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Hydrological drought is a serious issue globally, which is likely to be amplified by 21st century climate change. In the UK, the impacts of changes in river flow and groundwater drought severity in a future of climate change and higher water demand are potentially severe. Recent publication of a new nationally consistent set of river flow and groundwater level projections (the eFLaG dataset), based on state-of-the-art UKCP18 climate projections, offers a unique opportunity to quantitatively assess future UK hydrological drought susceptibility. The dataset includes a transient, multi-model ensemble of hydrological projections driven by a single regional climate model (RCM), with a 12-member perturbed-parameter ensemble, for 200 catchments and 54 boreholes spanning a period from 1961 to 2080. Assessment of a baseline period (1989–2018) shows that the RCM-driven projections adequately reproduce observed river flow and groundwater level regimes, improving our confidence in using these models for assessment of future drought. Across all hydrological models and most catchments, future low river flows are projected to decline consistently out to 2080. Drought durations, intensities and severities are all projected to increase in most (over 90 %, pooling across different drought characteristics) UK catchments. However, the trajectory of low groundwater levels and groundwater drought characteristics diverges from that of river flows. Whilst groundwater levels at most (> 85 %) boreholes are projected to decline (consistent with river flows), these declines are relatively modest (< 10 % reduction) in transient low groundwater levels by 2080, and, in fact, six show moderate increases. Groundwater drought characteristics in the far future (2050–2079) are often similar to those of the baseline (1989–2018), with only 33 % of boreholes showing an increase (towards worsening drought) of more than 10 % for drought severity (48 % of boreholes for drought intensity). Interestingly, for some boreholes, droughts are projected to be more prolonged and severe in the near future (2020–2049) before returning to shorter durations and lower severity in the far future. A number of explanatory factors for this divergence between river flow and groundwater are discussed. The sensitivity to seasonal changes in precipitation and potential evapotranspiration is proposed as a principal driver of divergence because low river flows are more influenced by shorter-term rainfall deficits in the summer half-year, whilst groundwater drought appears to be offset somewhat by the wetter winter signal in the RCM projections. Our results have important implications for water management, demonstrating a widespread increase in river flow drought severity and diminishing low flows that could have profound societal and environmental impacts unless mitigated. Furthermore, the divergence in projections of drought in river flows and groundwater levels brings into question the balance between surface and subsurface water resources. The projected contrast in fortunes of surface and subsurface water resources identified for the UK may be replicated in other parts of the world where climate projections suggest a shift towards drier summers and wetter winters. [ABSTRACT FROM AUTHOR]

Although the theoretical benefits of feedback are generally well established, in practice those benefits can be less than clear. This is particularly the case on shorter courses, where students have limited scope to integrate feedback into future assessment performance. If we accept that one of the key purposes of feedback is to encourage students to reflect on--and subsequently change--their performance, there is a strong argument for feedforward in such cases. This paper analyses the performance of 137 students on an MBA module in financial decision-making. An assignment was delivered to two groups, one of which was involved in a structured feedforward exercise. At the end of the module all students completed an evaluative questionnaire. In addition, a focus group was held with a group of students who had been involved with the feedforward exercise. The study found that increased support and guidance through the feedforward process had no significant impact on student performance, but that student satisfaction increased. The question of performance was found to be intertwined with complex issues of strategic approaches to learning, satisficing behaviour, "spoon-feeding" reactions and workload management. The study points to a need for more qualitative research into students' strategies for assessment.

Aims: To compare pharmacokinetics (PK) and safety of heat‐stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety. Methods: A phase 1, randomized, cross‐over study was undertaken in 2 UK and 1 Australian centres. Subjects were recruited into 2 groups: Group 1, women in TSL; Group 2, nonpregnant women of childbearing potential (Cohort A, combined oral contraception; Cohort B, nonhormonal contraception). Participants were randomized 1:1 to: Group 1, oxytocin 10 IU (17 μg) IM or oxytocin 240 IU (400 μg) IH immediately after delivery; Group 2, oxytocin 5 IU (8.5 μg) intravenously and oxytocin 240 IU (400 μg) IH at 2 separate dosing sessions. Results: Participants were recruited between 23 November 2016 to 4 March 2019. In Group 1, 17 participants were randomized; received either IH (n = 9) or IM (n = 8) oxytocin. After IH and IM administration, most plasma oxytocin concentrations were below quantification limits (2 pg/mL). In Group 2 (n = 14), oxytocin IH concentrations remained quantifiable ≤3 h postdose. Adverse events were reported in both groups, with no deaths reported: Group 1, IH n = 3 (33%) and IM n = 2 (25%); Group 2, n = 14 (100%). Conclusion: Safety profiles of oxytocin IH and IM were similar. However, PK profiles could not be established for oxytocin IH or IM in women in TSL, despite using a highly sensitive and specific assay. [ABSTRACT FROM AUTHOR]

Hydrological drought is a serious issue globally which is likely to be amplified by 21st 10 century climate change. In the UK, the impacts of changes in river flow and groundwater drought severity in a future of climate change and higher water demand are potentially severe. Recent publication of a new nationally-consistent set of river flow and groundwater level projections based on state-of-the-art UKCP18 climate projections offers a unique opportunity to quantitatively assess future UK hydrological drought susceptibility. The dataset includes a transient, multi-model ensemble of hydrological 15 projections driven by a single regional climate model (RCM) for 200 catchments and 54 boreholes spanning a period from 1961 to 2080. Assessment of a baseline period (1989-2018) shows that the RCM-driven projections adequately reproduce observed river flow and groundwater level regimes, improving our confidence in using these models for assessment of future drought. Across all hydrological models and most catchments, future low river flows are projected to decline consistently out to 2080. Drought durations, intensities and severities are all projected to increase in most UK catchments. However, the 20 trajectory of low groundwater levels and groundwater drought characteristics diverge from those of river flows. Whilst groundwater levels at most boreholes are projected to decline (consistent with river flows), the majority of boreholes show <10% reduction in transient low groundwater levels by 2080 and eight show moderate increases. Groundwater drought characteristics in the far future (2050-2079) are often similar to those of the baseline (1989-2018), and in some instances droughts are projected to be most prolonged and severe in the near future (2020-2049). A number of explanatory factors for 25 this divergence are discussed. The sensitivity to seasonal changes in precipitation and potential evapotranspiration is proposed as a principal driver of divergence because low river flows are more influenced by shorter-term rainfall deficits in the summer half-year, whilst groundwater drought appears to be offset somewhat by the wetter winter signal in the RCM projections. Our results have fundamental importance for water management, demonstrating a widespread increase in river flow drought severity and diminishing low flows that could have profound societal and environmental impacts unless 30 mitigated. Furthermore, the divergence in projections of drought in river flows and groundwater levels brings into question the balance between surface and subsurface water resources. The projected contrast in fortunes of surface and subsurface water resources identified for the UK may be replicated in other parts of the world where climate projections suggest a shift towards drier summers and wetter winters. [ABSTRACT FROM AUTHOR]

Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell-derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NBDNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM., Introduction Sphingolipids and their glycosylated derivatives, glycosphingolipids (GSLs), are essential structural components of mammalian cell membranes and are characterized by heterogenic composition among tissues and even in the same cell [...]

This paper presents an 'enhanced future FLows and Groundwater' (eFLaG) dataset of nationally consistent hydrological projections for the UK, based on the latest UK Climate Projections (UKCP18). The hydrological projections are derived from a range of river flow models (Grid-to-Grid, PDM, GR4J and GR6J), to provide an indication of hydrological model uncertainty, as well as groundwater level (Aquimod) and groundwater recharge (ZOODRM) models. A 12-member ensemble of transient projections of present and future (up to 2080) daily river flows, groundwater levels and groundwater recharge were produced using bias corrected data from the UKCP18 Regional (12 km) climate ensemble. Projections are provided for 200 river catchments, 54 groundwater level boreholes and 558 groundwater bodies, all sampling across the diverse hydrological and geological conditions of the UK. An evaluation was carried out, to appraise the quality of hydrological model simulations against observations and also to appraise the reliability of hydrological models driven by the RCM ensemble, in terms of their capacity to reproduce hydrological regimes in the current period. The dataset was originally conceived as a prototype climate service for drought planning for the UK water sector, so has been developed with drought, low river flow and low groundwater level applications as the primary focus. The evaluation metrics show that river flows and groundwater levels are, for the majority of catchments and boreholes, well simulated across the flow and level regime, meaning that the eFLaG dataset could be applied to a wider range of water resources research and management contexts, pending a full evaluation for the designated purpose. [ABSTRACT FROM AUTHOR]