Evaluation of a paediatric clinical ethics service

To evaluate a paediatric clinical ethics service incorporating both normative and empirical analysis.Section 1: Review of consensus guidelines to identify emerging standards for clinical ethics services (CES) and evaluation of the service in relation to these. Section 2: Description of service activity data. Section 3: Feedback from clinical staff involved in clinical ethics consultations was collected using a web-based survey.Four guideline documents were reviewed, and clear emerging consensus standards were identified. Our service fulfils identified knowledge and skill core competencies and at least partially fulfils all of the identified service-level standards. Clinicians report that clinical ethics consultation decreases their moral distress.There is emerging consensus for staff competencies and service-level standards for CES. The role of CES in staff well-being needs to be explored. Collaborative, multi-modal research to develop standards and evaluate CES is needed

The Movement Imagery Questionnaire-Revised, Second Edition (MIQ-RS) Is a Reliable and Valid Tool for Evaluating Motor Imagery in Stroke Populations

Mental imagery can improve motor performance in stroke populations when combined with physical therapy. Valid and reliable instruments to evaluate the imagery ability of stroke survivors are needed to maximize the benefits of mental imagery therapy. The purposes of this study were to: examine and compare the test-retest intra-rate reliability of the Movement Imagery Questionnaire-Revised, Second Edition (MIQ-RS) in stroke survivors and able-bodied controls, examine internal consistency of the visual and kinesthetic items of the MIQ-RS, determine if the MIQ-RS includes both the visual and kinesthetic dimensions of mental imagery, correlate impairment and motor imagery scores, and investigate the criterion validity of the MIQ-RS in stroke survivors by comparing the results to the KVIQ-10. Test-retest analysis indicated good levels of reliability (ICC range: .83–.99) and internal consistency (Cronbach α: .95–.98) of the visual and kinesthetic subscales in both groups. The two-factor structure of the MIQ-RS was supported by factor analysis, with the visual and kinesthetic components accounting for 88.6% and 83.4% of the total variance in the able-bodied and stroke groups, respectively. The MIQ-RS is a valid and reliable instrument in the stroke population examined and able-bodied populations and therefore useful as an outcome measure for motor imagery ability

Peripheral blood cytopenias in the aging general population and risk of incident hematological disease and mortality

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Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals

Anemia is a major and currently poorly understood clinical manifestation of hematopoietic aging. Upon aging, hematopoietic clones harboring acquired leukemia-associated mutations expand and become detectable, now referred to as clonal hematopoiesis (CH). To investigate the relationship between CH and anemia of the elderly, we explored the landscape and dynamics of CH in older individuals with anemia. From the prospective, population-based Lifelines cohort (n = 167 729), we selected all individuals at least 60 years old who have anemia according to World Health Organization criteria (n = 676) and 1:1 matched control participants. Peripheral blood of 1298 individuals was analyzed for acquired mutations at a variant allele frequency (VAF) of 1% or higher in 27 driver genes. To track clonal evolution over time, we included all available follow-up samples (n = 943). CH was more frequently detected in individuals with anemia (46.6%) compared with control individuals (39.1%; P = .007). Although no differences were observed regarding commonly detected DTA mutations (DNMT3A, TET2, ASXL1) in individuals with anemia compared with control individuals, other mutations were enriched in the anemia cohort, including TP53 and SF3B1. Unlike individuals with nutrient deficiency (P = .84), individuals with anemia of chronic inflammation and unexplained anemia revealed a higher prevalence of CH (P = .035 and P = .017, respectively) compared with their matched control individuals. Follow-up analyses revealed that clones may expand and decline, generally showing only a subtle increase in VAF (mean, 0.56%) over the course of 44 months, irrespective of the presence of anemia. Specific mutations were associated with different growth rates and propensities to acquire an additional hit. In contrast to smaller clones (<5% VAF), which did not affect overall survival, larger clones were associated with increased risk for death

Microparticles and crystal microstructure in polar ice sheets

The pollution input in polar ice sheets in Greenland and Antarctica is of atmospheric aeolian origin, just as all natural non-ice impurities as well. They thus provide potential information on the evolution of the atmospheric share of pollutants in the ocean. Aerosols found in ice are transported with atmospheric circulation and wind patterns and are deposited e.g. with precipitating snow. The impurity content in this so-called meteoric ice is relatively low compared to many other natural materials such as rocks (ppb to ppm range). The reason is that most aerosols in the atmosphere have been removed by fall-out or precipitation during transport from the impurities’ sources to the remote ice sheet. Non-ice constituents in polar ice cores have been studied in the last decades mainly for reconstructions of past atmospheric aerosol concentrations, with respect to questions conceding the global climate change. The fastest and easiest analytical way is chemical analysis of the melted water from ice cores. However despite the tiny concentrations, the interactions with and effects of impurities in the solid ice influence the physical properties of the material as a whole: e.g. electric as well as dielectric response and, in particular, mechanical behaviour thus “softness” of the material seems to be strongly controlled by impurities. Smaller concentrations of impurities (up to a few ‰) do soften the material as a whole, while larger concentrations of particles harden it, depending on the type of impurities of course. The underlying processes are partly hypothesised for decades, but not yet proven or understood satisfactorily as the quest for ppb to ppm concentrations in solid matrix material is a search for a “needle in a haystack”. To improve the data basis regarding the in-situ form of incorporation and spatial distribution of impurities in ice we used micro-cryo-Raman spectroscopy to identify the location, phase and composition of micrometer-sized inclusions in natural ice samples (NEEM ice core from Greenland and EPICA-DML ice core from Antarctica). The combination of Raman results with ice-microsctructure measurements and complementary impurity data provided by the standard analytical methods (IC, CFA, and DEP) allows for a more interdisciplinary approach interconnecting ice core chemistry and ice core physics. While the samples originating from interglacial times were dominated by sulfate salts—mainly gypsum, sodium sulfate (possibly thenardite) and iron–potassium sulfate (likely jarosite)—the glacial ice contained high numbers of mineral dust particles—in particular quartz, mica, feldspar, anatase, hematite and carbonaceous particles (black carbon). We cannot confirm cumulation of impurities in the grain boundary network as reported by other studies, neither micro-particles being dragged by migrating grain boundaries nor in form of liquid veins in triple junctions. We argue that mixing of impurities on the millimeter scale and chemical reactions are facilitated by the deforming ice matrix. Refs.: doi: 10.5194/tc-11-1075-2017 doi: 10.3389/feart.2019.00020 https://www.humboldt-foundation.de/web/trilateral-jagfos-2019.html http://www.nasonline.org/programs/kavli-frontiers-of-science/past-symposia/2019-jagfos.html Invited poster

Deprescribing opioids in chronic non-cancer pain : systematic review of randomised trials

Background Deprescribing, the process of reducing or discontinuing unnecessary or harmful medicines is an essential part of clinical practice. Objective To evaluate the efficacy of interventions designed to deprescribe opioid analgesics for pain relief in patients with chronic non-cancer pain. Methods We searched electronic databases, including clinical trial registries, from database inception to 13th January 2020 without restrictions, and conducted citation tracking. Our systematic review included randomised controlled trials (RCTs) evaluating interventions reducing the prescription, or use of opioid analgesics in patients with chronic pain versus control. Inventions could be aimed at the patient, clinician, or both. We excluded trials enrolling patients with cancer or illicit drug use. Two authors independently screened and extracted data. Outcome follow-up timepoints were short (≤ 3 months), intermediate (> 3 but < 12 months) or long (≥ 12 months) term. Primary outcome was the reduction in opioid dose [morphine milligram equivalent (MME) mg/day]. Methodological quality was assessed using the Cochrane Risk of Bias Tool. Results We included ten patient-focused RCT interventions (n = 835; median 37 participants) and 2 testing clinician-focused interventions (n = 291 clinicians); none at low risk of bias. Patient-focused interventions did not reduce opioid dose in the intermediate term [e.g. dose reduction protocol, mean difference (MD) − 19.9 MME, 95% CI − 107.5 to 67.7], nor did they increase the number of participants who ceased their dose, or increase the risk of serious adverse events or adverse events. One clinician intervention of education plus decision tools versus decision tools alone reduced the number of opioid prescriptions (risk difference (RD) − 0.1, 95% CI − 0.2 to − 0.1), dose (MD − 5.3 MME, 95% CI − 6.2 to − 4.5) and use (RD − 0.1, 95% CI − 0.1 to − 0.0) in the long term

A prognostic CpG score derived from epigenome-wide profiling of tumor tissue was independently associated with colorectal cancer survival

Background: Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and mostly based on different CIMP definitions. The current study aimed to comprehensively investigate the associations between DNA methylation on genes previously used to define CIMP status with CRC survival. Results: Patients with CRC followed up for a median of 5.2 years were divided into a study cohort (n = 568) and a validation cohort (n = 308). DNA methylation was measured in tumor tissue using the Illumina Infinium HumanMethylation450 BeadChip and restricted to 43 genes used to define CIMP status in previous studies. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of survival after CRC, including adjustment for tumor stage, microsatellite instability, and BRAF mutation status. In the study cohort, ten CpG sites were identified to be associated with CRC survival. Seven of these ten CpG sites were also associated with CRC survival in the validation cohort and were used to construct a prognostic score. CRC patients with a prognostic score of the lowest methylation level showed poorer disease-specific survival compared with patients with the highest methylation level in both the study cohort and the validation cohort (HR = 3.11 and 95% CI = 1.97–4.91, and HR = 3.06 and 95% CI = 1.71–5.45, respectively). Conclusions: A CpG panel consisting of seven CpG sites was found to be strongly associated with CRC survival, independent from important clinical factors and mutations associated with CIMP. Further studies are required to confirm these findings

Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness

A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission

Impurity Analysis and Microstructure Along the Climatic Transition From MIS 6 Into 5e in the EDML Ice Core Using Cryo-Raman Microscopy

Impurities in polar ice cores have been studied so far mainly for the purpose of reconstructions of past atmospheric aerosol concentrations. However, impurities also critically influence physical properties of the ice matrix itself. To improve the data basis regarding the in-situ form of incorporation and spatial distribution of impurities in ice we used micro-cryo-Raman spectroscopy to identify the location, phase and composition of micrometer-sized inclusions in natural ice samples around the transition from marine isotope stage (MIS) 6 into 5e in the EDML ice core. The combination of Raman results with ice-microsctructure measurements and complementary impurity data provided by the standard analytical methods (IC, CFA, and DEP) allows for a more interdisciplinary approach interconnecting ice core chemistry and ice core physics. While the interglacial samples were dominated by sulfate salts—mainly gypsum, sodium sulfate (possibly thenardite) and iron–potassium sulfate (likely jarosite)—the glacial ice contained high numbers of mineral dust particles—in particular quartz, mica, feldspar, anatase, hematite and carbonaceous particles (black carbon). We cannot confirm cumulation of impurities in the grain boundary network as reported by other studies, neither micro-particles being dragged by migrating grain boundaries nor in form of liquid veins in triple junctions. We argue that mixing of impurities on millimeter scale and chemical reactions are facilitated by the deforming ice matrix. We review possible effects of impurities on physical properties of ice, however the ultimate identification of the deformation agent and the mechanism behind remains challenging

Comprehensive preclinical evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9ORF72 disease

Hexanucleotide G4C2 repeat expansions in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intracellular poly-GA and reduced aggregate formation in a poly-GA over-expressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 months was well-tolerated and led to measurable brain penetration of antibodies. Long term treatment with anti-GA antibodies produced improvement in an open field movement test in aged C9ORF72450 mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model. Significance Immunotherapy has been proposed for neurodegenerative disorders including Alzheimer’s or Parkinson’s diseases. Recent reports using antibodies against poly-GA or active immunization suggested similar immunotherapy in ALS/FTD caused by repeat expansion in the C9ORF72 gene (1, 2). Here, we systematically characterized human antibodies against multiple DPR species and tested the biological effects of antibodies targeting poly-GA in different cellular and mouse models. Target engagement was shown in three independent cellular models. Anti-GA antibodies reduced the number of intracellular poly-GA aggregates in human T98G cells but not in cultured human neurons. Whereas chronic anti-GA treatment in BAC C9ORF72450 mice did not impact poly-GA levels and modestly improved one behavioral phenotype, poly-GA levels detected by immunoassays were increased and disease progression was unaltered in AAV-(G4C2)149 mice