Predicting the On-Study Relapse Rate for Multiple Sclerosis Patients in Clinical Trials

Background: The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III multiple sclerosis (MS) clinical trials. The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS. Methods: A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis. The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed. The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected. Subset 1 included age at disease onset, disease duration, gender, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline, and the disease course (RR and SP). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI. The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2. Results:The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p<0.05). A higher on-study relapse rate was associated with a shorter disease duration, lower entry EDSS, more pre-study relapses and more enhancing lesions in T1 at entry. The fitted Poisson model shows that disease duration (estimate=-0.02) and previous relapse number (estimate=0.59 for 1, 0.91 for 2 and 1.45 for 3 or more relapses vs 0 relapse) remain. We were able to confirm these findings in a second, independent dataset. Conclusions: The relapse number prior to entry into clinical trials together with disease duration are the best predictors for the on-study relapse rate. Disease course and gadolinium enhancement status, given the other covariates, have no significant influence on the on-study relapse rate

Reducing the Probability of False Positive Research Findings by Pre-Publication Validation - Experience with a Large Multiple Sclerosis Database

*Objective*&#xd;&#xa;We have assessed the utility of a pre-publication validation policy in reducing the probability of publishing false positive research findings. &#xd;&#xa;*Study design and setting*&#xd;&#xa;The large database of the Sylvia Lawry Centre for Multiple Sclerosis Research was split in two parts: one for hypothesis generation and a validation part for confirmation of selected results. We present case studies from 5 finalized projects that have used the validation policy and results from a simulation study.&#xd;&#xa;*Results*&#xd;&#xa;In one project, the &#x22;relapse and disability&#x22; project as described in section II (example 3), findings could not be confirmed in the validation part of the database. The simulation study showed that the percentage of false positive findings can exceed 20% depending on variable selection. &#xd;&#xa;*Conclusion*&#xd;&#xa;We conclude that the validation policy has prevented the publication of at least one research finding that could not be validated in an independent data set (and probably would have been a &#x22;true&#x22; false-positive finding) over the past three years, and has led to improved data analysis, statistical programming, and selection of hypotheses. The advantages outweigh the lost statistical power inherent in the process

Energy Spectrum of Quasi-Geostrophic Turbulence

We consider the energy spectrum of a quasi-geostrophic model of forced, rotating turbulent flow. We provide a rigorous a priori bound E(k) <= Ck^{-2} valid for wave numbers that are smaller than a wave number associated to the forcing injection scale. This upper bound separates this spectrum from the Kolmogorov-Kraichnan k^{-{5/3}} energy spectrum that is expected in a two-dimensional Navier-Stokes inverse cascade. Our bound provides theoretical support for the k^{-2} spectrum observed in recent experiments

Hund's rule and metallic ferromagnetism

We study tight-binding models of itinerant electrons in two different bands, with effective on-site interactions expressing Coulomb repulsion and Hund's rule. We prove that, for sufficiently large on-site exchange anisotropy, all ground states show metallic ferromagnetism: They exhibit a macroscopic magnetization, a macroscopic fraction of the electrons is spatially delocalized, and there is no energy gap for kinetic excitations.Comment: 17 page

Serum (1 → 3)-β-d-glucan measurement as an early indicator of Pneumocystis jirovecii pneumonia and evaluation of its prognostic value

AbstractPneumocystis jirovecii (carinii) pneumonia (PJP) is a major cause of disease in immunocompromised individuals. However, until recently no reliable and specific serological parameters for the diagnosis of PJP have been available. (1 → 3)-β-d-Glucan (BG) is a cell wall component of P. jirovecii and of various other fungi. Data from the past few years have pointed to serum measurement of BG as a promising new tool for the diagnosis of PJP. We therefore conducted a retrospective study on 50 patients with PJP and 50 immunocompromised control patients to evaluate the diagnostic performance of serum BG measurement. Our results show an excellent diagnostic performance with a sensitivity of 98.0% and a specificity of 94%. While the positive predictive value was only 64.7%, the negative predictive value was 99.8% and therefore a negative BG result almost rules out PJP. BG levels were already strongly elevated in an average of 5 days and up to 21 days before microbiological diagnosis demonstrating that the diagnosis could have been confirmed earlier. BG levels at diagnosis and maximum BG levels during follow-up did not correlate with the outcome of patients or with the P. jirovecii burden in the lung as detected by Real-Time PCR. Therefore, absolute BG levels seem to be of no prognostic value. Altogether, BG is a reliable parameter for the diagnosis of PJP and could be used as a preliminary test for patients at risk before a bronchoalveolar lavage is performed

Charge order, orbital order, and electron localization in the Magneli phase Ti4O7

The metal-insulator transition of the Magneli phase Ti4O7 is studied by means of augmented spherical wave (ASW) electronic structure calculations as based on density functional theory and the local density approximation. The results show that the metal-insulator transition arises from a complex interplay of charge order, orbital order, and singlet formation of those Ti 3d states which mediate metal-metal bonding inside the four-atom chains characteristic of the material. Ti4O7 thus combines important aspects of Fe3O4 and VO2. While the charge ordering closely resembles that observed at the Verwey transition, the orbital order and singlet formation appear to be identical to the mechanisms driving the metal-insulator transition of vanadium dioxide.Comment: 11 pages, 4 figures, more information at http://www.physik.uni-augsburg.de/~eyert

Antibiotic-Impregnated Versus Silver-Bearing External Ventricular Drainage Catheters: Preliminary Results in a Randomized Controlled Trial

Background: Evaluation of antibiotic-impregnated (AI) and ionized silver particle coated external ventricular drainage catheters (EVD) in patients with subarachnoid (SAH) or intracranial hemorrhage (ICH). Methods: Between February 2011 and June 2012, 40 patients with acute hydrocephalus due to SAH, ICH or intraventricular hemorrhage were enrolled in a prospective, randomized, mono-center pilot study. Primary endpoints were defined as: number of events of cerebrospinal fluid (CSF) infections. Secondary endpoints were defined as: neurosurgical complications following the placement of the EVD, number of revisions of EVD catheters, and cost effectiveness. Results: Sixty-one EVD placements in 40 patients, 32 antibiotic-coated (Bactiseal®), 29 silver-bearing catheters (VentriGuard®), have been performed. Confirmed or high suspicion of CSF infections occurred in 11 out of 61 events (confirmed infection: p=0.71, probable infection: p=0.90). Revisions of EVD were needed in 13 cases (22%) due to CSF infection, dysfunction, impaired healing, or malplacement (p=0.37). Conclusion: Regarding CSF infection rate and dysfunction, no statistical significant differences between the two EVD catheters Bactiseal® versus VentriGuard® were found. The silver-bearing catheter might offer a safe and cost-conscious alternative to the AI cathete

The influence of comorbidities on the treatment outcome in symptomatic lumbar spinal stenosis: A systematic review and meta-analysis

Background Lumbar spinal stenosis (LSS) affects mainly elderly patients. To this day, it is unclear whether comorbidities influence treatment success. The aim of this systematic review and meta-analysis was to assess the impact of comorbidities on the treatment effectiveness in symptomatic LSS. Methods We conducted a systematic review and meta-analysis and reviewed prospective or retrospective studies from Medline, Embase, Cochrane Library and CINAHL from inception to May 2020, including adult patients with LSS undergoing surgical or conservative treatment. Main outcomes were satisfaction, functional and symptoms improvement, and adverse events (AE). Proportions of outcomes within two subgroups of a comorbidity were compared with risk ratio (RR) as summary measure. Availability of ≥3 studies for the same subgroup and outcome was required for meta-analysis. Results Of 72 publications, 51 studies, mostly assessing surgery, there was no evidence reported that patients with comorbidities were less satisfied compared to patients without comorbidities (RR 1.06, 95% confidence interval (CI) 0.77 to 1.45, 94%), but they had an increased risk for AE (RR 1.46, 95% CI 1.06 to 2.01, 72%). A limited number of studies found no influence of comorbidities on functional and symptoms improvement. Older age did not affect satisfaction, symptoms and functional improvement, and AE (age >80 years RR 1.22, 95% CI 0.98 to 1.52, 60%). Diabetes was associated with more AE (RR 1.72, 95% CI 1.19 to 2.47, 58%). Conclusion In patients with LSS and comorbidities (in particular diabetes), a higher risk for AE should be considered in the treatment decision. Older age alone was not associated with an increased risk for AE, less functional and symptoms improvement, and less treatment satisfaction