Predictors of five-repetition sit-to-stand test performance in patients with lumbar degenerative disease

BACKGROUND The five-repetition sit-to-stand test (5R-STS) has recently been validated as an objective measure of functional impairment in patients with lumbar degenerative disease (LDD). Knowledge of factors influencing 5R-STS performance is useful to correct for confounders, create personalized adjusted test times, and potentially identify prognostic subgroups. We evaluate factors predicting the 5R-STS performance in patients with LDD. METHODS Patients with LDD requiring surgery were included. Each participant performed the 5R-STS and completed a questionnaire that included their age, gender, weight, height, body mass index (BMI), smoking status, education level, employment type, ability to work, analgesic drug usage, history of previous spinal surgery, and EQ5D depression and anxiety domain. Surgical indication and index level of the spinal pathology were also recorded. Predictors of 5R-STS were identified through multivariable linear regression. RESULTS The cohort consisted of 240 patients, 47.9% being female (mean age, 47.7 ± 13.6 years). In the final multivariable model incorporating confounders, height (regression coefficient (RC), 0.08; 95% confidence interval (CI), 0.003/0.16, p = 0.042) and being an active smoker (RC, 2.44; 95%CI, 0.56/4.32, p = 0.012) were significant predictors of worse 5R-STS performance. Full ability to work (RC, - 2.39; 95%CI, - 4.39/ - 0.39, p = 0.020) was associated with a better 5R-STS performance. Age, height, surgical indication, index level of pathology, history of previous spine surgery, history of pain, analgesic drug use, employment type, and severity of anxiety and depression symptoms demonstrated confounding effect on the 5R-STS time. CONCLUSIONS Greater height, being an active smoker, and inability to work are significant predictors of worse 5R-STS performance in patients with LDD. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03303300 and NCT03321357

Identifying clusters of objective functional impairment in patients with degenerative lumbar spinal disease using unsupervised learning

OBJECTIVES The five-repetition sit-to-stand (5R-STS) test was designed to capture objective functional impairment (OFI), and thus provides an adjunctive dimension in patient assessment. It is conceivable that there are different subsets of patients with OFI and degenerative lumbar disease. We aim to identify clusters of objectively functionally impaired individuals based on 5R-STS and unsupervised machine learning (ML). METHODS Data from two prospective cohort studies on patients with surgery for degenerative lumbar disease and 5R-STS times of ≥ 10.5 s-indicating presence of OFI. K-means clustering-an unsupervised ML algorithm-was applied to identify clusters of OFI. Cluster hallmarks were then identified using descriptive and inferential statistical analyses. RESULTS We included 173 patients (mean age [standard deviation]: 46.7 [12.7] years, 45% male) and identified three types of OFI. OFI Type 1 (57 pts., 32.9%), Type 2 (81 pts., 46.8%), and Type 3 (35 pts., 20.2%) exhibited mean 5R-STS test times of 14.0 (3.2), 14.5 (3.3), and 27.1 (4.4) seconds, respectively. The grades of OFI according to the validated baseline severity stratification of the 5R-STS increased significantly with each OFI type, as did extreme anxiety and depression symptoms, issues with mobility and daily activities. Types 1 and 2 are characterized by mild to moderate OFI-with female gender, lower body mass index, and less smokers as Type I hallmarks. CONCLUSIONS Unsupervised learning techniques identified three distinct clusters of patients with OFI that may represent a more holistic clinical classification of patients with OFI than test-time stratifications alone, by accounting for individual patient characteristics

Functional Multiplex Reporter Assay Using Tagged Gaussia Luciferase

We have developed a multiplex reporter system to monitor multiple biological variables in real-time. The secreted Gaussia luciferase was fused to ten different epitope tags (Gluc$_{tag}$), each expressed in different tumor cells. By immunobinding of the tags followed by Gluc$_{tag}$ detection, this system allowed the independent and real-time monitoring of mixed cell cultures in vitro and of mixed subcutaneous and intracranial tumor subpopulations in vivo

Aneurysm treatment within 6 h versus 6-24 h after rupture in patients with subarachnoid hemorrhage

BACKGROUND The risk of rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) is the highest during the initial hours after rupture. Emergency aneurysm treatment may decrease this risk, but is a logistic challenge and economic burden. We aimed to investigate whether aneurysm treatment <6 h after rupture is associated with a decreased risk of poor functional outcome compared to aneurysm treatment 6-24 h after rupture. METHODS We used data of patients included in the ULTRA trial (NCT02684812). All patients in ULTRA were admitted within 24 h after aneurysm rupture. For the current study, we excluded patients in whom the aneurysm was not treated <24 h after rupture. We calculated crude and adjusted risk ratios (aRR) with 95% confidence intervals using Poisson regression analyses for poor functional outcome (death or dependency, assessed by the modified Rankin Scale) after aneurysm treatment <6 h versus 6-24 h after rupture. Adjustments were made for age, sex, clinical condition on admission (WFNS scale), amount of extravasated blood (Fisher score), aneurysm location, tranexamic acid treatment, and aneurysm treatment modality. RESULTS We included 497 patients. Poor outcome occurred in 63/110 (57%) patients treated within 6 h compared to 145/387 (37%) patients treated 6-24 h after rupture (crude RR: 1.53, 95% CI: 1.24-1.88; adjusted RR: 1.36, 95% CI: 1.11-1.66). CONCLUSION Aneurysm treatment <6 h is not associated with better functional outcome than aneurysm treatment 6-24 h after rupture. Our results do not support a strategy aiming to treat every patient with a ruptured aneurysm <6 h after rupture

PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation

Poly ADP-ribose polymerase (PARP) is a protein involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy and in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways. In addition, PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy. Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor Olaparib in childhood medulloblastoma, ependymoma and high grade glioma (HGG). Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Pediatric high grade glioma, medulloblastoma and ependymoma gene expression profiling revealed that high PARP1 expression is associated with poor prognosis. Cell growth inhibition assays with Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.4 to 8.4 μM, irrespective of tumor type and PARP1 protein expression. Sensitization to radiation was observed in medulloblastoma, ependymoma and HGG cell lines with subcytotoxic concentrations of Olaparib, which coincided with persistence of double strand breaks. Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome

Cognitive functioning in glioblastoma patients during radiotherapy and temozolomide treatment: initial findings

The aim of this study was to evaluate cognitive functioning in newly-diagnosed glioblastoma multiforme (GBM) patients during treatment with radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ). Cognitive assessment took place following surgery, but prior to the start of RT (baseline), after 6 weeks of RT and concomitant TMZ (1st follow-up), and after three cycles of adjuvant TMZ (2nd follow-up). Standardized cognitive summary measures and delta scores for six cognitive domains were calculated at the individual level. Cognitive functioning of progression-free GBM patients was compared to that of matched healthy controls. Analyses were performed on a group of 13 GBM patients that were progression-free during follow-up. The results showed that the majority of patients had deficits in multiple cognitive domains at baseline. Between baseline and 1st follow-up, four patients improved in one cognitive domain, four patients deteriorated in one domain, one patient improved in one domain and deteriorated in another, and four patients remained stable in all six domains. Between 1st and 2nd follow-up, the majority of patients (11) remained stable in all six cognitive domains, whereas one patient declined in one domain, and one patient showed a deterioration in two domains. Overall, between baseline and 2nd follow-up, three patients improved in one cognitive domain, two patients deteriorated in two domains, one patient improved in one domain and deteriorated in another, and seven patients remained stable in all six cognitive domains. In conclusion, preceding treatment, the majority of GBM patients show clear-cut deficits in cognitive functioning. In the course of the first 6 months of their disease, however, progression-free GBM patients undergoing radiotherapy plus concomitant and adjuvant temozolomide treatment do not deteriorate in cognitive functioning

Absence of AKT1 Mutations in Glioblastoma

Background: Oncogenic activation of the PI3K signalling pathway plays a pivotal role in the development of glioblastoma multiforme (GBM). A central node in PI3K downstream signalling is controlled by the serine-threonine kinase AKT1. A somatic mutation affecting residue E17 of the AKT1 gene has recently been identified in breast and colon cancer. The E17K change results in constitutive AKT1 activation, induces leukaemia in mice, and accordingly, may be therapeutically exploited to target the PI3K pathway. Assessing whether AKT1 is activated by somatic mutations in GBM is relevant to establish its role in this aggressive disease. Methodology/Principal Findings: We performed a systematic mutational analysis of the complete coding sequence of the AKT1 gene in a panel of 109 tumor GBM samples and nine high grade astrocytoma cell lines. However, no somatic mutations were detected in the coding region of AKT1. Conclusions/Significance: Our data indicate that in GBM oncogenic deregulation of the PI3K pathway does not involve somatic mutations in the coding region of AKT1

Topographical Organization of Mu and Beta Band Activity Associated with Hand and Foot Movements in Patients with Perirolandic Lesions

To study the topographical organization of mu and beta band event-related desynchronization (ERD) associated with voluntary hand and foot movements, we used magnetoencephalographic (MEG) recordings from 19 patients with perirolandic lesions. Synthetic aperture magnetometry (SAM) was used to detect and localize changes in the mu (7 - 11 Hz) and beta (13 - 30 Hz) frequency bands associated with repetitive movements of the hand and foot and overlaid on individual coregistered magnetic resonance (MR) images. Hand movements showed homotopic and contralateral ERD at the sensorimotor (S/M) cortex in the majority of cases for mu and to a lesser extent for beta rhythms. Foot movements showed an increased heterotopic distribution with bilateral and ipsilateral ERD compared to hand movements. No systematic topographical segregation between mu and beta ERD could be observed. In patients with perirolandic lesions, the mu and beta band spatial characteristics associated with hand movements retain the expected functional-anatomical boundaries to a large extent. Foot movements have altered patterns of mu and beta band ERD, which may give more insight into the differential functional role of oscillatory activity in different voluntary movements

Increased cerebral (R)-[11C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study

<p>Abstract</p> <p>Background</p> <p>The aim of the present study was to investigate microglia activation over time following traumatic brain injury (TBI) and to relate these findings to glutamate release.</p> <p>Procedures</p> <p>Sequential dynamic <it>(R)</it>-[¹¹C]PK11195 PET scans were performed in rats 24 hours before (baseline), and one and ten days after TBI using controlled cortical impact, or a sham procedure. Extracellular fluid (ECF) glutamate concentrations were measured using cerebral microdialysis. Brains were processed for histopathology and (immuno)-histochemistry.</p> <p>Results</p> <p>Ten days after TBI, <it>(R)</it>-[¹¹C]PK11195 binding was significantly increased in TBI rats compared with both baseline values and sham controls (p < 0.05). ECF glutamate values were increased immediately after TBI (27.6 ± 14.0 μmol·L^-1) as compared with the sham procedure (6.4 ± 3.6 μmol·L^-1). Significant differences were found between TBI and sham for ED-1, OX-6, GFAP, Perl's, and Fluoro-Jade B.</p> <p>Conclusions</p> <p>Increased cerebral uptake of <it>(R)</it>-[¹¹C]PK11195 ten days after TBI points to prolonged and ongoing activation of microglia. This activation followed a significant acute posttraumatic increase in ECF glutamate levels.</p