Point estimation, confidence intervals, and P-values for optimal adaptive two-stage designs with normal endpoints.

Due to the dependency structure in the sampling process, adaptive trial designs create challenges in point and interval estimation and in the calculation of P-values. Optimal adaptive designs, which are designs where the parameters governing the adaptivity are chosen to maximize some performance criterion, suffer from the same problem. Various analysis methods which are able to handle this dependency structure have already been developed. In this work, we aim to give a comprehensive summary of these methods and show how they can be applied to the class of designs with planned adaptivity, of which optimal adaptive designs are an important member. The defining feature of these kinds of designs is that the adaptive elements are completely prespecified. This allows for explicit descriptions of the calculations involved, which makes it possible to evaluate different methods in a fast and accurate manner. We will explain how to do so, and present an extensive comparison of the performance characteristics of various estimators between an optimal adaptive design and its group-sequential counterpart.

Clinical and serological characterization of acute pleuropericarditis suggests an autoinflammatory pathogenesis and highlights risk factors for recurrent attacks.

PURPOSE: We describe the manifestations and course of patients with pleuropericarditis (PP). Serum parameters were analyzed to evaluate the contribution of autoimmune and autoinflammatory mechanisms to PP pathogenesis. Finally, we outline risk factors for recurrent PP attacks. METHODS: Electronic medical records of the University Hospital Heidelberg were screened for PP diagnosis between the years 2009 and 2021. A total of 164 patients were detected and compared to patients suffering from systemic lupus erythematosus (SLE)-associated PP. Follow-up data were collected until January 2023. RESULTS: In 57.3% of a total of 164 PP cases, no trigger was identified (idiopathic PP). The clinical manifestations were similar in subgroups with different triggers (idiopathic, post-cardiac injury and post-infectious). None of the patients in the idiopathic-PP (i-PP) group fulfilled the diagnostic criteria of an autoimmune disease and the i-PP group could be clearly discriminated by clinical, epidemiological and serological means from the control cohort of SLE-associated PP. After a median follow-up of 1048 days, the majority of PP patients (72.7%) had at least one PP relapse. Univariate analyses showed that CRP, SAA (serum amyloid A), troponin T, NT-BNP and post-cardiac injury were negatively correlated, while the presence of fever and an idiopathic trigger were positively correlated with recurrence of PP. Multivariate analyses showed that fever, an idiopathic trigger and low SAA values were risk factors for PP recurrence. CONCLUSION: This study highlights that most cases of PP are idiopathic and PP cases with various triggers have an identical clinical phenotype. Our data suggest that the clinical, epidemiological and serological characteristics of idiopathic PP considerably differ from patients with PP caused by autoimmune disease like SLE. We further demonstrate that PP has a high risk of recurrence and identify factors associated with this risk, allowing for a targeted secondary prophylaxis.

Role of multidrug-resistant bacteria in weaning from invasive mechanical ventilation.

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.

Extension of a conditional performance score for sample size recalculation rules to the setting of binary endpoints.

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 [Formula: see text] between the intervention and the control group, as well as the endpoint proportion [Formula: see text] in the control group. CONCLUSIONS: This research extends the theory of the conditional performance score to binary endpoints and demonstrates its application in practice.

Surgical Versus Dilational Tracheostomy in Patients with Severe Stroke: A SETPOINT2 Post hoc Analysis.

BACKGROUND: Tracheostomy in mechanically ventilated patients with severe stroke can be performed surgically or dilationally. Prospective data comparing both methods in patients with stroke are scarce. The randomized Stroke-Related Early Tracheostomy vs Prolonged Orotracheal Intubation in Neurocritical Care Trial2 (SETPOINT2) assigned 382 mechanically ventilated patients with stroke to early tracheostomy versus extubation or standard tracheostomy. Surgical tracheostomy (ST) was performed in 41 of 307 SETPOINT2 patients, and the majority received dilational tracheostomy (DT). We aimed to compare ST and DT in these patients with patients. METHODS: All SETPOINT2 patients with ST were compared with a control group of patients with stroke undergoing DT (1:2), selected by propensity score matching that included the factors stroke type, SETPOINT2 randomization group, Stroke Early Tracheostomy score, patient age, and premorbid functional status. Successful decannulation was the primary outcome, and secondary outcome parameters included functional outcome at 6 months and adverse events attributable to tracheostomy. Potential predictors of decannulation were evaluated by regression analysis. RESULTS: Baseline characteristics were comparable in the two groups of patients with stroke undergoing ST (n = 41) and matched patients with stroke undergoing DT (n = 82). Tracheostomy was performed significantly later in the ST group than in the DT group (median 9 [interquartile range {IQR} 5-12] vs. 9 [IQR 4-11] days after intubation, p = 0.025). Patients with ST were mechanically ventilated longer (median 19 [IQR 17-24] vs.14 [IQR 11-19] days, p = 0.008) and stayed in the intensive care unit longer (median 23 [IQR 16-27] vs. 17 [IQR 13-24] days, p = 0.047), compared with patients with DT. The intrahospital infection rate was significantly higher in the ST group compared to the DT group (14.6% vs. 1.2%, p = 0.002). At 6 months, decannulation rates (56% vs. 61%), functional outcomes, and mortality were not different. However, decannulation was performed later in the ST group compared to the DT group (median 81 [IQR 66-149] vs. 58 [IQR 32-77] days, p = 0.004). Higher baseline Stroke Early Tracheostomy score negatively predicted decannulation. CONCLUSIONS: In ventilated patients with severe stroke in need of tracheostomy, surgical and dilational methods are associated with comparable decannulation rate and functional outcome at 6 months. However, ST was associated with longer time to decannulation and higher rates of early infections, supporting the dilational approach to tracheostomy in ventilated patients with stroke.

Risk factors for long-term invasive mechanical ventilation: a longitudinal study using German health claims data.

BACKGROUND: Long-term invasive mechanical ventilation (IMV) is a major burden for those affected and causes high costs for the health care system. Early risk assessment is a prerequisite for the best possible support of high-risk patients during the weaning process. We aimed to identify risk factors for long-term IMV within 96 h (h) after the onset of IMV. METHODS: The analysis was based on data from one of Germany's largest statutory health insurance funds; patients who received IMV ≥ 96 h and were admitted in January 2015 at the earliest and discharged in December 2017 at the latest were analysed. OPS and ICD codes of IMV patients were considered, including the 365 days before intubation and 30 days after discharge. Long-term IMV was defined as evidence of invasive home mechanical ventilation (HMV), IMV ≥ 500 h, or readmission with (re)prolonged ventilation. RESULTS: In the analysis of 7758 hospitalisations, criteria for long-term IMV were met in 38.3% of cases, of which 13.9% had evidence of HMV, 73.1% received IMV ≥ 500 h and/or 40.3% were re-hospitalised with IMV. Several independent risk factors were identified (p < 0.005 each), including pre-diagnoses such as pneumothorax (OR 2.10), acute pancreatitis (OR 2.64), eating disorders (OR 1.99) or rheumatic mitral valve disease (OR 1.89). Among ICU admissions, previous dependence on an aspirator or respirator (OR 5.13), and previous tracheostomy (OR 2.17) were particularly important, while neurosurgery (OR 2.61), early tracheostomy (OR 3.97) and treatment for severe respiratory failure such as positioning treatment (OR 2.31) and extracorporeal lung support (OR 1.80) were relevant procedures in the first 96 h after intubation. CONCLUSION: This comprehensive analysis of health claims has identified several risk factors for the risk of long-term ventilation. In addition to the known clinical risks, the information obtained may help to identify patients at risk at an early stage. Trial registration The PRiVENT study was retrospectively registered at ClinicalTrials.gov (NCT05260853). Registered at March 2, 2022.

Longitudinal Evaluation of Biomechanical Indices in Fellow Eyes of Patients With Keratoconus Classified as Having Very Asymmetric Ectasia With Normal Topography.

PURPOSE: To evaluate the biomechanical longitudinal variability and progression of tomographically normal fellow eyes of patients with keratoconus. METHODS: Of 513 patients with keratoconus, 30 patients with tomographically normal fellow eyes were included in this study. Tomographic and biomechanical parameters of the Pentacam and Corvis ST (Oculus Optikgeräte GmbH) were analyzed in multiple follow-up examinations, including the ABCD grading, Belin/Ambrósio Enhanced Ectasia total deviation index (BAD-D), Corvis Biomechanical Index (CBI), Corvis Biomechanical Factor (CBiF), and Tomographic and Biomechanical Index (TBI). A mixed regression model was applied. The results were compared to a healthy control group (n = 17) and a keratoconus group (n = 20). RESULTS: Within a maximum observation period of 3.3 years, no fellow eye (0%) showed a progression to tomographically evident keratoconus. No significant change in tomographic or biomechanical parameters was detected over the study period. The indices BAD-D, CBI, CbiF, and TBI exhibited a certain variability over time, whereas the tomographic ABC parameters and maximum keratometry barely changed. This was also shown in the control group and for all parameters in the keratoconus group, except the TBI. CONCLUSIONS: During the observation period none of the normal fellow eyes progressed to tomographically detectable keratoconus. However, biomechanical parameters CBI, CbiF, and TBI showed pathological values in 43.3% of eyes and certain variability. Subsequent studies with a longer observation period are warranted to confirm the biomechanical trends seen in this study and to rate the ability of single measurements to diagnose early keratoconus. [J Refract Surg. 2024;40(1):e48-e56.].

Outcome analysis for patients with subarachnoid hemorrhage and vasospasm including endovascular treatment.

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.

Effect of Individualized Versus Standardized Blood Pressure Management During Endovascular Stroke Treatment on Clinical Outcome: A Randomized Clinical Trial.

BACKGROUND: Optimal blood pressure (BP) management during endovascular stroke treatment is not well established. We studied whether an individualized approach for managing BP during endovascular stroke treatment gives a better clinical outcome than an approach with standardized systolic BP targets. METHODS: The INDIVIDUATE study (Individualized Blood Pressure Management During Endovascular Treatment of Acute Ischemic Stroke Under Procedural Sedation) is a randomized clinical trial with a prospective randomized open blinded end point (PROBE) design. Patients were recruited between October 1, 2020 and July 7, 2022 at a single center at a tertiary care university hospital. Patients were eligible, when they were suffering from acute ischemic stroke of the anterior circulation with occlusions of the internal carotid artery and middle cerebral artery and a National Institutes of Health Stroke Scale score of ≥8 receiving endovascular stroke treatment in procedural sedation. The intervention consists of an individualized BP management strategy, where preinterventional baseline systolic BP (SBP) values are used as intraprocedural BP targets. As a control, the standard treatment aims to maintain the intraprocedural SBP between 140 and 180 mm Hg. The main prespecified outcome is the proportion of favorable functional outcomes 90 days after stroke, defined as a modified Rankin Scale score of 0 to 2. RESULTS: Two hundred fifty patients were enrolled and included in the analysis, mean (SD) age was 77 (12) years, 142 (57%) patients were women, and mean (SD) National Institutes of Health Stroke Scale score on admission was 17 (5.2). In all, 123 (49%) patients were treated with individualized and 127 (51%) with standard BP management. Mean (SD) intraprocedural SBP was similar in the individualized versus standard BP management group (157 [19] versus 154 [18] mm Hg; P=0.16). The rate of favorable functional outcome after 3 months was not significantly different between the individualized versus the standard BP management group (25% versus 24%; adjusted odds ratio, 0.81 [95% CI, 0.41-1.61]; P=0.56). CONCLUSIONS: Among patients treated with endovascular stroke treatment due to an acute ischemic stroke of the anterior circulation, no significant difference was seen between the individualized BP management strategy, where intraprocedural SBP was targeted to baseline values, and the standardized regimen of targeting SBP between 140 and 180 mm Hg. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04578288.

Long-Term Efficacy and Safety of Rituximab Versus Tacrolimus in Children With Steroid Dependent Nephrotic Syndrome.

Introduction: In the Rituximab for Relapse Prevention in Nephrotic Syndrome (RITURNS) trial, we demonstrated superior efficacy of single-course rituximab over maintenance tacrolimus in preventing relapses in children with steroid dependent nephrotic syndrome (SDNS) during a 1-year observation. Here we present the long-term outcomes of all 117 trial completers, who were followed up for another 2 years. Methods: Relapsing patients in the rituximab arm received a second course of rituximab, either with (n = 44) or without mycophenolate mofetil (MMF) cotreatment (n = 15). In the tacrolimus arm, second line rituximab monotherapy was initiated after relapses (n = 32) or electively (n = 24). Results: All 12-month relapse-free patients in the rituximab arm relapsed in the second postexposure year, resulting in similar median relapse-free survival times in the 2 trial arms (62 vs. 59 weeks). Second line rituximab in the tacrolimus arm was less effective than first-line therapy in patients switched to rituximab following a relapse (relapse-free survival 55 vs. 63 weeks, P < 0.01). B-cell counts 6 months post-rituximab predicted relapse risk both for first and second line therapy. MMF cotreatment yielded much improved 2-year relapse-free survival as compared to rituximab monotherapy (67% vs. 9%, P < 0.0001). Higher grade 2 adverse event rates were observed post-rituximab versus on tacrolimus (0.87 vs. 0.53 per year). Conclusion: The superior therapeutic effect of rituximab in SDNS vanishes during the second year post-exposure. Rituximab appears to yield longer remission when applied as first line as compared to second line therapy. Maintenance MMF following rituximab induces long-term disease remission.

Refractive outcomes after DMEK: meta-analysis.

In this meta-analysis and systematic literature review of refractive outcomes after Descemet membrane endothelial keratoplasty (DMEK), the extent of the refractive shift and an overview of reasons for refractive shift after DMEK are provided. The PubMed library was screened for articles containing the terms "Descemet membrane endothelial keratoplasty," "DMEK," "Descemet membrane endothelial keratoplasty combined with cataract surgery," "triple-DMEK" combined with "refractive outcomes," "refractive shift," and "hyperopic shift." The refractive outcomes after DMEK were analyzed and compared using a fixed and random effects model. The overall mean change of the spherical equivalent outcome when compared with the preoperative value in cases of DMEK or when compared with the preoperative target refraction in cases of DMEK combined with cataract surgery was +0.43 diopters (D) (95% CI, 0.31-0.55). When DMEK is combined with cataract surgery, a target refraction of -0.5 D is recommended to achieve emmetropia. Changes in the posterior corneal curvature are identified as the main cause of the refractive hyperopic shift.

Prevention of invasive ventilation (PRiVENT)-a prospective, mixed-methods interventional, multicentre study with a parallel comparison group: study protocol.

BACKGROUND: Invasive mechanical ventilation (IMV) is a standard therapy for intensive care patients with respiratory failure. With increasing population age and multimorbidity, the number of patients who cannot be weaned from IMV increases, resulting in impaired quality of life and high costs. In addition, human resources are tied up in the care of these patients. METHODS: The PRiVENT intervention is a prospective, mixed-methods interventional, multicentre study with a parallel comparison group selected from insurance claims data of the health insurer Allgemeine Ortskrankenkasse Baden-Württemberg (AOK-BW) conducted in Baden-Württemberg, Germany, over 24 months. Four weaning centres supervise 40 intensive care units (ICUs), that are responsible for patient recruitment. The primary outcome, successful weaning from IMV, will be evaluated using a mixed logistic regression model. Secondary outcomes will be evaluated using mixed regression models. DISCUSSION: The overall objective of the PRiVENT project is the evaluation of strategies to prevent long-term IMV. Additional objectives aim to improve weaning expertise in and cooperation with the adjacent Intensive Care Units. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT05260853).

Optimization of the two-stage group sequential three-arm gold-standard design for non-inferiority trials.

If design parameters are chosen appropriately, group sequential trial designs are known to be able to reduce the expected sample size under the alternative hypothesis compared to single-stage designs. The same holds true for the so-called 'gold-standard' design for non-inferiority trials, a design involving an experimental group, an active control group, and a placebo group. However, choosing design parameters that maximize the advantages of a two-stage approach for the three-arm gold-standard design for non-inferiority trials is not a straightforward task. In particular, optimal choices of futility boundaries for this design have not been thoroughly discussed in existing literature. We present a variation of the hierarchical testing procedure, which allows for the incorporation of binding futility boundaries at interim analyses. We show that this procedure maintains strong control of the family-wise type I error rate. Within this framework, we consider the futility and efficacy boundaries as well as the sample size allocation ratios as optimization parameters. This allows the investigation of the efficiency gain from including the option to stop for futility in addition to the ability to stop for efficacy. To analyze the extended designs, optimality criteria that include the design's performance under the alternative as well as the null hypothesis are introduced. On top of this, we discuss methods to limit the allocation of placebo patients in the trial while maintaining relatively good operating characteristics. The results of our numerical optimization procedure are discussed and a comparison of different approaches to designing a three-arm gold-standard non-inferiority trial is provided.

Risk Factors for Prolonged Mechanical Ventilation and Weaning Failure: A Systematic Review.

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 PaCO2 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.

Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC.

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.

Magnetic resonance guided adaptive stereotactic body radiotherapy for lung tumors in ultracentral location: the MAGELLAN trial (ARO 2021-3).

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 BED3/10: 155.83 Gy/85.25 Gy), may proceed up to 10 × 6.5 Gy (BED3/10: 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.

Effect of Early vs Standard Approach to Tracheostomy on Functional Outcome at 6 Months Among Patients With Severe Stroke Receiving Mechanical Ventilation: The SETPOINT2 Randomized Clinical Trial.

Importance: Many patients with severe stroke have impaired airway protective reflexes, resulting in prolonged invasive mechanical ventilation. Objective: To test whether early vs standard tracheostomy improved functional outcome among patients with stroke receiving mechanical ventilation. Design, Setting, and Participants: In this randomized clinical trial, 382 patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation were randomly assigned (1:1) to early tracheostomy (≤5 days of intubation) or ongoing ventilator weaning with standard tracheostomy if needed from day 10. Patients were randomized between July 28, 2015, and January 24, 2020, at 26 US and German neurocritical care centers. The final date of follow-up was August 9, 2020. Interventions: Patients were assigned to an early tracheostomy strategy (n = 188) or to a standard tracheostomy (control group) strategy (n = 194). Main Outcomes and Measures: The primary outcome was functional outcome at 6 months, based on the modified Rankin Scale score (range, 0 [best] to 6 [worst]) dichotomized to a score of 0 (no disability) to 4 (moderately severe disability) vs 5 (severe disability) or 6 (death). Results: Among 382 patients randomized (median age, 59 years; 49.8% women), 366 (95.8%) completed the trial with available follow-up data on the primary outcome (177 patients [94.1%] in the early group; 189 patients [97.4%] in the standard group). A tracheostomy (predominantly percutaneously) was performed in 95.2% of the early tracheostomy group in a median of 4 days after intubation (IQR, 3-4 days) and in 67% of the control group in a median of 11 days after intubation (IQR, 10-12 days). The proportion without severe disability (modified Rankin Scale score, 0-4) at 6 months was not significantly different in the early tracheostomy vs the control group (43.5% vs 47.1%; difference, -3.6% [95% CI, -14.3% to 7.2%]; adjusted odds ratio, 0.93 [95% CI, 0.60-1.42]; P = .73). Of the serious adverse events, 5.0% (6 of 121 reported events) in the early tracheostomy group vs 3.4% (4 of 118 reported events) were related to tracheostomy. Conclusions and Relevance: Among patients with severe stroke receiving mechanical ventilation, a strategy of early tracheostomy, compared with a standard approach to tracheostomy, did not significantly improve the rate of survival without severe disability at 6 months. However, the wide confidence intervals around the effect estimate may include a clinically important difference, so a clinically relevant benefit or harm from a strategy of early tracheostomy cannot be excluded. Trial Registration: ClinicalTrials.gov Identifier: NCT02377167.

Development and Verification of an Adjustment Factor for Determining the Axial Length Using Optical Biometry in Silicone Oil-Filled Eyes.

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.

Scheimpflug Versus Optical Coherence Tomography to Detect Subclinical Corneal Edema in Fuchs Endothelial Corneal Dystrophy.

PURPOSE: The purpose of this research was to compare the ability of Scheimpflug and anterior segment optical coherence tomography (OCT) in detecting subclinical corneal edema in patients with Fuchs endothelial corneal dystrophy (FECD) without clinical corneal edema. METHODS: In this single-center, consecutive case series, 47 eyes of 29 patients with FECD were analyzed. The main outcome measures were anterior/posterior keratometry and central/thinnest corneal thickness. The criteria for subclinical corneal edema were loss of regular isopachs, displacement of the thinnest point of the cornea, and presence of posterior surface depression. Tomographic analyses were performed using Scheimpflug imaging (Pentacam HR) and OCT (anterior segment swept-source optical coherence tomography). RESULTS: The measurement of the continuous variables revealed a significant difference between the 2 devices. The anterior curvature was steeper and the posterior curvature was flatter when measured with OCT ( P < 0.001). The OCT showed a lower central corneal thickness and thinnest corneal thickness ( P < 0.001). The agreement between both devices to detect subclinical corneal edema was high. The interdevice reliability for loss of parallel isopachs as measured by Cohen kappa coefficient was 0.84; for the displacement of the thinnest point of the cornea, it was 0.6, and for the focal posterior corneal surface depression, it was 0.62. Subclinical corneal edema was detected in 72.3% of the patients with both devices. In only 2 cases (4.3%), subclinical corneal edema was detected by one of the devices. CONCLUSIONS: Scheimpflug and OCT imaging were both able to detect tomographic patterns of subclinical corneal edema. Therefore, both devices can help decision-making, favoring early endothelial keratoplasty in symptomatic patients with FECD without clinical corneal edema.