Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II—Report from the German/Swiss SIOP-LGG 2004 cohort

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.     

A multitaxa assessment of the effectiveness of agri-environmental schemes for biodiversity management

Agri-environmental schemes (AES) aim to restore biodiversity and biodiversity-mediated ecosystem services in landscapes impoverished by modern agriculture. However, a systematic, empirical evaluation of different AES types across multiple taxa and functional groups is missing. Within one orthogonal design, we studied sown flowering AES types with different temporal continuity, size, and landscape context and used calcareous grasslands as seminatural reference habitat. We measured species richness of 12 taxonomic groups (vascular plants, cicadas, orthopterans, bees, butterflies, moths, hoverflies, flower visiting beetles, parasitoid wasps, carabid beetles, staphylinid beetles, and birds) representing 5 trophic levels. A total of 54,955 specimens were identified using traditional taxonomic methods, and bulk arthropod samples were identified through DNA metabarcoding, resulting in a total of 1,077 and 2,110 taxa, respectively. Species richness of most taxonomic groups, as well as multidiversity and richness of pollinators, increased with temporal continuity of AES types. Some groups responded to size and landscape context, but multidiversity and richness of pollinators and natural enemies were not affected. AES flowering fields supported different species assemblages than calcareous grasslands, but assemblages became more similar to those in seminatural grasslands with increasing temporal continuity. Our results indicate that AES flowering fields and seminatural grasslands function synergistically. Flowering fields support biodiversity even when they are relatively small and in landscapes with few remaining seminatural habitats. We therefore recommend a network of smaller, temporally continuous AES flowering fields of different ages, combined with permanent seminatural grasslands, to maximize benefits for biodiversity conservation and ecosystem service delivery in agricultural landscapes.

Human societies are facing a worldwide loss of biodiversity with alarming declines of insect diversity in temperate agricultural landscapes (1, 2). This loss of biodiversity is jeopardizing agricultural production as important ecosystem services ensuring crop yields are directly driven by biodiversity (3). Biodiversity, however, requires suitable habitats for species to persist, forage, nest, reproduce, and hibernate (4, 5). This challenge has been recognized and agri-environmental schemes (AES) have been introduced in the European Union and other regions to reverse biodiversity declines, to restore functional diversity, and to harness the benefits of ecosystem services, like pollination and pest control, in agricultural landscapes (6–8).An important component of AES to fulfill these goals is the establishing of habitats that provide limiting resources, such as food and shelter for a broad range of organisms. Typically, farmers are financially compensated on a per area basis, but the effectiveness of schemes is often unclear. Thus, compensations might not direct farmers’ decisions among different AES to the ecologically most meaningful ones (7). A variety of different habitats are created as AES, ranging from hedgerows to sown flower strips or flowering fields, with the latter being widely used due to their flexible applicability and public appreciation (4). Recent assessments, however, found that overall, European AES are not fulfilling their goals (6, 9). Particularly, the value of AES for securing biodiversity is under debate (10, 11). Beneficial effects previously reported focused on single taxonomic or trophic levels or ecosystem services and varied among study designs, taxa, or services assessed (12–14). Conclusive multitaxa approaches assessing potential services and disservices in one design are missing (8). Furthermore, it is unclear how different properties of AES habitats (e.g., their temporal continuity or size) and varying landscape context affect biodiversity across multiple taxonomic groups.Temporal continuity is an important factor affecting biodiversity. Higher temporal continuity increases heterogeneity within a habitat and creates niches for more species (15, 16). Temporal continuity also enables weak dispersers and higher tropic levels to colonize a habitat, with the latter being dependent on established populations of lower trophic levels (15). In AES habitats, the influence and the effects of temporal continuity have so far been neglected. Newly established flowering fields were found to be more attractive to pollinators than older flowering fields, but pollination services in adjacent fields peak 2 y after initial sowing (14, 17). Older AES habitats could potentially also benefit rare and endangered species with specific habitat requirements, if species assemblages in AES habitats change toward those in permanent species-rich seminatural grasslands with time or increased temporal continuity (18).Apart from temporal continuity, size might be an important predictor for the conservation value of AES habitats. Increasing habitat size leads to an increased species richness as it is accompanied with the establishment of larger, more stable populations and allows higher trophic levels to persist (19–21). It is unclear whether biodiversity in a landscape benefits more from few large habitats or a network of many small habitats (22, 23). Relationships between size and species richness might therefore be essential for the planning and strategic placement of AES habitats.Source habitats for biodiversity are needed in agricultural landscapes to build up local populations in newly established AES habitats from regional species pools (24). Seminatural habitats embedded in agricultural landscapes have been shown to support farmland diversity (25, 26), and thus AES habitats in complex landscapes with high proportions of seminatural habitats potentially host the highest diversity.Here, we investigate the effects of AES differing in temporal continuity, size, and surrounding landscape context over several years on multiple taxonomic groups within one study design. Different types of flowering fields are commonly established by farmers as part of AES to provide additional flower resources. These fields are sown with seed mixtures adapted to local soil properties and taken from regional species pools. After a certain timespan, often varying from 1 to 10 y, flowering fields are returned to crop production. The studied flowering fields differed in temporal continuity from: 1) Newly sown on arable land, over 2) refreshed (i.e., flower fields resown after 5 y) to 3) continuous, 6-y-old flowering fields. Species-rich calcareous grasslands were used as permanent control (Fig. 1 and Table 1). Calcareous grasslands are seminatural biodiversity hotspots in Europe and are preserved by low intensive mowing or grazing (27). We investigated species richness in these 4 AES types across 12 taxonomic groups belonging to 5 trophic levels, including pollinators (bees, butterflies, moths, flower visiting beetles, and hoverflies) and natural enemies (parasitoid wasps, carabid beetles, staphylinid beetles, and birds) as providers of important ecosystem services (3). Species were identified by classic taxonomic techniques (vascular plants, orthopterans, bees, butterflies, moths, flower visiting beetles, carabid beetles, staphylinid beetles, and birds) and DNA metabarcoding (cicadas, hoverflies, and parasitoid wasps). Repeated recordings of a subset of four taxonomic groups (plants, orthopterans, bees, and carabid beetles) within 2 y were performed to clarify whether short-term succession changed assemblages in newly established flowering fields toward those in seminatural calcareous grasslands. Apart from analyses for each taxonomic group, we performed a multidiversity analysis by calculating a diversity index across all taxa, pollinators, and natural enemies (28). Our study aims to judge which types of AES fulfill the goal of restoring biodiversity and ecosystem services in agricultural landscapes best, and should therefore be fostered. Such data are urgently needed to build the scientific basis for a successful transition of European Union and global policies to biodiversity-friendly and sustainable crop production.Open in a separate windowFig. 1.Study design on the landscape and site level. Biodiversity across 12 different taxonomic levels (from top to bottom: Vascular plants, orthopterans, cicadas, bees, butterflies, moths, flower visiting beetles, hoverflies, parasitoid wasps, carabid beetles, staphylinid beetles, birds) was recorded using a variety of classic methods (pan traps, pitfall traps, transect walks, light traps combined with taxonomic identification) as well as metabarcoding analyses (using samples collected with Malaise traps). The different types of flowering fields and calcareous grasslands were located along a gradient of temporal continuity (Table 1). All AES types covered independent gradients of seminatural habitat in the surrounding landscape and habitat size (purple, AES; yellow, arable land; light green, seminatural habitat; dark green, forest; gray, urban). Repeated recordings over 2 y were performed for vascular plants, orthopterans, bees, and carabid beetles to assess whether succession shifted assemblages in flowering fields toward those in seminatural calcareous grasslands.Table 1.Differences in temporal continuity

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.     

Ophthalmic and orbital considerations in the evaluation of skull base malignancies

Journal of Neuro-Oncology - The orbital contents, afferent and efferent visual pathways, and the cranial nerves involved in eye movement, corneal sensation and eyelid closure traverse the skull...     

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10^?3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = ?.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.     

Evaluation of <i>MGMT</i> Gene Methylation in Neuroendocrine Neoplasms

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O6 -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in welldifferentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.     

Inadequate antibiotic dosing in patients receiving sustained low efficiency dialysis

International Journal of Clinical Pharmacy - Background Patients requiring SLED are often critically ill and/or hemodynamically unstable, and often need antibiotic therapy for life-threatening...     

Longevity of occlusally-stressed restorations in posterior primary teeth

PURPOSE: To compile a survey of the longevity and reasons for failure of stainless steel crowns, amalgam, glass-ionomer, composite and compomer restorations in stress-bearing cavities of primary molars. METHODS: This work reviewed the dental literature of 1971 up to July 2003 for longitudinal, controlled clinical studies and retrospective cross-sectional studies. Only studies investigating the clinical performance of restorations in primary teeth with an observation period of at least 2 years were included. Annual failure rates of stainless steel crowns, amalgam, glass-ionomer, composite and compomer restorations were determined and failure reasons were discussed. RESULTS: Annual failure rates in stress-bearing cavities of primary molars were determined to be: 0-14% for stainless steel crowns, 0-35.3% for amalgam restorations, 0-25.8% for glass-ionomer restorations, 2-29.1% for atraumatic restorative treatments, 0-15% for composite restorations, and 0-11 for compomer restorations. Main reasons for failure were secondary caries, marginal deficiencies, fracture, and wear.