Baseline predictors of in-hospital mortality after acute traumatic spinal cord injury: data from a level I trauma center.

Comorbidity scores are important predictors of in-hospital mortality after traumatic spinal cord injury (tSCI), but the impact of specific pre-existing diseases is unknown. This retrospective cohort study aims at identifying relevant comorbidities and explores the influence of end-of-life decisions. In-hospital mortality of all patients admitted to the study center after acute tSCI from 2011 to 2017 was assessed. A conditional inference tree analysis including baseline data, injury characteristics, and Charlson Comorbidity Index items was used to identify crucial predictors. End-of-life decisions were recorded. Three-hundred-twenty-one patients were consecutively enrolled. The median length of stay was 95.7 days (IQR 56.8-156.0). During inpatient care, 20 patients (6.2%) died. These patients were older (median: 79.0 (IQR 74.7-83.2) vs. 55.5 (IQR 41.4-72.3) years) and had a higher Charlson Comorbidity Index score (median: 4.0 (IQR 1.75-5.50) vs. 0.0 (IQR 0.00-1.00)) compared to survivors. Pre-existing kidney or liver disease were identified as relevant predictors of in-hospital mortality. End-of-life decisions were observed in 14 (70.0%) cases. The identified impairment of kidney and liver, important for drug metabolism and elimination, points to the need of careful decisions on pharmaceutical treatment regimens after tSCI. Appropriate reporting of end-of-life decisions is required for upcoming studies.

Group sequential methods for the Mann-Whitney parameter.

Late phase clinical trials are occasionally planned with one or more interim analyses to allow for early termination or adaptation of the study. While extensive theory has been developed for the analysis of ordered categorical data in terms of the Wilcoxon-Mann-Whitney test, there has been comparatively little discussion in the group sequential literature on how to provide repeated confidence intervals and simple power formulas to ease sample size determination. Dealing more broadly with the nonparametric Behrens-Fisher problem, we focus on the comparison of two parallel treatment arms and show that the Wilcoxon-Mann-Whitney test, the Brunner-Munzel test, as well as a test procedure based on the log win odds, a modification of the win ratio, asymptotically follow the canonical joint distribution. In addition to developing power formulas based on these results, simulations confirm the adequacy of the proposed methods for a range of scenarios. Lastly, we apply our methodology to the FREEDOMS clinical trial (ClinicalTrials.gov Identifier: NCT00289978) in patients with relapse-remitting multiple sclerosis.

Intra-scanner repeatability of quantitative imaging features in a 3D printed semi-anthropomorphic CT phantom.

OBJECTIVES: Radiomics has shown to provide novel diagnostic and predictive disease information based on quantitative image features in study settings. However, limited data yielded contradictory results and important questions regarding the validity of the methods remain to be answered. The purpose of this study was to evaluate how clinical imaging techniques affect the stability of radiomics features by using 3D printed anthropomorphic CT phantom to test for repeatability and reproducibility of quantitative parameters. METHODS: 48 PET/CT validated lymph nodes of prostate cancer patients (24 metastatic, 24 non-metastatic) were used as a template to create a customized 3D printed anthropomorphic phantom. We subsequently scanned the phantom five times with a routine abdominal CT protocol. Images were reconstructed using iterative reconstruction and two soft tissue kernels and one bone kernel. Radiomics features were extracted and assessed for repeatability and susceptibility towards image reconstruction settings using concordance correlation coefficients. RESULTS: Our analysis revealed 19 of 86 features (22 %) as highly repeatable (CCC ≥ 0.85) with low susceptibility towards image reconstruction protocols. Most features analyzed depicted critical non-repeatability with CCC's < 0.75 even under entirely consistent imaging acquisition settings. Edge enhancing kernels result in higher variances between the scans and differences in repeatability and reproducibility were detected between PSMA-positive and negative lymph nodes with overall more stable features seen in tumor positive lymph nodes. CONCLUSIONS: Both, repeatability and reproducibility play a crucial role in the validation process of radiomics features in clinical routine. This phantom study shows that most radiomics features in contrast to previous studies, including phantom and clinical, do not depict sufficient intra-scanner repeatability to serve as reliable diagnostic tools.

Plasma calcitonin gene-related peptide (CGRP) in migraine and endometriosis during the menstrual cycle.

OBJECTIVE: Migraine, endometriosis, and the comorbidity of both are frequent pain disorders of special relevance for women. The neuropeptide calcitonin gene-related peptide (CGRP) is critically involved in migraine, and circumstantial evidence suggests a role in endometriosis. We assessed CGRP levels at different times of menstrual cycle in four groups: healthy women, women with migraine or endometriosis and with the comorbidity of both. METHODS: Women with episodic migraine and women with a histologically confirmed endometriosis were recruited from specialized centers. For CGRP determination with a commercial enzyme immunoassay kit, cubital vein blood samples were collected on menstrual cycle day 2 ± 2 (during menstruation) and on day 15 ± 2 (periovulatory period). The primary endpoint of the study was the absolute difference of CGRP plasma levels between the menstrual and the periovulatory phase of all study groups. Groups were compared using nonparametric test procedures. RESULTS: A total of 124 women were included in the study. The change of CGRP plasma levels between menstruation and the periovulatory period was different between groups (p = 0.007). Women with comorbid migraine and endometriosis showed an increase of CGRP in the menstrual phase of +6.32 (interquartile range, IQR -3.64-13.60) compared to the periovulatory time, while healthy controls had a decrease of -10.14 (-22.54-0.91, p = 0.004). CGRP levels were different in the periovulatory phase among groups (p = 0.008), with highest values in healthy controls. INTERPRETATION: CGRP levels change significantly during the menstrual cycle. Different patterns in women with the comorbidity point to a deviant regulation of CGRP release.

Cool enough? Lessons learned from cryoballoon-guided catheter ablation for atrial fibrillation in young adults.

INTRODUCTION: Cryoballoon (CB)-guided ablation of atrial fibrillation (AF) is established in symptomatic AF patients. This study sought to determine the safety and efficacy of CB pulmonary vein isolation (PVI) in young adults. METHODS AND RESULTS: A total of 93 consecutive patients aged <45 years referred to our center for AF ablation were included in this observational study. All patients received CB-guided PVI according to a standardized institutional protocol. Follow-up was performed in our outpatient clinic using 72-h Holter monitoring and periodic telephone interview. Recurrence was defined as any AF/atrial tachycardia (AT) episode >30 s following a 3-month blanking period. A propensity matched control group consisting of patients older than 45 years were used for further evaluation. Mean age was 35 ± 7 years, 22% suffered from persistent AF, 85% were male. Mean follow-up was 2.6 ± 2 years. At the end of the observational period, 83% of patients were free of any AF/AT episodes. There was an excellent overall 12-month success rate of 92%. In comparison to a matched group the overall recurrence rate was noticeably lower in the young group (15% vs. 27%). Increasing age was associated with a hazard ratio of 1.16 for recurrence. In a multivariate analysis model, left atrial diameter remained as significant predictor of AF/AT recurrence. The complication rate was low, no permanent phrenic nerve palsy was observed. CONCLUSION: CB-guided PVI in young adults is safe and effective with favorable long-term results. It may be considered as first-line therapy in this relatively healthy population.

Fingolimod after a first unilateral episode of acute optic neuritis (MOVING) - preliminary results from a randomized, rater-blind, active-controlled, phase 2 trial.

BACKGROUND: Neuroprotection and promotion of remyelination represent important therapeutic gaps in multiple sclerosis (MS). Acute optic neuritis (ON) is a frequent MS manifestation. Based on the presence and properties of sphingosine-1-phosphate receptors (S1PR) on astrocytes and oligodendrocytes, we hypothesized that remyelination can be enhanced by treatment with fingolimod, a S1PR modulator currently licensed for relapsing-remitting MS. METHODS: MOVING was an investigator-driven, rater-blind, randomized clinical trial. Patients with acute unilateral ON, occurring as a clinically isolated syndrome or MS relapse, were randomized to 6 months of treatment with 0.5 mg oral fingolimod or subcutaneous IFN-ß 1b 250 µg every other day. The change in multifocal visual evoked potential (mfVEP) latency of the qualifying eye was examined as the primary (month 6 vs. baseline) and secondary (months 3, 6 and 12 vs. baseline) outcome. In addition, full field visual evoked potentials, visual acuity, optical coherence tomography as well as clinical relapses and measures of disability, cerebral MRI, and self-reported visual quality of life were obtained for follow-up. The study was halted due to insufficient recruitment (n = 15), and available results are reported. RESULTS: Per protocol analysis of the primary endpoint revealed a significantly larger reduction of mfVEP latency at 6 months compared to baseline with fingolimod treatment (n = 5; median decrease, 15.7 ms) than with IFN-ß 1b treatment (n = 4; median increase, 8.15 ms) (p <  0.001 for interaction). Statistical significance was maintained in the secondary endpoint analysis. Descriptive results are reported for other endpoints. CONCLUSION: Preliminary results of the MOVING trial argue in support of a beneficial effect of fingolimod on optic nerve remyelination when compared to IFN-ß treatment. Interpretation is limited by the small number of complete observations, an unexpected deterioration of the control group and a difference in baseline mfVEP latencies. The findings need to be confirmed in larger studies. TRIAL REGISTRATION: The trial was registered as EUDRA-CT 2011-004787-30 on October 26, 2012 and as NCT01647880 on July 24, 2012.

Clinical decision-making on spinal cord injury-associated pneumonia: a nationwide survey in Germany.

STUDY DESIGN: Survey study. OBJECTIVES: Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP. SETTING: All departments for SCI-care in Germany. METHODS: The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of 'clinically defined pneumonia' were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART). RESULTS: The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38-81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7-41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/ß-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/ß-lactamase inhibitors with fluoroquinolones or carbapenems. CONCLUSIONS: This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP.

Additive Value of Transrectal Systematic Ventral Biopsies in Combination with Magnet Resonance Imaging/Ultrasound Fusion-Guided Biopsy in Patients with 3 or More Negative Prostate Biopsies.

INTRODUCTION: Patients with consistent suspicion for prostate cancer (PCa) and multiple negative prebiopsies prior to multiparametric magnetic resonance imaging (mpMRI) are still frequently evaluated for an image-guided biopsy and are reported with heterogeneous detection rates. The inclusion of a systematic biopsy (SB) is also still recommended with predominant sampling within the posterior/peripheral zone of the prostate. The aim of this study was (I) to evaluate PCa detection rates using a modified 10 core SB template including anterior biopsies in combination with mpMRI/ultrasound fusion-guided targeted biopsy (TB) in patients with 3 or more negative prebiopsies and (II) to compare mpMRI index lesion localization with histologically confirmed locali-zation from associated prostatectomy samples. METHODS: Overall 1,337 consecutive patients underwent sensor-based registration TB of the prostate and a subsequent 10-core SB between January 2012 and December 2015 at our institution. For this study, 101 patients with ≥3 negative prebiopsies and prostate imaging - reporting data system lesions ≥3 were pooled prospectively and underwent TB and a modified SB including 2 ventral (anterior) biopsies. Detection rates were estimated for the modified SB, TB, and its combination. A subgroup analysis of 35 patients undergoing prostatectomy was performed by a head-to-head comparison of mpMRI index lesion and histologically confirmed PCa index lesion localization. RESULTS: The overall detection rate for PCa was 54.5%. The combination of TB and SB detected 14 (25.4%) more cases missed by TB alone (p < 0.001) and 7 (12.7%) more cases missed by SB alone (p = 0.016), respectively. A postoperative Gleason upgrade was seen in 12/35 (34.3%) cases within the TB group and in 14/35 (40.0%) in the SB group, respectively. The subgroup analysis showed a predominant location of PCa index lesions anteriorly at the level of the midgland. The MRI detection rate of the anteriorly located index lesions was 70.4% (15/21 cases) with a clinically significant Gleason score (≥3 + 4 = 7a [International Society of Urological Pathology grade 2]) in 80.9%. Interestingly a modified SB template detected 90.5% (19/21) of the anteriorly located index lesions. CONCLUSION: Our data suggest that in patients with multiple prebiopsies PCa seems to be predominantly located anteriorly. We suggest the general integration of anterior biopsies despite TB in repeat biopsy patients.