Musculoskeletal misdiagnoses in children with brain tumors:A nationwide, multicenter case-control study

ObjectiveChildhood brain tumors belong to the cancer type with the longest diagnostic delay, the highest health care utilization prior to diagnosis, and the highest burden of long-term sequelae. We aimed to clarify whether prior musculoskeletal diagnoses in childhood brain cancer were misdiagnoses and whether it affected the diagnostic delay.Study designIn this retrospective, chart-reviewed case-control study we compared 28 children with brain tumors and a prior musculoskeletal diagnosis to a sex and age-matched control group of 56 children with brain tumors and no prior musculoskeletal diagnosis. Using the Danish registries, the cases were identified from consecutive cases of childhood brain cancers in Denmark over 23 years (1996-2018).ResultsOf 931 children with brain tumors, 3% (28/931) had a prior musculoskeletal diagnosis, of which 39% (11/28) were misdiagnoses. The misdiagnoses primarily included torticollis-related diagnoses which tended to a longer time interval from first hospital contact until a specialist was involved: 35 days (IQR 6-166 days) compared to 3 days (IQR 1-48 days), p = 0.07. When comparing the 28 children with a prior musculoskeletal diagnosis with a matched control group without a prior musculoskeletal diagnosis, we found no difference in the non-musculoskeletal clinical presentation, the diagnostic time interval, or survival. Infratentorial tumor location was associated with a seven-fold risk of musculoskeletal misdiagnosis compared to supratentorial tumor location.ConclusionMusculoskeletal misdiagnoses were rare in children with brain tumors and had no significant association to the diagnostic time interval or survival. The misdiagnoses consisted primarily of torticollis- or otherwise neck-related diagnoses

Development of chemical tools to monitor human Kallikrein 13 (KLK13) activity

Kallikrein 13 (KLK13) was first identified as an enzyme that is downregulated in a subset of breast tumors. This serine protease has since been implicated in a number of pathological processes including ovarian, lung and gastric cancers. Here we report the design, synthesis and deconvolution of libraries of internally quenched fluorogenic peptide substrates to determine the specificity of substrate binding subsites of KLK13 in prime and non-prime regions (according to the Schechter and Berger convention). The substrate with the consensus sequential motive ABZ-Val-Arg-Phe-Arg-ANB-NH2 demonstrated selectivity towards KLK13 and was successfully converted into an activity-based probe by the incorporation of a chloromethylketone warhead and biotin bait. The compounds described may serve as suitable tools to detect KLK13 activity in diverse biological samples, as exemplified by overexpression experiments and targeted labeling of KLK13 in cell lysates and saliva. In addition, we describe the development of selective activity-based probes targeting KLK13, to our knowledge the first tool to analyze the presence of the active enzyme in biological samples

Cosmopolitan Species As Models for Ecophysiological Responses to Global Change: The Common Reed \u3cem\u3ePhragmites australis\u3c/em\u3e

Phragmites australis is a cosmopolitan grass and often the dominant species in the ecosystems it inhabits. Due to high intraspecific diversity and phenotypic plasticity, P. australis has an extensive ecological amplitude and a great capacity to acclimate to adverse environmental conditions; it can therefore offer valuable insights into plant responses to global change. Here we review the ecology and ecophysiology of prominent P. australis lineages and their responses to multiple forms of global change. Key findings of our review are that: (1) P. australis lineages are well-adapted to regions of their phylogeographic origin and therefore respond differently to changes in climatic conditions such as temperature or atmospheric CO2; (2) each lineage consists of populations that may occur in geographically different habitats and contain multiple genotypes; (3) the phenotypic plasticity of functional and fitness-related traits of a genotype determine the responses to global change factors; (4) genotypes with high plasticity to environmental drivers may acclimate or even vastly expand their ranges, genotypes of medium plasticity must acclimate or experience range-shifts, and those with low plasticity may face local extinction; (5) responses to ancillary types of global change, like shifting levels of soil salinity, flooding, and drought, are not consistent within lineages and depend on adaptation of individual genotypes. These patterns suggest that the diverse lineages of P. australis will undergo intense selective pressure in the face of global change such that the distributions and interactions of co-occurring lineages, as well as those of genotypes within-lineages, are very likely to be altered. We propose that the strong latitudinal clines within and between P. australis lineages can be a useful tool for predicting plant responses to climate change in general and present a conceptual framework for using P. australis lineages to predict plant responses to global change and its consequences

Cosmopolitan Species as Models for Ecophysiological Responses to Global Change: The Common Reed Phragmites australis

Phragmites australis is a cosmopolitan grass and often the dominant species in the ecosystems it inhabits. Due to high intraspecific diversity and phenotypic plasticity, P. australis has an extensive ecological amplitude and a great capacity to acclimate to adverse environmental conditions; it can therefore offer valuable insights into plant responses to global change. Here we review the ecology and ecophysiology of prominent P. australis lineages and their responses to multiple forms of global change. Key findings of our review are that: (1) P. australis lineages are well-adapted to regions of their phylogeographic origin and therefore respond differently to changes in climatic conditions such as temperature or atmospheric CO2; (2) each lineage consists of populations that may occur in geographically different habitats and contain multiple genotypes; (3) the phenotypic plasticity of functional and fitness-related traits of a genotype determine the responses to global change factors; (4) genotypes with high plasticity to environmental drivers may acclimate or even vastly expand their ranges, genotypes of medium plasticity must acclimate or experience range-shifts, and those with low plasticity may face local extinction; (5) responses to ancillary types of global change, like shifting levels of soil salinity, flooding, and drought, are not consistent within lineages and depend on adaptation of individual genotypes. These patterns suggest that the diverse lineages of P. australis will undergo intense selective pressure in the face of global change such that the distributions and interactions of co-occurring lineages, as well as those of genotypes within-lineages, are very likely to be altered. We propose that the strong latitudinal clines within and between P. australis lineages can be a useful tool for predicting plant responses to climate change in general and present a conceptual framework for using P. australis lineages to predict plant responses to global change and its consequences

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III)

Background: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. Methods: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. Results: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). Conclusion: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment

Loss of IGF1R in human astrocytes alters complex I activity and support for neurons

The insulin/insulin-like growth factor 1 (IGF1) signalling pathways are implicated in longevity and in progression of Alzheimer's disease. Previously, we showed that insulin-like growth factor 1 receptor (IGF1R) and downstream signalling transcripts are reduced in astrocytes in human brain with progression of Alzheimer's neuropathology and developed a model of IGF1 signalling impairment in human astrocytes using an IGF1R-specific monoclonal antibody, MAB391. Here, we have established a novel human astrocyte-neuron co-culture system to determine whether loss of astrocytic IGF1R affects their support for neurons. Astrocyte-neuron co-cultures were developed using human primary astrocytes and differentiated Lund Human Mesencephalic Cells (LUHMES). Neurite outgrowth assays, performed to measure astrocytic support for neurons, showed astrocytes provided contact-mediated support for neurite outgrowth. Loss of IGF1R did not affect neurite outgrowth under control conditions but when challenged with hydrogen peroxide IGF1R-impaired astrocytes were less able to protect LUHMES. To determine how loss of IGF1R affects neuronal support MAB391-treated astrocytes were FACS sorted from GFP-LUHMES and their transcriptomic profile was investigated using microarrays. Changes in transcripts involved in astrocyte energy metabolism were identified, particularly NDUFA2 and NDUFB6, which are related to complex I assembly. Loss of complex I activity in MAB391-treated astrocytes validated these findings. In conclusion, reduced IGF1 signalling in astrocytes impairs their support for neurons under conditions of stress and this is associated with defects in the mitochondrial respiratory chain in astrocytes