Explore the vast range of titles available.

Background In clinical trials, the determination of an adequate sample size is a challenging task, mainly due to the uncertainty about the value of the effect size and nuisance parameters. One method to deal with this uncertainty is a sample size recalculation. Thereby, an interim analysis is performed based on which the sample size for the remaining trial is adapted. With few exceptions, previous literature has only examined the potential of recalculation in two-stage trials. Methods In our research, we address sample size recalculation in three-stage trials, i.e. trials with two pre-planned interim analyses. We show how recalculation rules from two-stage trials can be modified to be applicable to three-stage trials. We also illustrate how a performance measure, recently suggested for two-stage trial recalculation (the conditional performance score) can be applied to evaluate recalculation rules in three-stage trials, and we describe performance evaluation in those trials from the global point of view. To assess the potential of recalculation in three-stage trials, we compare, in a simulation study, two-stage group sequential designs with three-stage group sequential designs as well as multiple three-stage designs with recalculation. Results While we observe a notable favorable effect in terms of power and expected sample size by using three-stage designs compared to two-stage designs, the benefits of recalculation rules appear less clear and are dependent on the performance measures applied. Conclusions Sample size recalculation is also applicable in three-stage designs. However, the extent to which recalculation brings benefits depends on which trial characteristics are most important to the applicants.

Background Sample size calculation is a central aspect in planning of clinical trials. The sample size is calculated based on parameter assumptions, like the treatment effect and the endpoint’s variance. A fundamental problem of this approach is that the true distribution parameters are not known before the trial. Hence, sample size calculation always contains a certain degree of uncertainty, leading to the risk of underpowering or oversizing a trial. One way to cope with this uncertainty are adaptive designs. Adaptive designs allow to adjust the sample size during an interim analysis. There is a large number of such recalculation rules to choose from. To guide the choice of a suitable adaptive design with sample size recalculation, previous literature suggests a conditional performance score for studies with a normally distributed endpoint. However, binary endpoints are also frequently applied in clinical trials and the application of the conditional performance score to binary endpoints is not yet investigated. Methods We extend the theory of the conditional performance score to binary endpoints by suggesting a related one-dimensional score parametrization. We moreover perform a simulation study to evaluate the operational characteristics and to illustrate application. Results We find that the score definition can be extended without modification to the case of binary endpoints. We represent the score results by a single distribution parameter, and therefore derive a single effect measure, which contains the difference in proportions p I - p C between the intervention and the control group, as well as the endpoint proportion p C in the control group. Conclusions This research extends the theory of the conditional performance score to binary endpoints and demonstrates its application in practice.

Background Stereotactic Body Radiotherapy (SBRT) is a standard treatment for inoperable primary and secondary lung tumors. In case of ultracentral tumor location, defined as tumor contact with vulnerable mediastinal structures such as the proximal bronchial tree (PBT) or esophagus, SBRT is associated with an increased risk for severe complications. Magnetic resonance (MR)-guided SBRT can mitigate this risk based on gated dose delivery and daily plan adaptation. The MAGELLAN trial aims to find the maximum tolerated dose (MTD) of MR-guided SBRT of ultracentral lung tumors (ULT). Patients and methods MAGELLAN is a prospective phase I dose escalation trial. A maximum of 38 patients with primary and secondary ULT with a tumor size ≤ 5 cm will be enrolled. Ultracentral location is defined as an overlap of the planning target volume (PTV) with the PBT or esophagus. Patients are treated at a 0.35 Tesla MR-linac (MRIdian® Linac, ViewRay Inc. ) employing a gating strategy and daily plan adaptation. Dose escalation starts at 10 × 5.5 Gy (biologically effective dose BED 3/10 : 155.83 Gy/85.25 Gy), may proceed up to 10 × 6.5 Gy (BED 3/10 : 205.83 Gy/107.25 Gy) and is guided by a customized time-to-event continual reassessment method (TITE CRM) with backup element, which alternately assigns patients to dose escalation and backup cohorts. Discussion The results of the MAGELLAN trial will guide further research and clinical implementation of MR-guided SBRT as ablative treatment of ULT. Moreover, the combination of MR-guided radiotherapy with TITE-CRM including a backup element may serve as blueprint for future radiation dose escalation studies in critical locations. Trial Registration Registered at ClinicalTrials.gov: NCT04925583 on 14th June 2021.

Background Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients. Methods In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome. Results Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5–14.9, p  < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9–8.2, p  < 0.001) were the strongest predictors of poor outcome among the included patients. Conclusions Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.

Background Although multidrug-resistant bacteria (MDR) are common in patients undergoing prolonged weaning, there is little data on their impact on weaning and patient outcomes. Methods This is a retrospective analysis of consecutive patients who underwent prolonged weaning and were at a university weaning centre from January 2018 to December 2020. The influence of MDR colonisation and infection on weaning success (category 3a and 3b), successful prolonged weaning from invasive mechanical ventilation (IMV) with or without the need for non-invasive ventilation (NIV) compared with category 3c (weaning failure 3cI or death 3cII) was investigated. The pathogen groups considered were: multidrug-resistant gram-negative bacteria (MDRGN), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp. (VRE). Results A total of 206 patients were studied, of whom 91 (44.2%) showed evidence of MDR bacteria (32% VRE, 1.5% MRSA and 16% MDRGN), with 25 patients also meeting the criteria for MDR infection. 70.9% of the 206 patients were successfully weaned from IMV, 8.7% died. In 72.2% of cases, nosocomial pneumonia and other infections were the main cause of death. Patients with evidence of MDR (infection and colonisation) had a higher incidence of weaning failure than those without evidence of MDR (48% vs. 34.8% vs. 21.7%). In multivariate analyses, MDR infection (OR 4.9, p  = 0.004) was an independent risk factor for weaning failure, along with male sex (OR 2.3, p  = 0.025), Charlson Comorbidity Index (OR 1.2, p  = 0.027), pH (OR 2.7, p  < 0.001) and duration of IMV before admission (OR 1.01, p  < 0.001). In addition, MDR infection was the only independent risk factor for death (category 3cII), (OR 6.66, p  = 0.007). Conclusion Patients with MDR infection are significantly more likely to die during the weaning process. There is an urgent need to develop non-antibiotic approaches for the prevention and treatment of MDR infections as well as clinical research on antibiotic stewardship in prolonged weaning as well as in ICUs.

Background Endovascular thrombectomy (EVT)—often combined with intravenous thrombolysis—is the standard of care for acute ischemic stroke (AIS) secondary to large vessel occlusions (LVO). While indications keep expanding, the feasibility and utility of intra-procedural neuromonitoring of the sedated patient has neither been clarified nor characterized. Objective To evaluate the feasibility of near-infrared spectroscopy (NIRS) for cortical oxygenation and bispectral index (BIS) for electroencephalographic function as non-invasive neuromonitoring tools for AIS patients undergoing EVT, and assess their utility in predicting successful recanalization. Methods We extracted data on all patients receiving continuous NIRS and/or BIS monitoring in the Sedation versus Intubation for Endovascular Stroke TreAtment (SIESTA) clinical trial. SIESTA randomized AIS patients undergoing EVT for anterior proximal LVO to general anesthesia versus conscious sedation. For this analysis, the primary outcomes included changes in NIRS and BIS values pre- and post-recanalization and associations of parameter changes with successful or unsuccessful recanalization outcomes. Statistical analysis was performed using a Wilcoxon signed rank tests. Results Of the 150 patients, 66 were monitored continuously with NIRS, and 50 with BIS. An increased NIRS-derived cerebral tissue oxygenation (stated as tissue saturation index – TSI) was observed in affected hemisphere following successful recanalization, as well as a significant reduction in the difference between affected and unaffected hemispheres. In contrast, no significant changes were observed with BIS monitoring between pre- and post-recanalization status. Conclusion In this post-hoc analysis, changes in NIRS monitoring were associated with successful reperfusion. Non-invasive oximetry by NIRS may serve as a valuable tool during and after mechanical thrombectomy to detect and respond to an insufficient perfusion or re-occlusion.

As a complication of subarachnoid hemorrhage (SAH), vasospasm substantially contributes to its morbidity and mortality. We aimed at analyzing predictors of outcome for these patients including the role of endovascular treatment (ET). Our database was screened for patients with SAH treated in our Neuro-ICU from 2009 to 2019. Clinical parameters including functional outcome (modified Rankin Scale, mRS of 0–2 or 3–6 at discharge and after a median follow-up of 18 months) and details about ET were gathered on 465 patients, 241 (52%) of whom experienced vasospasm. Descriptive analyses were performed to identify explanatory variables for the dichotomized mRS score. A logistic regression model was fitted on 241 patients with vasospasm including age, Hunt and Hess Score, extraventricular drainage (EVD), forced hypertension, ET and delayed cerebral ischemia (DCI). The model found a Hunt and Hess Score of 5 (OR = 0.043, p  = 0.008), requirement of EVD (OR = 0.161, p  < 0.001), forced hypertension (OR = 0.242, p  = 0.001), ET (OR = 0.431, p  = 0.043) and DCI (OR = 0.229, p  < 0.001) to be negative predictors of outcome while age was not. Use of intraarterial nimodipine alone (OR = 0.778, p  = 0.705) or including balloon angioplasty (OR = 0.894, p = 0.902) and number of ETs per patient (OR = 0.757, p  = 0.416) were not significant in a separate model with otherwise identical variables. While DCI is clearly associated with poor outcome, the influence of ET on outcome remains inconclusive. Limited by their retrospective nature and an indication bias, these data encourage a randomized assessment of ET. Graphical abstract

The aim of this prospective clinical study was to establish and verify an adaptation for axial length (AL) measurement in silicone oil (SO)-filled pseudophakic eyes with a Scheimpflug and partial coherence interferometry (PCI)-based biometer. The AL was measured with a Pentacam AXL (OCULUS Optikgeräte GmbH, Wetzler, Germany) and IOLMaster 700 (Carl Zeiss Meditec, Jena, Germany). The coefficients of variation (CoV) and the mean systematic difference (95% confidence interval (CI)) between the devices were calculated. After implementing a setting for measuring AL in tamponaded eyes with a Pentacam based on data of 29 eyes, another 12 eyes were examined for verification. The mean AL obtained with the Pentacam was 25.53 ± 1.94 mm (range: 21.70 to 30.76 mm), and with IOLMaster, 24.73 ± 1.97 mm (ranged 20.84 to 29.92 mm), resulting in a mean offset of 0.80 ± 0.08 mm (95% CI: 0.77, 0.83 mm), p < 0.001. The AL values of both devices showed a strong linear correlation (r = 0.999). Verification data confirmed good agreement, with a statistically and clinically non-significant mean difference of 0.02 ± 0.04 (95% CI: −0.01, 0.05) mm, p = 0.134. We implemented a specific adaptation for obtaining reliable AL values in SO-filled eyes with the Pentacam AXL.

Introduction: Prolonged mechanical ventilation (PMV) and weaning failure are factors associated with prolonged hospital length of stay and increased morbidity and mortality. In addition to the burden these places on patients and their families, it also imposes high costs on the public health system. The aim of this systematic review was to identify risk factors for PMV and weaning failure. Methods: The study was conducted according to PRISMA guidelines. After a comprehensive search of the COCHRANE Library, CINHAL, Web of Science, MEDLINE, and the LILACS Database a PubMed request was made on June 8, 2020. Studies that examined risk factors for PMV, defined as mechanical ventilation ≥96 h, weaning failure, and prolonged weaning in German and English were considered eligible; reviews, meta-analyses, and studies in very specific patient populations whose results are not necessarily applicable to the majority of ICU patients as well as pediatric studies were excluded from the analysis. This systematic review was registered in the PROSPERO register under the number CRD42021271038. Results: Of 532 articles identified, 23 studies with a total of 23,418 patients met the inclusion criteria. Fourteen studies investigated risk factors of PMV including prolonged weaning, 9 studies analyzed risk factors of weaning failure. The concrete definitions of these outcomes varied considerably between studies. For PMV, a variety of risk factors were identified, including comorbidities, site of intubation, various laboratory or blood gas parameters, ventilator settings, functional parameters, and critical care scoring systems. The risk of weaning failure was mainly related to age, previous home mechanical ventilation (HMV), cause of ventilation, and preexisting underlying diseases. Elevated PaCO 2 values during spontaneous breathing trials were indicative of prolonged weaning and weaning failure. Conclusion: A direct comparison of risk factors was not possible because of the heterogeneity of the studies. The large number of different definitions and relevant parameters reflects the heterogeneity of patients undergoing PMV and those discharged to HMV after unsuccessful weaning. Multidimensional scores are more likely to reflect the full spectrum of patients ventilated in different ICUs than single risk factors.