Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Increased hospital costs are associated with low skeletal muscle mass in patients undergoing elective open aortic surgery

Objective

Low psoas muscle area is shown to be an indicator for worse postoperative outcome in patients undergoing vascular surgical. Additionally, it has been associated with longer durations of hospital stay in patients with cancer who undergo surgery and subsequently greater health care costs in Europe and the United States. We sought to evaluate this effect on hospital expenditure for patients undergoing vascular repair in a health care system with universal access.

Temporal integration as “common currency” of brain and self‐scale‐free activity in resting‐state EEG correlates with temporal delay effects on self‐relatedness

The self is a multifaceted phenomenon that integrates information and experience across multiple time scales. How temporal integration on the psychological level of the self is related to temporal integration on the neuronal level remains unclear. To investigate temporal integration on the psychological level, we modified a well‐established self‐matching paradigm by inserting temporal delays. On the neuronal level, we indexed temporal integration in resting‐state EEG by two related measures of scale‐free dynamics, the power law exponent and autocorrelation window. We hypothesized that the previously established self‐prioritization effect, measured as decreased response times or increased accuracy for self‐related stimuli, would change with the insertion of different temporal delays between the paired stimuli, and that these changes would be related to temporal integration on the neuronal level. We found a significant self‐prioritization effect on accuracy in all conditions with delays, indicating stronger temporal integration of self‐related stimuli. Further, we observed a relationship between temporal integration on psychological and neuronal levels: higher degrees of neuronal integration, that is, higher power‐law exponent and longer autocorrelation window, during resting‐state EEG were related to a stronger increase in the self‐prioritization effect across longer temporal delays. We conclude that temporal integration on the neuronal level serves as a template for temporal integration of the self on the psychological level. Temporal integration can thus be conceived as the “common currency” of neuronal and psychological levels of self.     

Tibial lengthening using a retrograde magnetically driven intramedullary lengthening device in 10 patients with preexisting ankle and hindfoot fusion

Background and purpose — Motorized intramedullary lengthening nails (ILNs) have been developed as an alternative to external fixators for long bone lengthening. The antegrade approach represents the standard method for tibial ILN insertion. In patients with preexisting ankle and hindfoot fusion a retrograde approach provides an alternative technique that has not been evaluated so far. We report the outcome of this method in 10 patients.Patients and methods — This retrospective study included 10 patients (mean age 18 years [13–25]) with preexisting ankle and hindfoot fusion who underwent tibial lengthening with a retrograde ILN (PRECICE). The mean leg length discrepancy (LLD) was 58 mm (36–80). The underlying conditions were congenital (n = 9) and post tumor resection (n = 1). The main outcome measures were: ILN reliability, distraction achieved, distraction index (DIX), time to bone healing, consolidation index (CIX), complications, and functional results.Results — All patients achieved the goal of lengthening (mean 48 mm [26–80]). Average DIX was 0.6 mm/day (0.5–0.7) and mean CIX was 44 days/cm (26–60). Delayed consolidation occurred in 2 patients and healed after ILN dynamization or nail exchange with grafting. Toe contractures in 2 other patients were resolved with physiotherapy or tenotomy. Until last follow-up (mean 18 months [12–30]) no true complications were encountered, knee motion remained unaffected, and full osseous consolidation occurred in all patients.Interpretation — In patients with LLD and preexisting ankle and hindfoot fusion distal tibial lengthening using a retrograde ILN is a reliable alternative to the standard approach with equivalent bone healing potential and low complication rates leaving the knee unaffected.

Fully implantable intramedullary lengthening nails (ILNs) with mechanical (Guichet and Casar 1997, Cole et al. 2001) and motorized (Baumgart et al. 1997, Schiedel et al. 2014) drive systems have been developed as an alternative to external fixators for bone lengthening (Mahboubian et al. 2012, Black et al. 2015, Laubscher et al. 2016). Recently, magnetically driven ILNs in particular have become increasingly popular (Kirane et al. 2014, Wagner et al. 2017) and in contrast to external fixation provide an equally safe and more comfortable option for limb lengthening and deformity correction (Szymczuk et al. 2019, Horn et al. 2019). Antegrade or retrograde femoral and antegrade tibial lengthening with the PRECICE limb lengthening system (NuVasive, San Diego, CA, USA) has been assessed by several studies (Kirane et al. 2014, Schiedel et al. 2014, Shabtai et al. 2014, Tiefenboeck et al. 2016, Wiebking et al. 2016, Fragomen and Rozbruch 2017, Wagner et al. 2017, Iobst et al. 2018, Cosic and Edwards 2020, Nasto et al. 2020).In tibial lengthening the antegrade approach represents the standard method for ILN implantation (Fragomen and Rozbruch 2017). In patients with preexisting ankle and hindfoot fusion a retrograde approach provides an alternative technique for tibial nail insertion. Approach-associated affections of the knee joint like anterior knee pain (Rothberg et al. 2019) and—in immature patients—damage to the proximal tibial growth plate (Wagner et al. 2017, Frommer et al. 2018) can be avoided. Despite these potential advantages, the use of a retrograde tibial nailing approach and distal tibial osteotomy in patients with preexisting ankle and hindfoot fusion has not been evaluated so far.     

Bone Mass,Bone Microstructure and Biomechanics in Patients with Hand Osteoarthritis

The impact of primary hand osteoarthritis (HOA) on bone mass, microstructure, and biomechanics in the affected skeletal regions is largely unknown. HOA patients and healthy controls (HCs) underwent high-resolution peripheral quantitative computed tomography (HR-pQCT). We measured total, trabecular, and cortical volumetric bone mineral densities (vBMDs), microstructural attributes, and performed micro–finite element analysis for bone strength. Failure load and scaled multivariate outcome matrices from distal radius and second metacarpal (MCP2) head measurements were analyzed using multiple linear regression adjusting for age, sex, and functional status and reported as adjusted Z-score differences for total and direct effects. A total of 105 subjects were included (76 HC: 46 women, 30 men; 29 HOA: 23 women, six men). After adjustment, HOA was associated with significant changes in the multivariate outcome matrix from the MCP2 head (p < .001) (explained by an increase in cortical vBMD (Δz = 1.07, p = .02) and reduction in the trabecular vBMD (Δz = −0.07, p = .09). Distal radius analysis did not show an overall effect of HOA; however, there was a gender-study group interaction (p = .044) explained by reduced trabecular vBMD in males (Δz = −1.23, p = .02). HOA was associated with lower failure load (−514 N; 95%CI, −1018 to −9; p = 0.05) apparent in males after adjustment for functional status. HOA is associated with reduced trabecular and increased cortical vBMD in the MCP2 head and a reduction in radial trabecular vBMD and bone strength in males. Further investigations of gender-specific changes of bone architecture in HOA are warranted. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Loss of mitochondrial ClpP,Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease

neurogenetics - Human RNF213, which encodes the protein mysterin, is a known susceptibility gene for moyamoya disease (MMD), a cerebrovascular condition with occlusive lesions and compensatory...