The development of Western Australian sand plain soils for agriculture

IN a recently published economic survey of the Australian wheat growing industry, it was reported that nearly two-thirds of the farms surveyed in Western Australia were located on lateritic sand plain. As a random selection was made of the eighty farms that were visited it is reasonable to conclude that a similar proportion of all the State\u27s wheat producing farms are on that type of country. This constitutes a remarkable change from the earlier days of wheat belt settlement when the sand plain soils were regarded as virtually useless and by-passed for development. It is the purpose of this article to give a brief account of the agricultural development of those soils in the south-western part of Western Australia and to consider the factors which have been responsible for the change

Sequential actions of Rab5 and Rab7 regulate endocytosis in the Xenopus oocyte

To explore the role of GTPases in endocytosis, we developed an assay using Xenopus oocytes injected with recombinant proteins to follow the uptake of the fluid phase marker HRP. HRP uptake was inhibited in cells injected with GTPγ S or incubated with aluminum fluoride, suggesting a general role for GTPases in endocytosis. Injection of Rab5 into oocytes, as well as Rab5:Q79L, a mutant with decreased GTPase activity, increased HRP uptake. Injection of Rab5:S34N, the dominant-negative mutant, inhibited HRP uptake. Injection of N-ethylmaleimide-sensitive factor (NSF) stimulated HRP uptake, and ATPase-defective NSF mutants inhibited HRP uptake when coinjected with Rab5:Q79L, confirming a requirement for NSF in endocytosis. Surprisingly, injection of Rab7:WT stimulated both uptake and degradation/activation of HRP. The latter appears to be due to enhanced transport to a late endosomal/prelysosomal degradative compartment that is monensin sensitive. Enhancement of uptake by Rab7 appears to function via an Rab5-sensitive pathway in oocytes since the stimulatory effect of Rab7 was blocked by coinjection of Rab5:S34N. Stimulation of uptake by Rab5 was blocked by Rab5:S34N but not by Rab7:T22N. Our results suggest that Rab7, while functioning downstream of Rab5, may be rate limiting for endocytosis in oocytes

Salt domes of the UAE and Oman: probing eastern Arabia

The emergent salt domes of the United Arab Emirates (UAE) have been investigated in detail and examples from central Oman have been studied for comparison. The salt domes contain exotic clasts of igneous, sedimentary and low-grade metamorphic rocks of the Arabian basement that have been brought to the surface from depths of over 8 km. The clasts thus provide an opportunity to examine the lithology, geochemical composition and age of the “basement” underlying this part of eastern Arabia, where no other outcrops are available for direct study. Five volcanic rocks give consistent latest Ediacaran U-Pb zircon crystallisation dates of ca. 560–545 Ma, with Neoproterozoic, Palaeoproterozoic and Neoarchaean ages of inherited zircons. These rocks, although strongly altered, preserve geochemical characteristics compatible with formation in a within-plate, extensional setting along the northern edge of Gondwana, adjacent to Prototethys. U-Pb analyses of detrital zircons in sedimentary and low-grade metamorphic rocks indicate deposition younger than ca. 597 Ma in UAE and <734 Ma in Oman. The two UAE sedimentary rocks may correlate with the Shuram and Khufai Formations of the Nafun Group (Huqf Supergroup) in Oman. Like the volcanic rocks, the two sedimentary samples from the UAE show derivation from the erosion of Neo-, Palaeoproterozoic and Neoarchaean sources. These sources could be from the Arabian basement itself or from other basement blocks such as those embedded in present-day Iran and Afghanistan, the precise whereabouts of which in Neoproterozoic times remains somewhat uncertain. The zircon age spectra of samples from the UAE show Neoproterozoic age peak characteristics of sources from both the western and eastern Arabian basement blocks, indicating that the two segments were juxtaposed by about 597 Ma, the maximum age of their deposition

Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT

Complex trials with innovative designs are becoming increasingly common and offer the potential to improve patient outcomes in a shorter time frame. There is evidence that patients with colorectal cancer fall into different subgroups with varying responsiveness to therapy, and that this variation is linked to genetic biomarkers. To the best of our knowledge, FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and remains one of the first umbrella trial designs to be launched globally. Objectives To identify novel therapies that improve disease control within the molecular subgroup of metastatic colorectal cancer in which the novel therapies were expected to be most effective. Design This was a Phase II/III molecularly stratified umbrella trial that used adaptive statistical methodology to decide which subtrial should close early; new subtrials were added as protocol amendments. Setting The maintenance setting following 16 weeks of first-line combination chemotherapy. Participants Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified subtrial or the non-stratified FOCUS4-N trial. Interventions Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted subtrials were activated: FOCUS4-B (PIK3CA mutation or PTEN overexpression) – aspirin versus placebo; FOCUS4-C (TP53 and RAS mutation) – adavosertib (AstraZeneca Ltd, Cambridge, UK) versus active monitoring; and FOCUS4-D (BRAF-PIK3CA-RAS wild type) – AZD8931 versus placebo. A non-stratified subtrial was also carried out: FOCUS4-N – capecitabine versus active monitoring. Main outcome measures The main outcome measure was progression-free survival from the time of randomisation to progression, comparing the intervention with active monitoring/placebo. Toxicity and overall survival data were collected in all randomised patients, and quality of life (using EuroQol-5 Dimensions) data were collected in FOCUS4-N only. Results Between January 2014 and October 2020, 1434 patients were registered from 88 hospitals in the UK. Successful biomarker testing was completed in 1291 out of 1382 samples (93%), and 908 out of 1315 patients (69%) completing 16 weeks of first-line therapy were eligible for randomisation, with 361 randomly allocated to a subtrial. FOCUS4-B evaluated aspirin versus placebo in the PIK3CA-mutant/ PTEN -loss subgroup, but recruited only six patients, so was closed for futility. FOCUS4-C evaluated adavosertib versus active monitoring in 67 patients in the RAS + TP53 double-mutant subgroup and met its primary end point, showing an improvement in progression-free survival (median 3.61 vs. 1.87 months; hazard ratio 0.35, 95% confidence interval 0.18 to 0.68; p = 0022). FOCUS4-D evaluated AZD8931 in 32 patients in the BRAF-PIK3CA-RAS wild-type subgroup and showed no benefit, so was discontinued after the first interim analysis. FOCUS4-N evaluated capecitabine monotherapy versus active monitoring in 254 patients and met its primary end point, showing improvement in progression-free survival (hazard ratio 0.40, 95% confidence interval 0.21 to 0.75; p &lt; 0.0001). Limitations FOCUS4-C and FOCUS4-N were closed early owing to COVID-19, so did not accrue their planned recruitment numbers. Conclusions Adaptive stratified medicine studies are feasible in common cancers but present challenges. Capecitabine monotherapy is an effective maintenance therapy. Wee1 inhibition using adavosertib shows significant clinical activity, notably in left-sided colorectal cancer. Trial registration This trial was registered as ISRCTN90061546. Funding This project was jointly funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership, and Cancer Research UK. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 9. See the NIHR Journals Library website for further project information

Unraveling ethnic disparities in antipsychotic prescribing among patients with psychosis: A retrospective cohort study based on electronic clinical records

BACKGROUND: Previous studies have shown mixed evidence on ethnic disparities in antipsychotic prescribing among patients with psychosis in the UK, partly due to small sample sizes. This study aimed to examine the current state of antipsychotic prescription with respect to patient ethnicity among the entire population known to a large UK mental health trust with non-affective psychosis, adjusting for multiple potential risk factors. METHODS: This retrospective cohort study included all patients (N = 19,291) who were aged 18 years or over at their first diagnoses of non-affective psychosis (identified with the ICD-10 codes of F20-F29) recorded in electronic health records (EHRs) at the South London and Maudsley NHS Trust until March 2021. The most recently recorded antipsychotic treatments and patient attributes were extracted from EHRs, including both structured fields and free-text fields processed using natural language processing applications. Multivariable logistic regression models were used to calculate the odds ratios (OR) for antipsychotic prescription according to patient ethnicity, adjusted for multiple potential contributing factors, including demographic (age and gender), clinical (diagnoses, duration of illness, service use and history of cannabis use), socioeconomic factors (level of deprivation and own-group ethnic density in the area of residence) and temporal changes in clinical guidelines (date of prescription). RESULTS: The cohort consisted of 43.10 % White, 8.31 % Asian, 40.80 % Black, 2.64 % Mixed, and 5.14 % of patients from Other ethnicity. Among them, 92.62 % had recorded antipsychotic receipt, where 24.05 % for depot antipsychotics and 81.72 % for second-generation antipsychotic (SGA) medications. Most ethnic minority groups were not significantly different from White patients in receiving any antipsychotic. Among those receiving antipsychotic prescribing, Black patients were more likely to be prescribed depot (adjusted OR 1.29, 95 % confidence interval (CI) 1.14-1.47), but less likely to receive SGA (adjusted OR 0.85, 95 % CI 0.74-0.97), olanzapine (OR 0.82, 95 % CI 0.73-0.92) and clozapine (adjusted OR 0.71, 95 % CI 0.6-0.85) than White patients. All the ethnic minority groups were less likely to be prescribed olanzapine than the White group. CONCLUSIONS: Black patients with psychosis had a distinct pattern in antipsychotic prescription, with less use of SGA, including olanzapine and clozapine, but more use of depot antipsychotics, even when adjusting for the effects of multiple demographic, clinical and socioeconomic factors. Further research is required to understand the sources of these ethnic disparities and eliminate care inequalities

Release characteristics of selected carbon nanotube polymer composites

Multi-walled carbon nanotubes (MWCNTs) are commonly used in polymer formulations to improve strength, conductivity, and other attributes. A developing concern is the potential for carbon nanotube polymer nanocomposites to release nanoparticles into the environment as the polymer matrix degrades or is mechanically stressed. Here, we review characteristics related to release potential of five sets of polymer systems: epoxy, polyamide, polyurethane, polyethylene, and polycarbonate. Our review includes consideration of general characteristics and use of the polymer (as related to potential MWCNT release) and its MWCNT composites; general potential for nanomaterial release (particularly MWCNTs) due to degradation and mechanical stresses during use; and potential effects of stabilizers and plasticizers on polymer degradation. We examine UV degradation, temperature extremes, acid-base catalysis, and stresses such as sanding. Based on a high-level summary of the characteristics considered, the potential for release of MWCNT with typical, intended consumer use is expected to be low. © 2013 Elsevier Ltd. All rights reserved

“Give us the tools!” - development of knowledge transfer tools to support the involvement of patient partners in the development of clinical trial protocols with patient-reported outcomes (PROs), in accordance with SPIRIT-PRO extension

Objectives (a) To adapt the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-patient-reported outcome (PRO) Extension guidance to a user-friendly format for patient partners and (b) to codesign a web-based tool to support the dissemination and uptake of the SPIRIT-PRO Extension by patient partners.Design A 1-day patient and public involvement session.Participants Seven patient partners.Methods A patient partner produced an initial lay summary of the SPIRIT-PRO guideline and a glossary. We held a 1-day PPI session in November 2019 at the University of Birmingham. Five patient partners discussed the draft lay summary, agreed on the final wording, codesigned and agreed the final content for both tools. Two additional patient partners were involved in writing the manuscript. The study compiled with INVOLVE guidelines and was reported according to the Guidance for Reporting Involvement of Patients and the Public 2 checklist.Results Two user-friendly tools were developed to help patients and members of the public be involved in the codesign of clinical trials collecting PROs. The first tool presents a lay version of the SPIRIT-PRO Extension guidance. The second depicts the most relevant points, identified by the patient partners, of the guidance through an interactive flow diagram.Conclusions These tools have the potential to support the involvement of patient partners in making informed contributions to the development of PRO aspects of clinical trial protocols, in accordance with the SPIRIT-PRO Extension guidelines. The involvement of patient partners ensured the tools focused on issues most relevant to them

Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT

Background Complex trials with innovative designs are becoming increasingly common and offer the potential to improve patient outcomes in a shorter time frame. There is evidence that patients with colorectal cancer fall into different subgroups with varying responsiveness to therapy, and that this variation is linked to genetic biomarkers. To the best of our knowledge, FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and remains one of the first umbrella trial designs to be launched globally. Objectives To identify novel therapies that improve disease control within the molecular subgroup of metastatic colorectal cancer in which the novel therapies were expected to be most effective. Design This was a Phase II/III molecularly stratified umbrella trial that used adaptive statistical methodology to decide which subtrial should close early; new subtrials were added as protocol amendments. Setting The maintenance setting following 16 weeks of first-line combination chemotherapy. Participants Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified subtrial or the non-stratified FOCUS4-N trial. Interventions Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted subtrials were activated: FOCUS4-B (PIK3CA mutation or PTEN overexpression) – aspirin versus placebo; FOCUS4-C (TP53 and RAS mutation) – adavosertib (AstraZeneca Ltd, Cambridge, UK) versus active monitoring; and FOCUS4-D (BRAF-PIK3CA-RAS wild type) – AZD8931 versus placebo. A non-stratified subtrial was also carried out: FOCUS4-N – capecitabine versus active monitoring. Main outcome measures The main outcome measure was progression-free survival from the time of randomisation to progression, comparing the intervention with active monitoring/placebo. Toxicity and overall survival data were collected in all randomised patients, and quality of life (using EuroQol-5 Dimensions) data were collected in FOCUS4-N only. Results Between January 2014 and October 2020, 1434 patients were registered from 88 hospitals in the UK. Successful biomarker testing was completed in 1291 out of 1382 samples (93%), and 908 out of 1315 patients (69%) completing 16 weeks of first-line therapy were eligible for randomisation, with 361 randomly allocated to a subtrial. FOCUS4-B evaluated aspirin versus placebo in the PIK3CA-mutant/PTEN-loss subgroup, but recruited only six patients, so was closed for futility. FOCUS4-C evaluated adavosertib versus active monitoring in 67 patients in the RAS + TP53 double-mutant subgroup and met its primary end point, showing an improvement in progression-free survival (median 3.61 vs. 1.87 months; hazard ratio 0.35, 95% confidence interval 0.18 to 0.68; p = 0022). FOCUS4-D evaluated AZD8931 in 32 patients in the BRAF-PIK3CA-RAS wild-type subgroup and showed no benefit, so was discontinued after the first interim analysis. FOCUS4-N evaluated capecitabine monotherapy versus active monitoring in 254 patients and met its primary end point, showing improvement in progression-free survival (hazard ratio 0.40, 95% confidence interval 0.21 to 0.75; p < 0.0001)