarean section may influence the risk of type 1 diabetes in offspring, but results from studies are conflicting. We aimed to evaluate the association between prelabor cesarean section and risk of childhood type 1 diabetes. Methods A Danish nationwide cohort study followed all singletons born during 1982-2010. Four national registers provided information on mode of delivery, outcome, and confounders. The risk of childhood type 1 diabetes with onset before the age of 15 years was assessed by Cox regression. A total of 1,760,336 singletons contributed 20,436,684 person-years, during which 4,400 were diagnosed with childhood type 1 diabetes. Results The hazard ratio (HR) for childhood type 1 diabetes was increased in children delivered by prelabor cesarean section compared with vaginal delivery when adjusted for year of birth, parity, sex, parental age, and education and paternal type 1 diabetes status at childbirth (HR = 1.2; 95% confidence interval [CI] = 1.0, 1.3), but not after additional adjustment for maternal type 1 diabetes status at childbirth (HR = 1.1; 95% CI = 0.95, 1.2). Delivery by intrapartum cesarean section was not associated with childhood type 1 diabetes. Paternal type 1 diabetes was a stronger risk factor for childhood type 1 (HR = 12; 95% CI = 10, 14) than maternal type 1 diabetes (HR = 6.5; 95% CI = 5.2, 8.0). Conclusions Delivery by prelabor cesarean section was not associated with an increased risk of childhood type 1 diabetes in the offspring.

Background: Infections are suspected environmental triggers for multiple sclerosis (MS). The relationship between the timing and cumulative number of childhood infections regarding pediatric MS risk is uninvestigated. Objectives: To investigate whether childhood infections contribute to pediatric MS. Methods: A nationwide nested case–control study with detailed MS case ascertainment including chart review was undertaken. For each MS case, we selected five control children using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data with the cumulative number of childhood infections as exposure and MS as outcome. Hazard ratios (HRs) including 95% confidence intervals (CIs) were estimated using Cox regression. Results: We identified 212 children with MS and 1,060 controls. Median age at MS onset was 15.3 years (range: 7.6–17.8 years); 72% were girls. Each infection during the preceding 3 years increased the hazard for MS by 11% (95% CI = 1.01–1.22, p = 0.04); having 5+ infections compared with 0–4 infections in the preceding 3 years doubled the hazard for MS (HR: 2.18; 95% CI = 1.12–4.30, p = 0.02). Conclusion: Children with MS appeared to have more infections in the 3 years preceding MS clinical onset; accordingly, immune response to infections may influence MS pathogenesis.

End-stage renal failure is associated with persistent systemic inflammation. The aim of this study was to investigate if systemic inflammation at the time of kidney transplantation is linked to poor graft survival, major adverse cardiovascular events (MACE), and increased mortality, and if these processes are modulated by naturally occurring cytokine-specific autoantibodies (c-aAbs), which have been shown to regulate cytokine activity in vitro. Serum levels of cytokines, high-sensitivity C-reactive protein (hsCRP) and c-aAbs specific for interleukin (IL)-1α, tumor necrosis factor (TNF)-α, IL-6, and IL-10 were measured at the time of transplantation in a retrospective cohort study of 619 kidney transplanted patients with a median follow-up of 4.9 years (range 1.2-8.2 years). Systemic inflammation was associated with all-cause mortality in simple and multiple Cox regression analyses. IL-10-specific c-aAbs were associated with MACE after transplantation, suggesting that IL-10 may be a protective factor. Similarly, patients with a history of MACE before transplantation had lower levels of TNF-α-specific c-aAbs, hence we hypothesized that TNF may be a risk factor of MACE. These findings support that pro-inflammatory activity before transplantation is a pathological driver of MACE and all-cause mortality after transplantation. This information adds to pretransplantation risk estimation in renal transplant candidates.

To investigate cardiometabolic effects and their predictors in youths with first-episode psychosis (FEP) treated with quetiapine-extended release (ER) versus aripiprazole.Youths with FEP who were 12 to 17 years of age were randomized to quetiapine-ER or aripiprazole in the 12-week, double-blinded, Tolerability and Efficacy of Antipsychotics (TEA) trial. Primary outcome was change in body weight; secondary outcomes were changes in body mass index (BMI) and waist circumference (WC), blood pressure (BP), heart rate, and lipid and glucose metabolism parameters. Possible predictors of cardiometabolic changes were examined.Altogether, 113 patients (schizophrenia-spectrum disorders = 93%; age [mean ± SD] = 15.7 ± 1.4 years; male participants = 30.1%) were randomized to quetiapine-ER (n = 55) or aripiprazole (n = 58). Quetiapine-ER led to significant increases in body weight (4.88 kg, 95% CI = 3.92-5.83, p .0001), BMI z-score (0.43, 95% CI = 0.33-0.53, p .0001), and WC z-score (0.97, CI = 0.7-1.23, p .0001). Changes were significantly smaller with aripiprazole (all between-group p values .0001): body weight: 1.97 kg (CI = 0.97-2.97, p = .0001), BMI z-score: 0.10 (CI = -0.01 to 0.20, p = .0646), and WC z-score: 0.18 (CI = -0.09 to 0.45, p = .1968). Lipid and glucose metabolism parameters increased significantly at week 4 and week 12 only with quetiapine-ER (p range = 0.0001-0.037). Quetiapine-ER was associated with an increased occurrence of obesity, elevated blood lipids and hyperinsulinemia (p range = 0.004-0.039). Early weight gain, obesity, or type 2 diabetes in the family significantly predicted weight and BMI gain at week 12.In youths with FEP, quetiapine-ER was associated with significantly greater weight gain and adverse changes in metabolic outcomes than was aripiprazole. Early weight gain must be addressed and family lifestyle factors taken into consideration when treating youths with antipsychotics.Tolerance and Effect of Antipsychotics in Children and Adolescents With Psychosis (TEA); https://clinicaltrials.gov; NCT01119014.

Summary Epidemiological studies of related individuals are often complicated by the fact that follow-up on the event type of interest is incomplete due to the occurrence of other events. We suggest a class of frailty models with cause-specific hazards for correlated competing events in related individuals. The frailties are based on sums of gamma distributed variables and offer closed form expressions for the observed intensities. An inference procedure with a recursive baseline estimator is proposed, and its large sample properties are established. The estimator readily handles cluster left-truncation as occurring in the Nordic twin registers. The performance in finite samples is investigated by simulations and an example on prostate cancer in twins is provided for illustration.

We suggest an estimator for the proportional odds cumulative incidence model for competing risks data. The key advantage of this model is that the regression parameters have the simple and useful odds ratio interpretation. The model has been considered by many authors, but it is rarely used in practice due to the lack of reliable estimation procedures. We suggest such procedures and show that their performance improve considerably on existing methods. We also suggest a goodness-of-fit test for the proportional odds assumption. We derive the large sample properties and provide estimators of the asymptotic variance. The method is illustrated by an application in a bone marrow transplant study and the finite-sample properties are assessed by simulations.

Left-truncation occurs frequently in survival studies, and it is well known how to deal with this for univariate survival times. However, there are few results on how to estimate dependence parameters and regression effects in semiparametric models for clustered survival data with delayed entry. Surprisingly, existing methods only deal with special cases. In this paper, we clarify different kinds of left-truncation and suggest estimators for semiparametric survival models under specific truncation schemes. The large-sample properties of the estimators are established. Small-sample properties are investigated via simulation studies, and the suggested estimators are used in a study of prostate cancer based on the Finnish twin cohort where a twin pair is included only if both twins were alive in 1974.

BACKGROUND: Pediatric-onset multiple sclerosis (MS) affects life at a stage vital for social and educational achievements and psychiatric co-morbidity is common after MS onset. Few studies have examined psychiatric morbidity before MS onset.METHODS: In this nationwide study, detailed case ascertainment was performed in all children with pediatric MS, including chart review. For each MS patient, we selected five controls using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data as a nested case-control study with psychiatric morbidity as exposure and MS as outcome, and a matched cohort study with MS as exposure and psychiatric co-morbidity as outcome. Hazard ratios (HR) including 95% confidence intervals (CI) were estimated using Cox regression.RESULTS: We identified 212 children with MS and 1060 controls. No association between psychiatric morbidity and the rate of MS was found before MS onset. After MS onset, children with MS had two times higher hazard for psychiatric co-morbidity compared with children without MS (HR=2.0; 95% CI=1.3-3.1; pCONCLUSION: Psychiatric morbidity seems to commence after MS onset, making screening for neuropsychiatric conditions pertinent in newly-diagnosed children with MS.

Background Patients with end-stage renal disease (ESRD) have high morbidity and mortality rates, with cardiovascular diseases and infections being the major causes of death. Mannose-binding lectin (MBL) has been suggested to play a protective role in this regard. The aim of this study was to investigate a possible clinical association of MBL genotypes (MBL2) with outcome among patients on dialysis or with a functioning graft. Methods A total of 98 patients with ESRD accepted for living-donor renal transplantation or on the waiting list for transplantation were included and prospectively followed for an average of 9 years (range 7.5-9.9). Medical records were evaluated regarding transplantation status, diabetes mellitus, vascular parameters and infections for all the patients. Cox regression models and logistic regression analysis were used for statistical analyses. The cohort was divided into two groups according to the MBL2 genotype (normal A/A versus variant A/O or O/O). Results We found no evidence for an association between the MBL2 genotype and all-cause mortality, cardiovascular events or bacterial infections (pneumonia, urinary tract infection, fistula infection or other infections). Conclusion In this cohort, the MBL2 genotype did not seem to be associated with any long-term clinical effects in ESRD patients on dialysis or with a functioning graft.

The marginal approach and the conditional approach are two different ways to model clustered dental failure time data. We compare the two approaches in the context of a Cox regression analysis, where the aim is to estimate the effect of a covariate (e.g., dental treatment) on the risk of failure. Specifically, we treat within-cluster correlation as if it was introduced by unobserved cluster level covariates, and study the small sample behaviour of the marginal and the conditional approach. We show that in a non-randomized setting where an unobserved cluster variable is correlated with the variable of interest, both the marginal and the conditional approaches can give misleading results. We argue that this is an important message, since most often it is assumed that the frailty term and the covariates of interest are independent.

BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy.PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1].RESULTS: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47).CONCLUSIONS: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

BACKGROUND:Studies link antibiotic treatment and delivery by cesarean section with increased risk of chronic diseases through changes of the gut-microbiota. We aimed to evaluate the association of broad-spectrum antibiotic treatment during the first two years of life with subsequent onset of childhood type 1 diabetes and the potential effect-modification by mode of delivery. MATERIALS AND METHODS:A Danish nationwide cohort study including all singletons born during 1997-2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox regression. A total of 858,201 singletons contributed 5,906,069 person-years, during which 1,503 children developed type 1 diabetes. RESULTS:Redemption of broad-spectrum antibiotics during the first two years of life was associated with an increased rate of type 1 diabetes during the following 13 years of life (HR 1.13; 95% CI 1.02 to 1.25), however, the rate was modified by mode of delivery. Broad-spectrum antibiotics were associated with an increased rate of type 1 diabetes in children delivered by either intrapartum cesarean section (HR 1.70; 95% CI 1.15 to 2.51) or prelabor cesarean section (HR 1.63; 95% CI 1.11 to 2.39), but not in vaginally delivered children. Number needed to harm was 433 and 562, respectively. The association with broad-spectrum antibiotics was not modified by parity, genetic predisposition or maternal redemption of antibiotics during pregnancy or lactation. CONCLUSIONS:Redemption of broad-spectrum antibiotics during infancy is associated with an increased risk of childhood type 1 diabetes in children delivered by cesarean section.

Epidemiological studies of related individuals are often complicated by the fact that follow-up on the event type of interest is incomplete due to the occurrence of other events. We suggest a class of frailty models with cause-specific hazards for correlated competing events in related individuals. The frailties are based on sums of gamma distributed variables and offer closed form expressions for the observed intensities. An inference procedure with a recursive baseline estimator is proposed, and its large sample properties are established. The estimator readily handles cluster left-truncation as occurring in the Nordic twin registers. The performance in finite samples is investigated by simulations and an example on prostate cancer in twins is provided for illustration.