Regional disparities in the beneficial effects of rising CO2 concentrations on crop water productivity

Rising atmospheric CO2 concentrations ([CO2]) are expected to enhance photosynthesis and reduce crop water use1. However, there is high uncertainty about the global implications of these effects for future crop production and agricultural water requirements under climate change. Here we combine results from networks of field experiments1, 2 and global crop models3 to present a spatially explicit global perspective on crop water productivity (CWP, the ratio of crop yield to evapotranspiration) for wheat, maize, rice and soybean under elevated [CO2] and associated climate change projected for a high-end greenhouse gas emissions scenario. We find CO2 effects increase global CWP by 10[0;47]%–27[7;37]% (median[interquartile range] across the model ensemble) by the 2080s depending on crop types, with particularly large increases in arid regions (by up to 48[25;56]% for rainfed wheat). If realized in the fields, the effects of elevated [CO2] could considerably mitigate global yield losses whilst reducing agricultural consumptive water use (4–17%). We identify regional disparities driven by differences in growing conditions across agro-ecosystems that could have implications for increasing food production without compromising water security. Finally, our results demonstrate the need to expand field experiments and encourage greater consistency in modelling the effects of rising [CO2] across crop and hydrological modelling communities

Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20–25 mg m−2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m−2 and escalated in an accelerated titration design to 25 mg m−2. Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m−2. The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h−1 m−2 in cycle 1 to 18 (3–37) ml h−1 m−2 with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m−2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent

Quantification of Collagen Ultrastructure after Penetrating Keratoplasty – Implications for Corneal Biomechanics

Purpose: To quantify long-term changes in stromal collagen ultrastructure following penetrating keratoplasty (PK), and evaluate their possible implications for corneal biomechanics. Methods: A pair of 16 mm post-mortem corneo-scleral buttons was obtained from a patient receiving bilateral penetrating keratoplasty 12 (left)/28 (right) years previously. Small-angle x-ray scattering quantified collagen fibril spacing, diameter and spatial order at 0.5 mm or 0.25 mm intervals along linear scans across the graft margin. Corresponding control data was collected from two corneo-scleral buttons with no history of refractive surgery. Wide-angle x-ray scattering quantified collagen fibril orientation at 0.25 mm (horizontal)×0.25 mm (vertical) intervals across both PK specimens. Quantification of orientation changes in the graft margin were verified by equivalent analysis of data from a 13 year post-operative right PK specimen obtained from a second patient in a previous study, and comparison made with new and published data from normal corneas. Results: Marked changes to normal fibril alignment, in favour of tangentially oriented collagen, were observed around the entire graft margin in all PK specimens. The total number of meridional fibrils in the wound margin was observed to decrease by up to 40%, with the number of tangentially oriented fibrils increasing by up to 46%. As a result, in some locations the number of fibrils aligned parallel to the wound outnumbered those spanning it by up to five times. Localised increases in fibril spacing and diameter, with an accompanying reduction in matrix order, were also evident. Conclusions: Abnormal collagen fibril size and spatial order within the PK graft margin are indicative of incomplete stromal wound remodelling and the long term persistence of fibrotic scar tissue. Lasting changes in collagen fibril orientation in and around PK wounds may alter corneal biomechanics and compromise the integrity of the graft-host interface in the long term