Absence of moment fragmentation in the mixed B-site pyrochlore Nd₂GaSbO₇

Nd-based pyrochlore oxides of the form Nd$_{2}B_{2}$O$_{7}$ have garnered a significant amount of interest owing to the moment fragmentation physics observed in Nd$_{2}$Zr$_{2}$O$_{7}$ and speculated in Nd$_{2}$Hf$_{2}$O$_{7}$. Notably this phenomenon is not ubiquitous in this family, as it is absent in Nd$_{2}$Sn$_{2}$O$_{7}$, which features a smaller ionic radius on the $B$-site. Here, we explore the necessary conditions for moment fragmentation in the Nd pyrochlore family through a detailed study of the mixed $B$-site pyrochlore Nd$_{2}$GaSbO$_{7}$. The $B$-site of this system is characterized by significant disorder and an extremely small average ionic radius. Similarly to Nd$_{2}$Sn$_{2}$O$_{7}$, we find no evidence for moment fragmentation through our bulk characterization and neutron scattering experiments, indicating that chemical pressure (and not necessarily the $B$-site disorder) plays a key role in the presence or absence of this phenomenon in this material family. Surprisingly, the presence of significant $B$-site disorder in Nd$_{2}$GaSbO$_{7}$ does not generate a spin glass ground state and instead the same all-in-all-out magnetic order identified in other Nd pyrochlores is found here.Comment: 11 pages, 8 figure

Percentage of Patients with Preventable Adverse Drug Reactions and Preventability of Adverse Drug Reactions – A Meta-Analysis

BACKGROUND: Numerous observational studies suggest that preventable adverse drug reactions are a significant burden in healthcare, but no meta-analysis using a standardised definition for adverse drug reactions exists. The aim of the study was to estimate the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions in adult outpatients and inpatients. METHODS: Studies were identified through searching Cochrane, CINAHL, EMBASE, IPA, Medline, PsycINFO and Web of Science in September 2010, and by hand searching the reference lists of identified papers. Original peer-reviewed research articles in English that defined adverse drug reactions according to WHO's or similar definition and assessed preventability were included. Disease or treatment specific studies were excluded. Meta-analysis on the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions was conducted. RESULTS: Data were analysed from 16 original studies on outpatients with 48797 emergency visits or hospital admissions and from 8 studies involving 24128 inpatients. No studies in primary care were identified. Among adult outpatients, 2.0% (95% confidence interval (CI): 1.2-3.2%) had preventable adverse drug reactions and 52% (95% CI: 42-62%) of adverse drug reactions were preventable. Among inpatients, 1.6% (95% CI: 0.1-51%) had preventable adverse drug reactions and 45% (95% CI: 33-58%) of adverse drug reactions were preventable. CONCLUSIONS: This meta-analysis corroborates that preventable adverse drug reactions are a significant burden to healthcare among adult outpatients. Among both outpatients and inpatients, approximately half of adverse drug reactions are preventable, demonstrating that further evidence on prevention strategies is required. The percentage of patients with preventable adverse drug reactions among inpatients and in primary care is largely unknown and should be investigated in future research

Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool

Aim To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings. Methods The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the ‘gold standard’ (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist). Main Outcome Measures Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories. Results Preliminary work—Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52–90%. Phase 3: Percentage exact agreement ranged from 35–70%. Overall, individuals had better agreement with the ‘gold standard’. Conclusion Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Adverse drug reactions causing admission to a paediatric hospital: A pilot study

What is known and Objective: It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. Methods: Prospective observational study over a 2-week period. Results and Discussion: There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. What is new and Conclusion: This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations(internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population

Oocyte Factors Suppress Mitochondrial Polynucleotide Phosphorylase to Remodel the Metabolome and Enhance Reprogramming

Oocyte factors not only drive somatic cell nuclear transfer reprogramming but also augment the efficiency and quality of induced pluripotent stem cell (iPSC) reprogramming. Here, we show that the oocyte-enriched factors Tcl1 and Tcl1b1 significantly enhance reprogramming efficiency. Clonal analysis of pluripotency biomarkers further show that the Tcl1 oocyte factors improve the quality of reprogramming. Mechanistically, we find that the enhancement effect of Tcl1b1 depends on Akt, one of its putative targets. In contrast, Tcl1 suppresses the mitochondrial polynucleotide phosphorylase (PnPase) to promote reprogramming. Knockdown of PnPase rescues the inhibitory effect from Tcl1 knockdown during reprogramming, whereas PnPase overexpression abrogates the enhancement from Tcl1 overexpression. We further demonstrate that Tcl1 suppresses PnPase’s mitochondrial localization to inhibit mitochondrial biogenesis and oxidation phosphorylation, thus remodeling the metabolome. Hence, we identified the Tcl1-PnPase pathway as a critical mitochondrial switch during reprogramming

Costs and benefits of cold acclimation in field-released Drosophila

One way animals can counter the effects of climatic extremes is via physiological acclimation, but acclimating to one extreme might decrease performance under different conditions. Here, we use field releases of Drosophila melanogaster on two continents across a range of temperatures to test for costs and benefits of developmental or adult cold acclimation. Both types of cold acclimation had enormous benefits at low temperatures in the field; in the coldest releases only cold-acclimated flies were able to find a resource. However, this advantage came at a huge cost; flies that had not been cold-acclimated were up to 36 times more likely to find food than the cold-acclimated flies when temperatures were warm. Such costs and strong benefits were not evident in laboratory tests where we found no reduction in heat survival of the cold-acclimated flies. Field release studies, therefore, reveal costs of cold acclimation that standard laboratory assays do not detect. Thus, although physiological acclimation may dramatically improve fitness over a narrow set of thermal conditions, it may have the opposite effect once conditions extend outside this range, an increasingly likely scenario as temperature variability increases under global climate change