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Patients with B-cell-derived malignancies are at increased risk of severe coronavirus disease 2019 (COVID-19) due to the inherent immune dysfunction and/or treatment. To protect patients in general and patients with B-cell-derived malignancies in particular from COVID-19, management of these patients was changed toward virtual consultations during the pandemic. Whether the COVID-19 pandemic itself and/or changes in management have led to excess mortality among hematological patients during the COVID-19 pandemic in Denmark has not yet been investigated.

To the Editor: We thank Pham et al1 for their interest in our study on patients with atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS),2 and we appreciate the opportunity to discuss and clarify our analysis further.

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.

Background Patients receiving total hip arthroplasty (THA) due to metastatic bone disease of the hip (MBD) are at an increased risk of post-operative joint dislocation compared to other populations. Different joint solutions have been developed with the purpose of reducing the dislocation risk compared to regular THAs. One of these solutions, the constrained liner (CL), has been used increasingly at our department in recent years. This design, however, is prone to polyethylene wear and higher revision rates. An alternative is the dual mobility cup (DM), which has been shown to reduce the risk of dislocation in other high-risk populations. Few studies have investigated DM for THA due to MBD, and no studies have directly compared these two treatments in this population. We therefore decided to conduct a trial to investigate whether DM is non-inferior to CL regarding the post-operative joint dislocation risk in patients receiving THA due to MBD. Materials and methods This study is a single-center, randomized, open-label, two-arm, non-inferiority trial. We will include 146 patients with MBD of the hip who are planned for THA at the Department of Orthopedic Surgery, Rigshospitalet. Patients with previous osteosynthesis or endoprosthetic surgery of the afflicted hip, or who are planned to receive partial pelvic reconstruction or total femoral replacement, will be excluded. Patients will be stratified by whether subtrochanteric bone resection will be performed and allocated to either CL or DM in a 1:1 ratio. The primary outcome is the 6 months post-operative joint dislocation rate. Secondary outcomes include overall survival, implant survival, the rate of other surgical- and post-operative complications, and quality of life and functional outcome scores. Discussion This study is designed to investigate whether DM is non-inferior to CL regarding the risk of post-operative dislocation in patients receiving THA due to MBD. To our knowledge, this, Background: Patients receiving total hip arthroplasty (THA) due to metastatic bone disease of the hip (MBD) are at an increased risk of post-operative joint dislocation compared to other populations. Different joint solutions have been developed with the purpose of reducing the dislocation risk compared to regular THAs. One of these solutions, the constrained liner (CL), has been used increasingly at our department in recent years. This design, however, is prone to polyethylene wear and higher revision rates. An alternative is the dual mobility cup (DM), which has been shown to reduce the risk of dislocation in other high-risk populations. Few studies have investigated DM for THA due to MBD, and no studies have directly compared these two treatments in this population. We therefore decided to conduct a trial to investigate whether DM is non-inferior to CL regarding the post-operative joint dislocation risk in patients receiving THA due to MBD. Materials and methods: This study is a single-center, randomized, open-label, two-arm, non-inferiority trial. We will include 146 patients with MBD of the hip who are planned for THA at the Department of Orthopedic Surgery, Rigshospitalet. Patients with previous osteosynthesis or endoprosthetic surgery of the afflicted hip, or who are planned to receive partial pelvic reconstruction or total femoral replacement, will be excluded. Patients will be stratified by whether subtrochanteric bone resection will be performed and allocated to either CL or DM in a 1:1 ratio. The primary outcome is the 6 months post-operative joint dislocation rate. Secondary outcomes include overall survival, implant survival, the rate of other surgical- and post-operative complications, and quality of life and functional outcome scores. Discussion: This study is designed to investigate whether DM is non-inferior to CL regarding the risk of post-operative dislocation in patients receiving THA due to MBD. To our knowledge, this trial is the first of it

Introduction: The documented treatment-induced excess mortality in Hodgkin lymphoma (HL) has led to significant changes in treatment regimens aimed at maintaining efficacy while reducing toxicity. These modifications include the replacement of alkylator-based regimens with anthracycline-based combinations and the adoption of highly conformal radiotherapy. Danish and Nordic radiation oncologists were pioneers in implementing these changes nationwide 10-15 years earlier than most other nations. These early adaptations make Danish HL data uniquely valuable for assessing long-term mortality in a cohort where modern treatment regimens have been implemented nationwide throughout the entire study period. The impact of these treatment modifications on mortality risk in HL survivors remains unclear, therefore, this study aims to assess cause-specific mortality among HL patients treated with contemporary strategies. Methods: This nationwide, unselected study included all HL patients in Denmark aged 15-40 years at diagnosis and treated between 1995 and 2015. Patients were followed from diagnosis until emigration, death, or the study end. HL cases were identified through meticulous individual record reviews of medical records, national registries, and pathology data. Disease-specific death due to HL was the primary outcome, with other cause-specific mortality as a competing risk. Cox proportional hazard models assessed factors influencing overall survival and cause-specific survival. A landmark analysis was conducted to compare the risk of death between the study population and the national background population. Results: Among 1,348 included HL patients, 66.5% had Ann Arbor stage I-II at the time of diagnosis. During 18,731 person-years of follow-up, 139 deaths occurred, resulting in a 5-year overall survival rate of 94.6% (95% CI 93.4-95.8). Factors associated with higher overall mortality risk included older age, advanced disease stage at diagnosis, earlier

This work considers targeted maximum likelihood estimation (TMLE) of treatment effects on absolute risk and survival probabilities in classical time-to-event settings characterized by right-censoring and competing risks. TMLE is a general methodology combining flexible ensemble learning and semiparametric efficiency theory in a two-step procedure for substitution estimation of causal parameters. We specialize and extend the continuous-time TMLE methods for competing risks settings, proposing a targeting algorithm that iteratively updates cause-specific hazards to solve the efficient influence curve equation for the target parameter. As part of the work, we further detail and implement the recently proposed highly adaptive lasso estimator for continuous-time conditional hazards with -penalized Poisson regression. The resulting estimation procedure benefits from relying solely on very mild nonparametric restrictions on the statistical model, thus providing a novel tool for machine learning based semiparametric causal inference for continuous-time time-to-event data. We apply the methods to a publicly available dataset on follicular cell lymphoma where subjects are followed over time until disease relapse or death without relapse. The data display important time-varying effects which can be captured by the highly adaptive lasso. In our simulations, that are designed to imitate the data, we compare our methods to a similar approach based on random survival forests and to the discrete-time TMLE. This article is protected by copyright. All rights reserved.

Targeted maximum likelihood estimation is a general methodology combining flexible ensemble learning and semiparametric efficiency theory in a two-step procedure for estimation of causal parameters. Proposed targeted maximum likelihood procedures for survival and competing risks analysis have so far focused on events taken values in discrete time. We here present a targeted maximum likelihood estimation procedure for event times that take values in R+. We focuson the estimation of intervention-specific mean outcomes with stochastic interventions on a time-fixed treatment. For data-adaptive estimation of nuisance parameters, we propose a new flexible highly adaptive lasso estimation method for continuous-time intensities that can be implemented with L1-penalized Poisson regression. In a simulation study the targeted maximum likelihood estimator based on the highly adaptive lasso estimator proves to be unbiased and achieve proper coverage in agreement with the asymptotic theory and further displays efficiency improvements relative to a Kaplan-Meier approach.

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 dis

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: 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.

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 (<18 years) with MS onset during 2008–2015 in Denmark with a medical record–validated MS diagnosis. The control groups were children from the general population or children with non-brain-related chronic diseases. Outcomes were register-based on 9–12 grade point average, psychiatric comorbidity, and healthcare visits. 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 < 0.0001) and a higher rate of all hospital visits (p < 0.0001) but a lower rate of hospital admissions (p = 0.001). Conclusion: Children with MS have a seemingly standard school performance but increased psychiatric comorbidity and a high rate of healthcare utilization.

We consider a log-linear model for survival data, where both the location and scale parameters depend on covariates and the baseline hazard function is completely unspecified. This model provides the flexibility needed to capture many interesting features of survival data at a relatively low cost in model complexity. Estimation procedures are developed and asymptotic properties of the resulting estimators are derived using empirical process theory. Finally, a resampling procedure is developed to estimate the limiting variances of the estimators. The finite sample properties of the estimators are investigated by way of a simulation study, and a practical application to lung cancer data is illustrated.

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&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 1.12–2.31, p = 0.010; PHH3 MI hot spot HR = 1.59, 95% CI 1.15–2.21, p = 0.006; Ki-67 hot spot HR = 1.06, 95% CI 1.02–1.11. 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.