Dyslipidemia in children with chronic kidney disease-findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study.

BACKGROUND: Dyslipidemia is an important and modifiable risk factor for CVD in children with CKD. METHODS: In a cross-sectional study of baseline serum lipid levels in a large prospective cohort study of children with stage 3-5 (predialysis) CKD, frequencies of abnormal lipid levels and types of dyslipidemia were analyzed in the entire cohort and in subpopulations defined by fasting status or by the presence of nephrotic range proteinuria. Associated clinical and laboratory characteristics were determined by multivariable linear regression analysis. RESULTS: A total of 681 patients aged 12.2 ± 3.3 years with a mean eGFR of 26.9 ± 11.6 ml/min/1.73 m2 were included. Kidney diagnosis was classified as CAKUT in 69%, glomerulopathy in 8.4%, and other disorders in 22.6% of patients. Nephrotic range proteinuria (defined by a urinary albumin/creatinine ratio > 1.1 g/g) was present in 26.9%. Dyslipidemia was found in 71.8%, and high triglyceride (TG) levels were the most common abnormality (54.7%). Fasting status (38.9%) had no effect on dyslipidemia status. Except for a significant increase in TG in more advanced CKD, lipid levels and frequencies of dyslipidemia were not significantly different between CKD stages. Hypertriglyceridemia was associated with younger age, lower eGFR, shorter duration of CKD, higher body mass index (BMI-SDS), lower serum albumin, and higher diastolic blood pressure. CONCLUSIONS: Dyslipidemia involving all lipid fractions, but mainly TG, is present in the majority of patients with CKD irrespective of CKD stage or fasting status and is significantly associated with other cardiovascular risk factors.

A Comparison of Additional Benefit Assessment Methods for Time-to-Event Endpoints Using Hazard Ratio Point Estimates or Confidence Interval Limits by Means of a Simulation Study.

BACKGROUND: For time-to-event endpoints, three additional benefit assessment methods have been developed aiming at an unbiased knowledge about the magnitude of clinical benefit of newly approved treatments. The American Society of Clinical Oncology (ASCO) defines a continuous score using the hazard ratio point estimate (HR-PE). The European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) developed methods with an ordinal outcome using lower and upper limits of the 95% HR confidence interval (HR-CI), respectively. We describe all three frameworks for additional benefit assessment aiming at a fair comparison across different stakeholders. Furthermore, we determine which ASCO score is consistent with which ESMO/IQWiG category. METHODS: In a comprehensive simulation study with different failure time distributions and treatment effects, we compare all methods using Spearman's correlation and descriptive measures. For determination of ASCO values consistent with categories of ESMO/IQWiG, maximizing weighted Cohen's Kappa approach was used. RESULTS: Our research depicts a high positive relationship between ASCO/IQWiG and a low positive relationship between ASCO/ESMO. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 corresponds to ESMO categories. Using ASCO values of 21 and 38 as cutoffs represents IQWiG categories. LIMITATIONS: We investigated the statistical aspects of the methods and hence implemented slightly reduced versions of all methods. CONCLUSIONS: IQWiG and ASCO are more conservative than ESMO, which often awards the maximal category independent of the true effect and is at risk of overcompensating with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and underpowered/overpowered studies influence all methods in some degree. Nevertheless, ESMO is the most liberal one. HIGHLIGHTS: For the additional benefit assessment, the American Society of Clinical Oncology (ASCO) uses the hazard ratio point estimate (HR-PE) for their continuous score. In contrast, the European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) use the lower and upper 95% HR confidence interval (HR-CI) to specific thresholds, respectively. ESMO generously assigns maximal scores, while IQWiG is more conservative.This research provides the first comparison between IQWiG and ASCO and describes all three frameworks for additional benefit assessment aiming for a fair comparison across different stakeholders. Furthermore, thresholds for ASCO consistent with ESMO and IQWiG categories are determined, enabling a comparison of the methods in practice in a fair manner.IQWiG and ASCO are the more conservative methods, while ESMO awards high percentages of maximal categories, especially with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and under/-overpowered studies influence all methods. Nevertheless, ESMO is the most liberal one. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 correspond to the categories of ESMO. Using ASCO values of 21 and 38 as cutoffs represents categories of IQWiG.

Efficacy of supervised immersive virtual reality-based training for the treatment of chronic fatigue in post-COVID syndrome: study protocol for a double-blind randomized controlled trial (IFATICO Trial).

BACKGROUND: The treatment of persistent fatigue after COVID-19 infection is complex. On the one hand, it involves maintaining a sufficient level of physical and mental activity to counteract possible degenerative processes of the body and nervous system. On the other hand, physical and mental activities can also lead to worsening of symptoms. Therefore, the challenge in treating Post-COVID fatigue is to stimulate the body and central nervous system in a way that stimulates growth and improvement, but does not overtax individual physical and mental limits. Special training programs try to take these characteristics into account, but often reach their limits. A promising approach is offered by new fitness technologies based on immersive virtual realities that stimulate both body and brain while minimizing physical and psychological stress. The aim of this study is to investigate the efficacy of supervised immersive Virtual Reality (VR)-based activity training compared to conventional activity training for patients with Post-COVID-associated fatigue. METHODS: In a single centre, individually randomised, prospective, double-blind two-arm exploratory superiority trial with parallel group design, N = 100 patients with persistent fatigue after COVID-19 infection will be recruited. The intervention includes a supervised immersive neuromuscular training (12 sessions of 30 min over 6 weeks) based on a novel VR-exercise device. We will systematically compare the effects of this intervention on Post-COVID-associated fatigue with a supervised conventional activation program of comparable scope without an immersive environment. The primary outcome is the difference between groups in absolute change in the mean fatigue symptom severity measured on the Fatigue Severity Scale (FSS) from baseline to posttreatment assessment. Posttreatment assessment in both groups will be conducted by blinded outcome assessors. At three and six months afterwards, patients are sent self-report questionnaires for follow up. The main analysis will be based on the intention-to-treat principle. DISCUSSION: To the best of our knowledge, this is the first exploratory study on a supervised immersive neuromuscular training for the treatment of persistent fatigue after COVID-19 infection. TRIAL REGISTRATION: German register for clinical studies (ID: DRKS00032059) Prospectively registered on June 16th 2023. URL of trial registration.

An Online Decision Aid for Patients With Metastatic Melanoma­Results of the Randomized Controlled Trial "PEF-Immun".

BACKGROUND: Treatment decisions in metastatic melanoma (MM) depend on patient preferences and require the patients' involvement in the decision-making process. Patients often feel overwhelmed by the complexity of treatment options with their individual advantages and disadvantages. We developed an online patient decision aid (PtDA) to facilitate shared decision making (SDM). METHODS: We conducted a two-center, two-armed, prospective, open randomized controlled trial with MM patients who were facing a decision about first-line treatment. They were randomly allotted (1:1) to the use or non-use of the PtDA before discussing the choice of treatment with a physician (intervention group [IG] and control group [CG], respectively). The primary endpoint of the study was patient knowledge about first-line treatment options (multiple-choice test, 10 items, range 0-40 points). The secondary endpoints were the degree of SDM (ratings of audio recordings of the patient-physician discussions by third-party observers) and satisfaction with the decision that was taken on later follow-up. RESULTS: 120 of the 128 randomized patients completed the baseline questionnaire and were included in the analysis (59% male, median age 66 years). The primary endpoint, i.e., the mean difference in knowledge after discussion with a physician, was significantly higher in the intervention group (mean difference -3.22, 95% CI [-6.32;-0.12], p = 0.042). No difference was found in either of the secondary endpoints (SDM and satisfaction with the decision). The patients in the intervention group rated the PtDA as very useful. CONCLUSION: PtDA improved MM patients' knowledge about their options for treatment. Both patients who used it and patients who did not were highly satisfied with their treatment decisions. Additional physician training seems necessary to promote SDM.

Optimal sample size allocation for two-arm superiority and non-inferiority trials with binary endpoints.

The sample size of a clinical trial has to be large enough to ensure sufficient power for achieving the aim the study. On the other side, for ethical and economical reasons it should not be larger than necessary. The sample size allocation is one of the parameters that influences the required total sample size. For two-arm superiority and non-inferiority trials with binary endpoints, we performed extensive computations over a wide range of scenarios to determine the optimal allocation ratio that minimizes the total sample size if all other parameters are fixed. The results demonstrate, that for both superiority and non-inferiority trials the optimal allocation may deviate considerably from the case of equal sample size in both groups. However, the saving in sample size when allocating the total sample size optimally as compared to balanced allocation is typically small.

START NOW: a cognitive behavioral skills training for adolescent girls with conduct or oppositional defiant disorder - a randomized clinical trial.

BACKGROUND: Conduct disorder (CD) and oppositional defiant disorder (ODD) both convey a high risk for maladjustment later in life and are understudied in girls. Here, we aimed at confirming the efficacy of START NOW, a cognitive-behavioral, dialectical behavior therapy-oriented skills training program aiming to enhance emotion regulation skills, interpersonal and psychosocial adjustment, adapted for female adolescents with CD or ODD. METHODS: A total of 127 girls were included in this prospective, cluster randomized, multi-center, parallel group, quasi-randomized, controlled phase III trial, which tested the efficacy of START NOW (n = 72) compared with standard care (treatment as usual, TAU, n = 55). All female adolescents had a clinical diagnosis of CD or ODD, were 15.6 (±1.5) years on average (range: 12-20 years), and were institutionalized in youth welfare institutions. The two primary endpoints were the change in number of CD/ODD symptoms between (1) baseline (T1) and post-treatment (T3), and (2) between T1 and 12-week follow-up (T4). RESULTS: Both treatment groups showed reduced CD/ODD symptoms at T3 compared with T1 (95% CI: START NOW = -4.87, -2.49; TAU = -4.94, -2.30). There was no significant mean difference in CD/ODD symptom reduction from T1 to T3 between START NOW and TAU (-0.056; 95% CI = -1.860, 1.749; Hedge's g = -0.011). However, the START NOW group showed greater mean symptom reduction from T1 to T4 (-2.326; 95% CI = -4.274, -0.378; Hedge's g = -0.563). Additionally, secondary endpoint results revealed a reduction in staff reported aggression and parent-reported irritability at post assessment. CONCLUSIONS: Although START NOW did not result in greater symptom reduction from baseline to post-treatment compared with TAU, the START NOW group showed greater symptom reduction from baseline to follow-up with a medium effect size, which indicates a clinically meaningful delayed treatment effect.

Randomized Controlled Feasibility Trial of Robot-assisted Versus Conventional Open Partial Nephrectomy: The ROBOCOP II Study.

BACKGROUND: There is no evidence from randomized controlled trials (RCTs) comparing robot-assisted partial nephrectomy (RAPN) and open partial nephrectomy (OPN). OBJECTIVE: To assess the feasibility of trial recruitment and to compare surgical outcomes between RAPN and OPN. DESIGN, SETTING, AND PARTICIPANTS: ROBOCOP II was designed as single-center, open-label, feasibility RCT. Patients with suspected localized renal cell carcinoma referred for PN were randomized at a 1:1 ratio to either RAPN or OPN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the feasibility of recruitment, assessed as the accrual rate. Secondary outcomes included perioperative and postoperative data. Data were analyzed descriptively in a modified intention-to-treat population consisting of randomized patients who underwent surgery. RESULTS AND LIMITATIONS: A total of 50 patients underwent RAPN or OPN (accrual rate 65%). In comparison to OPN, RAPN had lower blood loss (OPN 361 ml, standard deviation [SD] 238; RAPN 149 ml, SD 122; difference 212 ml, 95% confidence interval [CI] 105-320; p < 0.001), less need for opioids (OPN 46%; RAPN 16%; difference 30%, 95% CI 5-54; p = 0.024), and fewer complications according to the mean Comprehensive Complication Index (OPN 14, SD 16; RAPN 5, SD 15; difference 9, 95% CI 0-18; p = 0.008). OPN has a shorter operative time (OPN 112 min, SD 29; RAPN 130 min, SD 32; difference -18 min, 95% CI -35 to -1; p = 0.046) and warm ischemia time (OPN 8.7 min, SD 7.1; RAPN 15.4 min, SD 7.0; difference 6.7 min, 95% CI -10.7 to -2.7; p = 0.001). There were no differences between RAPN and OPN regarding postoperative kidney function. CONCLUSIONS: This first RCT comparing OPN and RAPN met the primary outcome of the feasibility of recruitment; however, the window for future RCTs is closing. Each approach has advantages over the other, and both remain safe and effective options. PATIENT SUMMARY: For patients with a kidney tumor, open surgery and robot-assisted keyhole surgery are both feasible and safe approaches for partial removal of the affected kidney. Each approach has known advantages. Long-term follow-up will explore differences in quality of life and cancer control outcomes.

Protocol of the IntenSify-Trial: An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy.

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2 ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.

Estimation of treatment effects in early-phase randomized clinical trials involving external control data.

There are good reasons to perform a randomized controlled trial (RCT) even in early phases of clinical development. However, the low sample sizes in those settings lead to high variability of the treatment effect estimate. The variability could be reduced by adding external control data if available. For the common setting of suitable subject-level control group data only available from one external (clinical trial or real-world) data source, we evaluate different analysis options for estimating the treatment effect via hazard ratios. The impact of the external control data is usually guided by the level of similarity with the current RCT data. Such level of similarity can be determined via outcome and/or baseline covariate data comparisons. We provide an overview over existing methods, propose a novel option for a combined assessment of outcome and baseline data, and compare a selected set of approaches in a simulation study under varying assumptions regarding observable and unobservable confounder distributions using a time-to-event model. Our various simulation scenarios also reflect the differences between external clinical trial and real-world data. Data combinations via simple outcome-based borrowing or simple propensity score weighting with baseline covariate data are not recommended. Analysis options which conflate outcome and baseline covariate data perform best in our simulation study.

Aspirin use and bleeding events during thrombocytopenia after autologous stem-cell transplantation for multiple myeloma.

Background: In patients with cardiovascular (CV) comorbidities that necessitate antiplatelet therapy (APT), its optimal management during chemotherapy-induced thrombocytopenia remains elusive, as the risk of bleeding has to be balanced against the risk of CV events. The purpose of this study was to assess the risk for bleeding with APT during thrombocytopenia in patients with multiple myeloma undergoing high-dose chemotherapy and subsequent autologous stem-cell transplantation (ASCT) with and without acetylsalicylic acid (ASA) as comedication. Methods: We assessed patients who underwent ASCT at the Heidelberg University Hospital between 2011 and 2020 for bleeding events, management strategies for ASA intake during thrombocytopenia, transfusion requirements, and the occurrence of CV events. Results: There were 57/1,113 patients who continued ASA until at least 1 day after ASCT; thus, a continuous platelet inhibition during thrombocytopenia was assumed. Most of the patients (41/57) continued ASA until they had a platelet count of 20-50/nl. This range reflects the kinetics of thrombocytopenia and nondaily measurements of platelets during ASCT. A tendency toward a higher risk for bleeding events in the ASA group was demonstrated (1.9% (control group) vs. 5.3% (ASA), p = 0.082). The risk factors for bleeding in multivariate analysis were the duration of thrombocytopenia < 50/nl, a history of gastrointestinal bleeding, and diarrhea. The factors predicting the duration of thrombocytopenia were age >60 years, a hematopoietic stem-cell transplantation comorbidity index ≥3, and an impaired bone marrow reserve at admission. CV events occurred in three patients; none of them took ASA or had an indication for APT. Conclusions: The intake of ASA until thrombocytopenia with a platelet count of 20-50/nl appears safe, although an elevated risk cannot be excluded. If ASA is indicated for the secondary prevention of CV events, the evaluation of risk factors for bleeding and a prolonged time of thrombocytopenia before conditioning is crucial to adapt the strategy for ASA intake during thrombocytopenia.

Characterization of Postural Sway in Women with Osteoporosis and a Control Group by Means of Linear and Nonlinear Methods.

The mechanisms underlying the altered postural control and risk of falling in patients with osteoporosis are not yet fully understood. The aim of the present study was to investigate postural sway in women with osteoporosis and a control group. The postural sway of 41 women with osteoporosis (17 fallers and 24 non-fallers) and 19 healthy controls was measured in a static standing task with a force plate. The amount of sway was characterized by traditional (linear) center-of-pressure (COP) parameters. Structural (nonlinear) COP methods include spectral analysis by means of a 12-level wavelet transform and a regularity analysis via multiscale entropy (MSE) with determination of the complexity index. Patients showed increased body sway in the medial-lateral (ML) direction (standard deviation in mm: 2.63 ± 1.00 vs. 2.00 ± 0.58, p = 0.021; range of motion in mm: 15.33 ± 5.58 vs. 10.86 ± 3.14, p = 0.002) and more irregular sway in the anterior-posterior (AP) direction (complexity index: 13.75 ± 2.19 vs. 11.18 ± 4.44, p = 0.027) relative to controls. Fallers showed higher-frequency responses than non-fallers in the AP direction. Thus, postural sway is differently affected by osteoporosis in the ML and AP directions. Clinically, effective assessment and rehabilitation of balance disorders can benefit from an extended analysis of postural control with nonlinear methods, which may also contribute to the improvement of risk profiles or a screening tool for the identification of high-risk fallers, thereby prevent fractures in women with osteoporosis.

Arterial Stiffness and Chronic Kidney Disease Progression in Children.

BACKGROUND AND OBJECTIVES: CKD has been linked to increased arterial stiffness in adults, but data in children with CKD remain conflicting. We aimed to investigate the longitudinal dynamics and determinants of pulse wave velocity in children with CKD and its association with CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed an analysis of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study, which prospectively followed children aged 6-17 years with CKD stages 3-5. Follow-up was censored at the time of KRT initiation. Two separate analyses were performed: with absolute pulse wave velocity (primary outcome) and with pulse wave velocity standardized to height (z score; restricted to participants ≤17 years) as a sensitivity analysis. RESULTS: In total, 667 patients with a mean baseline eGFR of 27 ml/min per 1.73 m2 were included. Pulse wave velocity above the 95th percentile was observed in 124 (20%) patients at baseline. Absolute pulse wave velocity increased gradually over the median follow-up of 2.7 (interquartile range, 0.7-4.4) years, whereas pulse wave velocity z score remained relatively stable. Absolute pulse wave velocity over time associated with time; older age; higher mean arterial pressure, LDL cholesterol, and albuminuria; and lower ferritin. Pulse wave velocity z score (n=628) was associated with the same variables and additionally, with higher diastolic BP z score, lower height z score, younger age, and girls. Of 628 patients, 369 reached the composite end point of CKD progression (50% eGFR loss, eGFR <10 ml/min per 1.73 m2, or the start of KRT) during a median follow-up of 2.4 (interquartile range, 0.9-4.6) years. Pulse wave velocity z score did not associate with CKD progression by univariable or multivariable proportional hazard analysis correcting for the established predictors eGFR, proteinuria, and BP. CONCLUSIONS: Pulse wave velocity is increased in children with CKD but does not associate with eGFR or CKD progression.

Clinical characterization and possible pathophysiological causes of the Deventilation Syndrome in COPD.

In daily routine, many COPD patients report early onset augmented dyspnea following use of NIV (Deventilation Syndrome, DVS) as a negative side-effect. The aim of this study is the clinical characterization and concrete definition of DVS. This monocenter prospective observational study collected demographic, physiologic and symptomatic data from 67 in-patients with severe COPD Gold III-IV and chronic hypercapnic failure before, during and after use of an established NIV. During their inpatient follow-up, we examined patients during the first hour after termination of nocturnal NIV. DVS was defined by the authors as an increase of ≥ 2 points on the Borg scale during the first 30 min in patients who reported repeated dyspnea after the use of NIV. We monitored cardiovascular and respiratory data and measured diaphragm excursion. Subjective dyspnea was documented by use of the Borg scale and questionnaires. In addition, respirator and demographic data were collected. DVS occurred in 58% of our COPD patient collective, showing predominant emphysema phenotype. Patients with DVS were more severely ill than non-DVS concerning bronchial obstruction (FEV1 0.6 vs. 0.8 l, p < 0.05) and hypercapnia during spontaneous breathing (pre NIV pCO2: 54.5 vs. 49.3 mmHg, p < 0.02). DVS patients showed significantly higher respiratory rates (RR) (20.1 vs. 18.1/min p < 0.05) after termination of NIV. This trial characterizes and defines early onset augmented dyspnea after the use of NIV, referred to as DVS. It is hereby brought to attention as a frequent side effect of long-term home ventilation and possible pathophysiologic mechanisms are elucidated.

An adaptive design for early clinical development including interim decision for single-arm trial with external controls or randomized trial.

In early clinical development, randomized controlled trials (RCT) or single-arm trials with external controls (SATwEC) are design options, which allow adjustment for confounding: RCT via design, SATwEC via analysis using propensity score methods. SATwEC requires less investment than RCT. However, if the confounder space substantially differs between the experimental and external control group, the SATwEC might lead to inappropriate decisions for further development. We develop an adaptive two-stage design (ATD) for early clinical development that reduces the risk of unreliable decision-making at the end of a SATwEC. In Stage I, subjects are solely assigned to the experimental group. If at the interim the propensity score distributions of internal and external data are comparable based on the preference score, the subjects in stage II will again be solely assigned to the experimental arm; if not, a randomized stage II will be conducted. In a simulation study guided by a motivating example, data is generated using a time-to-event model with observable and unobservable confounders. The confounder space is varied to investigate the impact on false go/stop probabilities as well as a loss function, which reflects the quality of treatment effect estimates and decision-making. The proposed ATD provides a compromise between optimizing quality (as expressed by false go/stop probabilities and the loss function) and investment (defined by sample size and trial duration).

Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study.

BACKGROUND: Long COVID is defined as the persistence of symptoms beyond 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To better understand the long-term course and etiology of symptoms we analyzed a cohort of patients with COVID-19 prospectively. METHODS: Patients were included at 5 months after acute COVID-19 in this prospective, noninterventional, follow-up study. Patients followed until 12 months after COVID-19 symptom onset (n = 96; 32.3% hospitalized, 55.2% females) were included in this analysis of symptoms, quality of life (based on an SF-12 survey), laboratory parameters including antinuclear antibodies (ANAs), and SARS-CoV-2 antibody levels. RESULTS: At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnea (37.5%), and problems with concentration (39.6%), finding words (32.3%), and sleeping (26.0%). Females showed significantly more neurocognitive symptoms than males. ANA titers were ≥1:160 in 43.6% of patients at 12 months post-COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titer ≥1:160 versus <1:160. Compared with patients without symptoms, patients with ≥1 long-COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2 antibody levels but had a significantly reduced physical and mental life quality compared with patients without symptoms. CONCLUSIONS: Neurocognitive long-COVID symptoms can persist ≥1 year after COVID-19 symptom onset and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titer elevations. This may indicate autoimmunity as a cofactor in etiology of long COVID.

Estimands-A Basic Element for Clinical Trials.

BACKGROUND: Clinical trials are of central importance for the evaluation and comparison of treatments. The transparency and intelligibility of the treatment effect under investigation is an essential matter for physicians, patients, and health-care authorities. The estimand framework has been introduced because many trials are deficient in this respect. METHODS: Introduction, definition, and application of the estimand framework on the basis of an example and a selective review of the literature. RESULTS: The estimand framework provides a systematic approach to the definition of the treatment effect under investigation in a clinical trial. An estimand consists of five attributes: treatment, population, variable, population-level summary, and handling of intercurrent events. Each of these attributes is defined in an interdisciplinary discussion during the trial planning phase, based on the clinical question being asked. Special attention is given to the handling of intercurrent events (ICEs): these are events-e.g., discontinuation or modification of treatment or the use of emergency medication-that can occur once the treatment has begun and might affect the possibility of observing the endpoints or their interpretability. There are various strategies for the handling of ICEs; these can, for example, also reflect the existing intention-to-treat (ITT) principle. Per-protocol analyses, in contrast, are prone to bias and cannot be represented in a sensible manner by an estimand, although they may be performed as a supplementary analysis. The discussion of potential intercurrent events and how they should appropriately be handled in view of the aim of the trial must already take place in the planning phase. CONCLUSION: Use of the estimand framework should make it easier for both physicians and patients to understand what trials reveal about the efficacy of treatment, and to compare the results of different trials.

ROBOCOP II (ROBOtic assisted versus conventional open partial nephrectomy) randomised, controlled feasibility trial: clinical trial protocol.

INTRODUCTION: Randomised controlled trials comparing robotic-assisted partial nephrectomy (RAPN) and open PN (OPN) are lacking. Therefore, we aim to report the study protocol and a trial update for a randomised controlled feasibility trial comparing RAPN versus OPN for renal neoplasms. METHODS AND ANALYSIS: The ROBOtic assisted versus conventional Open Partial nephrectomy II trial is designed as a single-centre, randomised, open-label, feasibility trial. Participation will be offered to patients with renal neoplasms and deemed feasible for both, OPN and RAPN. We aim to enrol 50 patients within 15 months using a 1:1 allocation ratio. The primary endpoint of the trial is feasibility of recruitment and will be successful if one third of eligible patients agree to participate. Secondary endpoints include perioperative results, health-related quality of life, inflammatory response as well as surgical ergonomics of the operating team. If the primary outcome, feasibility of recruitment, is successful, the secondary results of the trial will be used for planning a confirmative phase III trial. ETHICS AND DISSEMINATION: Ethical approval was obtained from the local institutional review board (Ethik-Kommission II at Heidelberg University: 2020-542N). Results will be made publicly available in peer-reviewed scientific journals and presented at appropriate congresses and social media. TRIAL REGISTRATION NUMBER: NCT04534998.

Influence of Cognitive Impairment on Rehabilitation Received and Its Mediating Effect on Functional Recovery.

BACKGROUND: Cognitive impairment (CI) has been reported to negatively impact rehabilitation outcomes. Knowledge about differences in rehabilitation received in dependence of CI as a potential mediating factor is limited. OBJECTIVE: To analyze whether CI affects amount and frequency of rehabilitation received and if associations between CI and rehabilitation outcome are mediated by the provided amount of therapy. METHODS: Observational cohort study in ward-based geriatric rehabilitation consecutively including 373 patients (mean age 82.0±6.69 years, mean MMSE 23.66±5.31). Outcome measures were amount, frequency, and type of multi-professional therapy sessions and rehabilitation outcome assessed with the Barthel Index (BI). Cognitive status was measured with the Mini-Mental-State Examination (MMSE) classifying three patient subgroups according to cognitive status. RESULTS: Patients with more severe CI received least total therapy hours (TTH) (MMSE < 17, 13.67±6.58 versus MMSE 17-26, 16.12±7.19 and MMSE > 26, 17.79±8.88 h, p = 0.014) and were less often included in occupational therapy (MMSE < 17, 48.9%versus MMSE 17-26, 65.5%and MMSE > 26, 71.4%, p = 0.019) and group-based physiotherapy (MMSE < 17, 73.3%versus MMSE 17-26, 88.5%and MMSE > 26, 81.2%, p = 0.027). Regression models showed that CI negatively impacted TTH (ß= 0.24, p = 0.003) and rehabilitation outcome (ß= 0.41, p = 0.008). In the mediation model, TTH accounted for 23.18%(p < 0.001) of the relationship between CI and rehabilitation outcome. CONCLUSION: Cognitive impairment negatively impacted rehabilitation received. The lower TTH partly mediated the negative association between CI and rehabilitation outcome. Future research should identify specific barriers to therapy provision and optimal length, intensity, and dosage of rehabilitation programs to optimize rehabilitation outcomes in CI.

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases: A Genome-wide Association Study Among Patients with Obstructive Uropathies.

BACKGROUND: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. OBJECTIVE: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. DESIGN SETTING AND PARTICIPANTS: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues. RESULTS AND LIMITATIONS: Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10-7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization. CONCLUSIONS: This study identified CDH12 as a candidate gene for kidney injury in PUV. PATIENT SUMMARY: We found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.

Gene Polymorphisms of NOD2, IL23R, PTPN2 and ATG16L1 in Patients with Crohn's Disease: On the Way to Personalized Medicine?

Genetic and environmental factors are involved in the pathogenesis of inflammatory bowel diseases (IBD). The study aimed at investigating the potential influence of single nucleotide polymorphisms (SNPs) NOD2 rs2066844, NOD2 rs2066845, NOD2 rs2066847, IL23R rs11209026, PTPN2 rs2542151, PTPN2 rs7234029, and ATG16L1 rs2241880 on the response to immunomodulatory therapies and disease course in Crohn's disease (CD). This is an uncontrolled retrospective monocentric study including patients from the IBD outpatient clinic of Heidelberg University Hospital. Therapy responses and disease courses were related to genetic findings. 379 patients with CD were included. The presence of at least one PTPN2 rs7234029 risk allele was associated with nonresponse to anti-interleukin-12/23 treatment (89.9% vs. 67.6%, p = 0.005). The NOD2 rs2066844 risk allele was associated with a first-degree family history of colon cancer (12.7% vs. 4.7%, p = 0.02), the ATG16L1 rs2241880 risk allele with ileal CD manifestation (p = 0.027), and the IL23R rs11209026 risk allele with a higher rate of CD-related surgeries per disease year (0.08 vs. 0.02, p = 0.025). The results of this study underline the relevance of genetic influences in CD. The association of the PTPN2 rs7234029 risk allele with nonresponse to anti-interleukin-12/23 treatment in CD patients is a novel finding and requires further investigation.