Background: Dementia leads to a high burden of disability and the number of dementia patients worldwide doubled between 1990 and 2016. Nevertheless, some studies indicated a decrease in dementia risk which may be due to a bias caused by conventional analysis methods that do not adequately account for missing disease information due to death. Methods: This study re-examines potential trends in dementia incidence over four decades in the Framingham Heart Study. We apply a multistate modeling framework tailored to interval-censored illness-death data and define three non-overlapping birth cohorts (1915-1924, 1925-1934, and 1935-1944). Trends are evaluated based on both dementia prevalence and dementia risk, using age as the underlying timescale. Additionally, age-conditional dementia probabilities stratified by sex are estimated. Results: A total of 731 out of 3828 individuals were diagnosed with dementia. The multistate model analysis revealed no temporal decline in dementia risk across birth cohorts, irrespective of sex. When stratified by sex and adjusted for education, women consistently exhibited higher lifetime age-conditional risks (46 Conclusions: We recommend using a combination of multistate approach and separation into birth cohorts to adequately estimate trends of disease risk in cohort studies as well as to communicate patient-relevant outcomes such age-conditional disease risks.

Censoring makes time-to-event data special and requires customized statistical techniques. Survival and event history analysis therefore builds on hazards as the identifiable quantities in the presence of rather general censoring schemes. The reason is that hazards are conditional quantities, given previous survival, which enables estimation based on the current risk set-those still alive and under observation. But it is precisely their conditional nature that has made hazards subject of critique from a causal perspective: A beneficial treatment will help patients survive longer than had they remained untreated. Hence, in a randomized trial, randomization is broken in later risk sets, which, however, are the basis for statistical inference. We survey this dilemma-after all, mapping analyses of hazards onto probabilities in randomized trials is viewed as still having a causal interpretation-and argue that a causal interpretation is possible taking a functional point of view. We illustrate matters with examples from benefit-risk assessment: Prolonged survival may lead to more adverse events, but this need not imply a worse safety profile of the novel treatment. These examples illustrate that the situation at hand is conveniently parameterized using hazards, that the need to use survival techniques is not always fully appreciated and that censoring not necessarily leads to the question of "what, if no censoring?" The discussion should concentrate on how to correctly interpret causal hazard contrasts and analyses of hazards should routinely be translated onto probabilities.

BACKGROUND:The goal of evidence-based medicine is to make clinical decisions based on the best available, relevant evidence. For this to be possible, studies such as randomized controlled trials (RCTs), which are widely considered to provide the best evidence of all forms of primary research, must be visible and have an impact on clinical practice guidelines. We further investigated the impact of publicly and commercially sponsored RCTs on clinical practice guidelines by measuring direct and indirect impactful citations and the time to guideline impact. METHODS:We considered the sample from the IMPACT study, where a total of 691 RCTs (120 German investigator-initiated trials (IITs), 200 international IITs, 171 German industry-sponsored trials (ISTs) and 200 international ISTs) was sampled from registries (DFG-/BMBF-Websites, the German Clinical Trials Register, and from ClinicalTrials.gov) and followed prospectively. First, all eligible IITs were sampled. Then, ISTs were randomly selected while ensuring balance across certain trial characteristics. Next, the corresponding publications in the form of original research articles were identified. A search was then conducted for (1) systematic reviews (SRs) citing these articles and (2) clinical practice guidelines (CPGs) that cited either the original articles or the SRs. The methods and results of this effort were already published. In this investigation we aimed to better characterize the impact of RCTs in CPGs. Therefore, we identified all citations of the original articles and SRs in the citing CPGs and classified them into impactful and non-impactful. This allowed us to calculate an estimate for the guideline impact of a trial. In addition, we estimated the time-to-guideline-impact, defined as the time to a direct and indirect impactful citation in a CPG. Direct means that the publication of a trial was cited in the main text of a CPG. Indirect means that the publication was cited and included in the findings of a SR and the SR was cited in the main text of a CPG. We also investigated to what extent pre-defined study characteristics influenced the guideline impact using multivariable negative binomial regression as well as the time-to-guideline impact using multivariable Cox proportional hazards regression. RESULTS:Overall, 22% of RCTs impacted a CPG. For international ISTs, only 15% of trials had an impact in CPGs. Overall, of the 405 associated guidelines, 331 were impacted. Larger trials were associated with more impactful main text citations in CPGs and earlier time-to-guideline impact, while international industry-sponsored trials were associated with smaller impact on CPGs and longer time-to-guideline impact. IITs funded by governmental bodies in Germany reached an impact on CPGs that is on par with German ISTs or international IITs and ISTs. CONCLUSION:This study demonstrated that a considerable number of trials previously identified as being linked to CPGs have had impact in those CPGs (85%). International ISTs seem to have a lower impact on CPGs, and fewer of them influence CPGs at all.

Introduction: Myelofibrosis is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms, often resulting in significant morbidity and mortality. Allogeneic hematopoietic stem-cell transplantation (SCT) remains the only potentially curative treatment but is associated with considerable risks. Ruxolitinib, a JAK1/2 inhibitor, improves splenomegaly and symptoms but does not offer a cure. The primary objective of this study was to compare event-free survival (EFS) between patients who underwent SCT after 3 months of ruxolitinib induction therapy and those who continued ruxolitinib due to lack of a suitable donor (HLA-identical sibling or 10/10 matched unrelated donor). Methods: This prospective, multicenter clinical trial (RuxoAllo study, NCT03333187) enrolled 87 myelofibrosis patients, all of whom began with ruxolitinib induction. Major inclusion criteria comprised primary or secondary myelofibrosis with intermediate-2 or high-risk disease, or intermediate-1 risk with high-risk cytogenetics, transfusion dependency, or thrombocytopenia; all patients were ruxolitinib-naïve and aged ≥18 years. After screening, 73 were assigned to either transplantation (SCT group, n=57) or continued ruxolitinib therapy (ContRuxo group, n=16). Efficacy endpoints included EFS and overall survival (OS). Safety endpoints included incidence of acute and chronic graft-versus-host disease, disease-related mortality, and non-relapse mortality. EFS was defined as survival without relapse, disease progression, death, or change in therapy. Safety was evaluated through adverse events, laboratory parameters, and ECOG performance status. Quality of life (QoL) was assessed before, during, and after treatment. Results: At baseline, the median patient age was 58 years, with 71% having primary myelofibrosis and 63% being male. In the Full Analysis Population, SCT showed significantly improved EFS, with a median EFS not reach for the SCT group vs. 18 months for the ContRuxo group (P<0.001). SCT was associated with 84% reduced risk of death or progression, with a hazard ratio of 0.16 (95% CI: 0.06–0.46). Multivariable adjustment with patient- and disease-specific variables confirmed the independent benefit of SCT, with a hazard ratio of 0.18 (P<0.001). Subgroup analyses confirmed consistent benefits of SCT across age and DIPSS risk groups. Three-year OS was 84% for the SCT group vs. ContRuxo 83%. Spleen responses were notable after ruxolitinib induction but did not differ significantly between arms thereafter. The cumulative incidence of grade II–IV acute graft-versus-host disease by day 100 was 7% (95% CI: 2–15), while chronic graft-versus-host disease occurred in 63% (95% CI: 49–75%) at 3 years, with 32% classified as moderate or severe. Disease-related mortality was lower in the SCT group (9% vs. 17%). Relapse/progression rates at 3 years were significantly higher in the ContRuxo group (56% vs. 18%, p=0.02), whereas non-relapse mortality was higher in the SCT group (0% vs. 7%, p=0.04). Severe adverse events were more frequent with SCT (50%) compared to ContRuxo (31%), including infections, cytopenias, and graft-versus-host disease. Ruxolitinib was mainly associated with hematological toxicities. QoL initially declined following SCT but improved substantially over time, with a 45% reduction in symptom burden and an 8% increase in overall well-being by 24 months. In contrast, QoL in the ContRuxo group remained more stable, with only modest symptom relief (22% reduction) and a 5% decline in functional QoL. Conclusion: The RuxoAllo prospective study demonstrates that SCT following ruxolitinib induction significantly improves EFS and disease control compared to continued ruxolitinib in patients with myelofibrosis, particularly in those with intermediate- or high-risk disease. Despite a relatively low non-relapse mortality of 7%, SCT remains associated with substantial risks, including graft-versus-host disease and other toxicities, underscoring the need for careful patient selection. Ruxolitinib remains valuable for symptom management and can serve as an effective bridge to transplant. These findings support SCT as the preferred curative approach for eligible myelofibrosis patients and highlight the importance of strategies to mitigate transplant-related morbidity.

INTRODUCTION:Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear. METHODS:We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimated glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy or death due to kidney disease) in EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure. RESULTS:In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid and urine albumin-to-creatinine ratio mediated 79.4%, 33.2% and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%) and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis. CONCLUSIONS:Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.

Background: T-cell-receptor (TCR)- T-cell therapies have shown promising results in cancer patients, most notably to date in patients with advanced melanoma. However, there is little data on delayed sequential dosing of TCR-T-cell therapies in patients with progressive disease. Split-dosing of TCR or CAR (chimeric antigen receptor)-T cells has been performed mostly to decrease toxicity and to increase total cell dose by infusion of the cells on two or three consecutive days. We postulated first that a “second hit” of tumor directed TCR-T cells might increase anti-tumor activity and lead to an altered and improved TCR-T-cell evolution in vivo with reduced T-cell exhaustion and second, that combination therapies of TCR-T cells with BRAF/MEK-inhibition (MAPKi) would be safe and could lead to synergistic activity. Methods: In support of these hypotheses we report on a 64-year-old male patient with advanced melanoma and progressive disease. The patient was screened for the IMA203CD8 trial but found to be non-eligible due to high tumor volume. Instead, he received IMA203CD8 as compassionate use with two sequential doses of IMA203CD8 TCR-T-cell therapy targeting PRAME combined with MAPKi at the University Hospital of Bonn, Germany. Results: Since his initial diagnosis in 2020, the patient experienced several relapses under treatment (radiotherapy, MAPKi, immune checkpoint inhibition and radiotherapy) and was eventually included in the IMA203CD8 trial. However, rapid progression of the disease made him ineligible from the trial. With no alternative therapeutic options available, he underwent a compassionate use treatment attempt with IMA203CD8. After standard lymphodepletion, the patient received the first dose of IMA203CD8 on day 0 (400 TCR-T cells/m2 BSA ), and the second infusion of IMA203CD8 on day +11 (800 TCR-T cells/m2 BSA). On day +1 after first IMA203CD8 infusion, the patient developed cytokine release syndrome (CRS) grade II with fever and oxygen dependency as well as a CRS-related immune effector cell associated neurotoxicity syndrome (ICANS) grade II. Dexamethasone and Tocilizumab were initiated, which led to quick termination of ICANS but he had continuous high fever and intermittent oxygen dependency (CRS grade II), so that Anakinra was added alongside high-dose Dexamethasone and Tocilizumab on day +3. With this, CRS improved to grade I on day +5 and completely resolved on day +8. The patient developed delirium on day +7 with visual phenomena and thought disorder. A CT-scan of the brain was unremarkable. Under short-course low-dose neuroleptic medication the symptoms rapidly resolved. Interleukin 2 (IL-2) was administered on day +9 and +10 in keeping with the trial protocol. On day +11 the patient received the second IMA203CD8 infusion which resulted only in self-limiting CRS grade I with fever on days +14 and +15 and no ICANS. IL-2 was administered from day +12 until day +21 without incident. The patient was discharged on day +22 with no additional toxicities and in overall good condition. Subsequent outpatient monitoring did not show further events. In the first follow-up on day +42 after the first IMA203CD8 infusion, the patient showed remarkable tumor reduction and is in good condition at the time of submission. Conclusion: Here we present for the first time that a delayed sequential application of IMA203CD8 TCR-T cells in a heavily pretreated melanoma patient with progressive disease is safe and well manageable. Clinically, the second infusion also led to a second TCR-T-cell response with low grade CRS, but despite prolonged CRS after the first infusion and the increased second cell dose, this did not lead to severe toxicities. Additionally, as we could previously show with IMA203 TCR-T cells, IMA203CD8 TCR-T cells can be administered simultaneously with MAPKi and the combination is feasible, safe, and possibly beneficial. Although the individual contribution of the second IMA203CD8 infusion on the tumor response currently cannot be ultimately distinguished, longer follow-up and detailed assessment of the immune response will shed more light on the potential benefits of a delayed second infusion of T-cell therapies, as this novel approach could help increase anti-tumor activity of TCR- and CAR-T-cell therapies and enhance T-cell status potentially long-term with reduced T-cell exhaustion.

BACKGROUND:Prophylactic antibiotics are still controversial during allogeneic hematopoietic stem cell transplantation (allo-HSCT). In our transplant center, we suspended antibiotic prophylaxis during allo-HSCT in 2017. OBJECTIVE:The main objective of this study was the detailed analysis of the potentially beneficial impact of omittance of standard antibiotic prophylaxis during allo-HSCT in survival and Graft-versus-Host disease (GvHD) development, especially with consideration of confounding factors and competing events. Secondary objectives were the evaluation of the risk of severe infections and transplant-related mortality without antibiotic prophylaxis, the detailed assessment of bacterial and viral infections including multiresistant pathogens as well as occurrence of relapse in both groups. This study aims to support the development of future antibiotic strategies in allo-HSCT. STUDY DESIGN:We retrospectively analyzed patient outcome in the time periods before (between December 2012 and February 2017) and after suspension (between March 2017 and June 2020) of antibiotic prophylaxis during allo-HSCT. Relevant clinical outcome parameters of the patients (n = 221) were collected by chart-review in the two groups (with antibiotic prophylaxis n = 101 versus without antibiotic prophylaxis n = 120). All patients were 18 years or older. Propensity score methods were used to adjust for potentially confounding patient characteristics. To address competing events, transitions between moderate/severe acute and chronic GvHD, relapse and death were analyzed using an inverse-propensity score weighted multistate modeling approach. RESULTS:While we observed a trend towards an improved outcome in the cohort without antibiotic prophylaxis, the inverse-propensity-score-weighted analyses did not show significant differences between the two groups in overall survival (OS) (P = .811) or development of acute GvHD (aGvHD) grade 3/4 (P = .158) and chronic moderate/severe GvHD (cGvHD) (P = .686). Multistate analysis respecting competing events revealed comparable estimated probabilities without antibiotic prophylaxis versus with antibiotic prophylaxis in OS (35.0% [95% CI: 28.2%-42.7%] versus 35.3% [95% CI: 27.8%-41.1%]) as well as development of aGvHD grade 3/4 (7.7% [95% CI: 5.9%-12.2%] vs. 10.6% [95% CI: 7.7%-15.7%]) and moderate/severe cGvHD (21.0% [95% CI: 17.7%-30.0%] vs. 23.8% [95% CI: 19.6%-31.4%]). Similar analyses showed also no significant differences in relapse rate, transplant-related mortality, relapse-related mortality, or GvHD-free/relapse-free survival between the two groups. An observed increase in severe infections without antibiotic prophylaxis did not lead to a significantly higher mortality rate. Viral reactivation and detection of multiresistant bacteria were comparable, yet a higher incidence of Clostridioides difficile infections was observed in patients receiving antibiotic prophylaxis. CONCLUSION:Our study supports previous reports of noninferiority of allo-HSCT without use of antibiotic prophylaxis with close monitoring and rapid intervention, if infection is suspected. The trend towards improved outcomes without antibiotic prophylaxis, however, might not only be due to the absence of antibiotic prophylaxis but also due to additional progresses in the field over the recent years. While the present study is too small to draw definite conclusions, these results strongly warrant further multicenter studies addressing the potential benefit of omitting antibiotic prophylaxis during allo-HSCT.

Biomarkers in chronic lymphocytic leukemia (CLL) allow assessment of prognosis. However, the validity of current prognostic biomarkers based on a single assessment point remains unclear for patients who have survived one or more years. Conditional survival (CS) studies that address how prognosis may change over time, especially in prognostic subgroups, are still rare. We performed CS analyses to estimate 5-year survival in 1-year increments, stratified by baseline disease characteristics and known risk factors in two community-based cohorts of CLL patients (Freiburg University Hospital (n = 316) and Augsburg University Hospital (n = 564)) diagnosed between 1984 and 2021. We demonstrate that 5-year CS probability is stable (app. 75%) for the entire CLL patient cohort over 10 years. While age, sex, and stage have no significant impact on CS, patients with high-risk disease features such as non-mutated IGHV, deletion 17p, and high-risk CLL-IPI have a significantly worse prognosis at diagnosis, and 5-year CS steadily decreases with each additional year survived. Our results confirm that CLL patients have a stable survival probability with excess mortality and that the prognosis of high-risk CLL patients declines over time. We infer that CS-based prognostic information is relevant for disease management and counseling of CLL patients.

During a fatal disease, patients often request updated information on their prognosis. After patients have already survived a certain time, conditional survival captures their future survival probability. We investigated conditional overall and failure-free survival in 473 younger mantle cell lymphoma (MCL) patients from a randomized phase III trial comparing immunochemotherapies R-CHOP and alternating R-CHOP/R-DHAP before autologous transplantation. Using conditional Kaplan-Meier method and Cox regression, we estimated subsequent survival of patients who had survived 1-8 years, considering MIPI, Ki-67, and treatment failure status. Starting at a lower level, R-CHOP patients only showed increasing subsequent survival as they survived longer (5-year conditional survival: 72% and 81% after surviving 1 and 7 years), while R-CHOP/R-DHAP patients had stable future survival over time (77% and 78%). The prognostic value of MIPI diminished after 3 years in R-CHOP patients but remained unchanged after R-CHOP/R-DHAP. Patients with treatment failure had markedly inferior survival compared with those in ongoing remission, regardless of the time survived. The longer patients remained in remission, the longer they would stay free of treatment failures. Our results enable personalized counselling for younger MCL patients by offering dynamic prognosis and underscore the importance of highly effective first-line treatment to improve survival.

Purpose: Endovascular therapy of erection-related arteries was shown to be a promising treatment option for patients with severe erectile dysfunction. Purpose of this study was to assess the longer-term safety and clinical success rate of endovascular revascularization of erection-related arteries with the Angiolite BTK stent in patients with arteriogenic erectile dysfunction. Materials and Methods: A total of 147 consecutive men (63.5±9.3 years) with erectile dysfunction due to 345 atherosclerotic lesions underwent endovascular revascularization. Patients received an International Index of Erectile Function (IIEF)-15 questionnaire at 30.3±7.2 months (follow-up [FU] period no less than 18 months) after stenting. An improvement by 4 points in the erectile function domain consisting of 6 questions (IIEF-6) was defined as minimal clinically important difference (MCID). Results: Technical success was achieved in 99% of lesions. One major adverse event occurred after endovascular revascularization. Sixty-eight (46%) patients completed their latest FU at least 18 months following the last intervention. Minimal clinically important difference was achieved in 54% (37/68) of patients. Conclusions: In patients with arteriogenic erectile dysfunction not responding to phosphodiesterase-5-inhibitors (PDE-5-Is), endovascular therapy with a novel thin-strut sirolimus-eluting stent is a safe and effective treatment option during short- and longer-term FU. Clinical Impact Patients with severe erectile dysfunction profit greatly from endovascular therapy of erection-related arteries. Stable clinical outcomes are seen beyond a 1-year timeframe. It is proven that, the drug-eluting stent therapy for atherosclerotic ED in patients who have not responded to PDE-5-I therapy is safe and effective during longer-term follow-up.

BACKGROUND Even though the population-attributable fraction (PAF) is a well-established metric, it is often incorrectly estimated or interpreted not only in clinical application, but also in statistical research articles. The risk of bias is especially high in more complex time-to-event data settings. METHODS We explain how the PAF can be defined, identified and estimated in time-to-event settings with competing risks and time-dependent exposures. By using multi-state methodology and inverse probability weighting, we demonstrate how to reduce or completely avoid severe types of biases including competing risks bias, immortal time bias and confounding due to both baseline and time-varying patient characteristics. RESULTS The method is exemplarily applied to a real data set. Moreover, we estimate the number of deaths that were attributable to ventilator-associated pneumonia in France in the year 2016. The example demonstrates how, under certain simplifying assumptions, PAF estimates can be extrapolated to a target population of interest. CONCLUSIONS Defining and estimating the PAF in advanced time-to-event settings within a framework that unifies causal and multi-state modelling enables to tackle common sources of bias and allows straightforward implementation with standard software packages.

The dexamethasone suppression test (DST) assesses the functionality of the HPA axis and can be regarded as the first potential biomarker in psychiatry. In 1981, a group of researchers at the University of Michigan published a groundbreaking paper regarding its use for diagnosing melancholic depression, reporting a diagnostic sensitivity of 67% and a specificity of 95%. While this study generated much enthusiasm and high expectations in the field of biological psychiatry, subsequent studies produced equivocal results, leading to the test being rejected by the American Psychiatric Association. The scientific reasons leading to the rise and fall of the DST are assessed in this review, suggestions are provided as to how the original test can be improved, and its potential applications in clinical psychiatry are discussed. An improved, standardized, and validated version of the DST would be a biologically meaningful and useful biomarker in psychiatry, providing a tool for clinicians caring for depressed patients in the areas of diagnosis, treatment, and prognosis, and predicting the risk of suicide. Additionally, such a test could be a crucial part in the generation of biologically homogenous patient cohorts, necessary for the successful development of new psychotropic medications.

Background: Current evidence indicates that erectile dysfunction (ED) is an independent risk factor for future cardiovascular events. This study aimed to estimate the cost-effectiveness of screening and subsequent preventive treatment for cardiovascular risk factors among men newly diagnosed with ED from the Swiss healthcare system perspective. Methods: Based on known data on ED and cardiovascular disease (CVD) prevalence and incidence costs and effects of a screening intervention for cardiovascular risk including corresponding cardiovascular prevention in men with ED were calculated for the Swiss population over a period of 10 years. Results: Screening and cardiovascular prevention over a period of 10 years in Swiss men with ED of all seriousness degrees, moderate and severe ED only, or severe ED only can probably avoid 41,564, 35,627, or 21,206 acute CVD events, respectively. Number needed to screen (NNS) to prevent one acute CVD event is 30, 23, and 10, respectively. Costs for the screening intervention are expected to be covered at the seventh, the fifth, and the first year, respectively. Conclusion: Screening and intervention for cardiovascular risk factors in men suffering from ED is a cost-effective tool not only to strengthen prevention and early detection of cardiovascular diseases but also to avoid future cardiovascular events.

Abstract Complex clinical endpoints are present in studies in cancer. Especially in studies on hematopoietic stem-cell transplantation (HSCT), various risks exist after HSCT. Patients can experience acute and chronic graft versus host disease (GVHD) or need to undergo immunosuppressive therapy (IST), a relapse can occur, or patients can die after relapse or without former relapse (nonrelapse mortality, NRM). Sometimes, endpoints can be reasonably combined in a composite endpoint, as, for example, relapse and NRM are combined into disease-free survival (DFS). In this case, standard survival techniques, as Kaplan–Meier estimation of the DFS probability, can be applied. Often, interest focuses on endpoints for which competing risks are present, as, for example, GVHD, with death without prior GVHD as competing risk. This results in a competing risks model, a special case of a multistate model. A more complex multistate model is required when the effects of events occurring in the course of the study on further disease process shall be investigated, as, for example, the effect of GVHD on relapse and NRM. Another endpoint of interest is time under IST. As patients usually experience multiple episodes of IST, thus switching back and forth between “IST” and “no IST” during follow-up, the multistate model used for analysis must be adapted for this event structure. The aim of this nontechnical report is to explain use and interpretation of Cox-type regression models suitable for the different situations in a randomized trial on the effects of anti-T-cell globulin as GVHD prophylaxis. Clin Cancer Res; 19(1); 12–21. ©2012 AACR.

With great interest, we have read the paper “New weighting methods when cases are only a subset of events in a nested case-control study” by Qian M. Zhou, Xuan Wang, Yingye Zheng, and Tianxi Cai published in Biometrical Journal , 64 (7), 1240–1259. In this work, Zhou et al. (2022) propose three novel weights for estimation in the proportional hazards model using a sample obtained via an untypical version of nested-case control (NCC) sampling where only a subset of events is sampled. We congratulate the authors for their relevant contribution to this important topic. As a competitor to their weighting schemes, the authors also consider the weights 𝜅 1,𝑖 (see Equation (2) ), for which they refer to the paper by Edelmann et al. (2020). In this paper, the untypical NCC (which Edelmann et al., 2020, call modified NCC) is compared with other methods that only sample a subset of events. However, the weights that we actually used in Edelmann et al. (2020) were 𝜔 𝐾𝑀,𝑖 , which are provided in Equation (1) below. The weights 𝜅 1,𝑖 clearly do not coincide with 𝜔 𝐾𝑀,𝑖 . Since the weights 𝜔 𝐾𝑀,𝑖 used in Edelmann et al. (2020) lead to a substantially better performance of the corresponding hazard ratio estimates (see Table 1), we believe that this issue needs to be clarified. Moreover, we would like to point out the interested reader to an alternative choice of weights, which have been proposed in Ohneberg (2019, Section 3.2.2).

Introduction Modern information and communication technologies (ICT) have become increasingly important in daily life as well as in patient-physician interaction, health monitoring and health related information (E-Health). Progress in allogeneic stem cell transplantation (allo-SCT) has led to improved survival and increasing numbers of patients. However, with a multitude of potential complications, follow-up of allo-SCT patients remains complex requiring close monitoring, support and treatment with a plethora of medical fields involved. Early studies have shown that E-Health can benefit caretaking of these patients. So far, only little information is known about the patients’ current use of E-Health and their perspective on its potential. Yet, this knowledge is of particular importance for re-structurization of follow-up after allo-SCT including the standardized use of E-Health and its comprehensive acceptance. This multicenter study aims to close this knowledge gap by investigating the patients’ view towards E-Health and use of telemedicine after allo-SCT. The results will help to facilitate the implementation of E-Health in standard follow-up after allo-SCT and other cellular therapies with a focus on patients’ perspective. Methods and Results Between May 2021 and June 2022, 237 patients after allo-SCT were asked to answer a structured questionnaire at the university hospitals Aachen, Bonn, Cologne and Duesseldorf (Center for Integrated Oncology, CIO ABCD) in Germany. Overall, 219 patients returned the questionnaire leading to a response rate of 92%. Of these, 34% were female and 66% were male with a median age of 59 years (range 18-81). In our patient cohort, the current distribution of internet-enabled computers/smartphones is over 90% and the electronic devices are mainly used for daily life activities. Nevertheless, the use of ICT in medical monitoring and patient-physician interaction is still limited. Only a minority of patients have digitized medication plans, use digital monitoring of health data/fitness-apps or own wearables for health monitoring such as smartwatches. In contrast, the majority of patients favors additional online patient-physician interaction such as scheduling and transmission of medical reports and 65% of the patients support real-time transmission of health data through wearables to the physician for a limited time period. Of note, 40-50% of patients have concerns regarding data safety, even more when using messenger services (67%). The majority of patients considers online chats or video calls with their physician to be beneficial and expects an improvement of the treatment quality through increased use of E-Health. Additionally, most patients favor local treatment with online correspondence between their local practitioner and a specialized center, especially if the patients are present during the online communication or with intermittent personal patient contact to the center. Subgroup analyses revealed that in most areas there is no gender difference in use and perspective on E-Health. However, male patients consider online chats more beneficial and expect an improved patient-physician interaction through increased use of ICT compared to females. Age and educational attainment are very significant factors in patients’ view on E-Health. Younger (<60 years) as well as higher educated patients favor increased use of online communication, applications and devices in almost all regards and expect benefits of patient-physician interaction and treatment quality, which is in significant contrast to the views of older or less educated patients. Hometown size or distance to a specialized center does not show a relevant impact on the view on E-Health. This is also true for time after allo-SCT or frequency of outpatient visits at the time of questioning. Conclusions Dissemination of internet-enabled devices is wide and the potential of E-Health is high in patients after allo-SCT. The majority of patients favors further standardized implementation of E-Health technologies and telemedically supported caretaking post allo-SCT and potentially other cellular therapies to improve patient-physician interaction and cross-sectoral care. Future research should focus on patients’ needs in the context of data safety and exchange of medical information in interdisciplinary care processes to successfully integrate new E-Health technologies.

State-of-the art selection methods fail to identify weak but cumulative effects of features found in many high-dimensional omics datasets. Nevertheless, these features play an important role in certain diseases. We present Netboost, a three-step dimension reduction technique. First, a boosting-based filter is combined with the topological overlap measure to identify the essential edges of the network. Second, sparse hierarchical clustering is applied on the selected edges to identify modules and finally module information is aggregated by the first principal components. We demonstrate the application of the newly developed Netboost in combination with CoxBoost for survival prediction of DNA methylation and gene expression data from 180 acute myeloid leukemia (AML) patients and show, based on cross-validated prediction error curve estimates, its prediction superiority over variable selection on the full dataset as well as over an alternative clustering approach. The identified signature related to chromatin modifying enzymes was replicated in an independent dataset, the phase II AMLSG 12-09 study. In a second application we combine Netboost with Random Forest classification and improve the disease classification error in RNA-sequencing data of Huntington's disease mice. Netboost is a freely available Bioconductor R package for dimension reduction and hypothesis generation in high-dimensional omics applications.

A recent study reported increased mortality of heads in government. To avoid the time-dependent bias (also known as immortal-time bias), survival from last election was compared between election winners and runners-up. We claim that this data manipulation results in bias due to conditioning on future events; survival should be compared from first election as well as winning should be considered as a time-dependent covariate. We collected the missing life-time periods and redesigned the study to display this bias using Lexis diagrams and multistate methodology. We found that the bias that we termed the healthy candidate bias was even more severe than the time-dependent bias.