Haloperidol (oral) versus olanzapine (oral) for people with schizophrenia and schizophrenia-spectrum disorders.

BACKGROUND: Schizophrenia is often a severe and disabling psychiatric disorder. Antipsychotics remain the mainstay of psychotropic treatment for people with psychosis. In limited resource and humanitarian contexts, it is key to have several options for beneficial, low-cost antipsychotics, which require minimal monitoring. We wanted to compare oral haloperidol, as one of the most available antipsychotics in these settings, with a second-generation antipsychotic, olanzapine. OBJECTIVES: To assess the clinical benefits and harms of haloperidol compared to olanzapine for people with schizophrenia and schizophrenia-spectrum disorders. SEARCH METHODS: We searched the Cochrane Schizophrenia study-based register of trials, which is based on monthly searches of CENTRAL, CINAHL, ClinicalTrials.gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed and WHO ICTRP. We screened the references of all included studies. We contacted relevant authors of trials for additional information where clarification was required or where data were incomplete. The register was last searched on 14 January 2023. SELECTION CRITERIA: Randomised clinical trials comparing haloperidol with olanzapine for people with schizophrenia and schizophrenia-spectrum disorders. Our main outcomes of interest were clinically important change in global state, relapse, clinically important change in mental state, extrapyramidal side effects, weight increase, clinically important change in quality of life and leaving the study early due to adverse effects. DATA COLLECTION AND ANALYSIS: We independently evaluated and extracted data. For dichotomous outcomes, we calculated risk ratios (RR) and their 95% confidence intervals (CI) and the number needed to treat for an additional beneficial or harmful outcome (NNTB or NNTH) with 95% CI. For continuous data, we estimated mean differences (MD) or standardised mean differences (SMD) with 95% CIs. For all included studies, we assessed risk of bias (RoB 1) and we used the GRADE approach to create a summary of findings table. MAIN RESULTS: We included 68 studies randomising 9132 participants. We are very uncertain whether there is a difference between haloperidol and olanzapine in clinically important change in global state (RR 0.84, 95% CI 0.69 to 1.02; 6 studies, 3078 participants; very low-certainty evidence). We are very uncertain whether there is a difference between haloperidol and olanzapine in relapse (RR 1.42, 95% CI 1.00 to 2.02; 7 studies, 1499 participants; very low-certainty evidence). Haloperidol may reduce the incidence of clinically important change in overall mental state compared to olanzapine (RR 0.70, 95% CI 0.60 to 0.81; 13 studies, 1210 participants; low-certainty evidence). For every eight people treated with haloperidol instead of olanzapine, one fewer person would experience this improvement. The evidence suggests that haloperidol may result in a large increase in extrapyramidal side effects compared to olanzapine (RR 3.38, 95% CI 2.28 to 5.02; 14 studies, 3290 participants; low-certainty evidence). For every three people treated with haloperidol instead of olanzapine, one additional person would experience extrapyramidal side effects. For weight gain, the evidence suggests that there may be a large reduction in the risk with haloperidol compared to olanzapine (RR 0.47, 95% CI 0.35 to 0.61; 18 studies, 4302 participants; low-certainty evidence). For every 10 people treated with haloperidol instead of olanzapine, one fewer person would experience weight increase. A single study suggests that haloperidol may reduce the incidence of clinically important change in quality of life compared to olanzapine (RR 0.72, 95% CI 0.57 to 0.91; 828 participants; low-certainty evidence). For every nine people treated with haloperidol instead of olanzapine, one fewer person would experience clinically important improvement in quality of life. Haloperidol may result in an increase in the incidence of leaving the study early due to adverse effects compared to olanzapine (RR 1.99, 95% CI 1.60 to 2.47; 21 studies, 5047 participants; low-certainty evidence). For every 22 people treated with haloperidol instead of olanzapine, one fewer person would experience this outcome. Thirty otherwise relevant studies and several endpoints from 14 included studies could not be evaluated due to inconsistencies and poor transparency of several parameters. Furthermore, even within studies that were included, it was often not possible to use data for the same reasons. Risk of bias differed substantially for different outcomes and the certainty of the evidence ranged from very low to low. The most common risks of bias leading to downgrading of the evidence were blinding (performance bias) and selective reporting (reporting bias). AUTHORS' CONCLUSIONS: Overall, the certainty of the evidence was low to very low for the main outcomes in this review, making it difficult to draw reliable conclusions. We are very uncertain whether there is a difference between haloperidol and olanzapine in terms of clinically important global state and relapse. Olanzapine may result in a slightly greater overall clinically important change in mental state and in a clinically important change in quality of life. Different side effect profiles were noted: haloperidol may result in a large increase in extrapyramidal side effects and olanzapine in a large increase in weight gain. The drug of choice needs to take into account side effect profiles and the preferences of the individual. These findings and the recent inclusion of olanzapine alongside haloperidol in the WHO Model List of Essential Medicines should increase the likelihood of it becoming more easily available in low- and middle- income countries, thereby improving choice and providing a greater ability to respond to side effects for people with lived experience of schizophrenia. There is a need for additional research using appropriate and equivalent dosages of these drugs. Some of this research needs to be done in low- and middle-income settings and should actively seek to account for factors relevant to these. Research on antipsychotics needs to be person-centred and prioritise factors that are of interest to people with lived experience of schizophrenia.

The role of depression and other psychological factors in work ability among breast cancer survivors in Australia.

OBJECTIVE: Identifying modifiable factors affecting work ability among cancer survivors is important. The primary aim of the present study was to examine the effects of depression and related psychological factors on work ability among breast cancer survivors in Australia. METHODS: In this cross-sectional electronic and postal survey, Australian breast cancer survivors were investigated. Work status and conditions before and after cancer treatment were analysed. Work ability was measured using the Work Limitation Questionnaire©-Short Form (WLQ-SF) with its four domains (time management, physical tasks, mental-interpersonal tasks, and output tasks). Three psychological factors were investigated: depression, fear of cancer recurrence, and demoralisation. Sociodemographic and clinical data were also collected. Multivariate regression analysis was used to identify the associations of psychological factors with WLQ-SF. RESULTS: Among eligible survivors, 310 (50%) responded to the survey and were analysed. Nearly one third reported their work conditions had changed after cancer treatment. The depressed group reported limited work ability in 35%-44% of the four domains of WLQ-SF, while the non-depressed group reported limited work ability in only 8%-13%. At-work productivity loss was approximately fourfold higher in the depressed group than in the non-depressed group. In multivariate analysis, at-work productivity loss was associated with depression, demoralisation, and past history of anxiety. CONCLUSIONS: After breast cancer treatment, work conditions changed toward lower wages and working hours. Depression, demoralisation, and past history of anxiety were associated with lower work ability. Further evaluations of work rehabilitation in breast cancer survivors are warranted.

Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models.

BACKGROUND: Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor-stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. METHODS: MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. RESULTS: Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated 'omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. CONCLUSIONS: This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

Factitious Disorder (Munchausen Syndrome) in Plastic Surgery: A Systematic Review of 42 Cases.

INTRODUCTION: Patients with factitious disorder (FD) or "Munchausen syndrome" intentionally fabricate or induce medical problems for psychological gratification. They may deceive plastic surgeons into performing multiple unnecessary procedures. We undertook the first systematic review of FD case reports in plastic surgery. Our aims were 2-fold: (1) describe the adverse outcomes associated with these cases and (2) identify strategies for their prevention by surgeons. METHODS: MEDLINE, EMBASE, and SCOPUS databases were searched. We included cases in which an adult with FD presented to a plastic surgeon. Our search returned a total of 42 eligible cases reported from North America (43%), Europe (37%), and Asia (20%). RESULTS: Seventy-six percent of patients were women, and 62% worked in health care. Sixty percent had a comorbid psychiatric disorder, the most common (50%) being depression. Ninety-three percent of our sample presented with self-induced lesions. The average delay in diagnosis of FD was 54 months, with 46% of patients receiving multiple surgical procedures in this time, including debridement (36%) and skin grafts (39%). Surgical wounds were frequently exploited by patients to remain in, or return to, hospital: 50% contaminated or manipulated their wounds to prevent healing. Thirty-six percent of cases resulted in significant long-term disability (24%) or disfigurement (12%). Ten percent of patients received an amputation. Outcomes were improved when patients were confronted by surgeons, however, and 62% were willing to see a psychiatrist. Surgeons were able to support recovery in 33% of cases-for example, by using occlusive wound dressings. CONCLUSIONS: Patients with FD who present to plastic surgeons are high risk: the majority require surgical intervention for severe self-injury, and many engage in harmful behaviors, such as "doctor-shopping." Early recognition of FD in plastic surgery is, therefore, crucial and may be achieved via careful examination of lesions for unusual morphology. Medical records may reveal extensive health care service use and negative investigations. Finally, plastic surgeons may play an important role in managing such patients. Management strategies include direct observation by nursing staff in the postoperative period and use of strict occlusive dressings to prevent access to surgical wounds.

Crops For the Future (CFF): an overview of research efforts in the adoption of underutilised species.

MAIN CONCLUSION: Crops For the Future (CFF), as an entity, has established a broad range of research activities to promote the improvement and adoption of currently underutilised crops. This paper summarises selected research activities at Crops For the Future (CFF) in pursuit of its mission 'to develop solutions for diversifying future agriculture using underutilised crops'. CFF is a research company focussed on the improvement of underutilised crops, so that they might be grown and consumed more widely with benefits to human food and nutritional security; its founding guarantors were the Government of Malaysia and the University of Nottingham. From its base in Malaysia, it engages in research around the world with a focus on species and system diversification. CFF has adopted a food system approach that adds value by delivering prototype food, feed and knowledge products. Bambara groundnut (Vigna subterranea) was adopted as an exemplar crop around which to develop CFF's food system approach with emphasis on the short-day photoperiod requirement for pod-filling and the hard-to-cook trait. Selective breeding has allowed the development of lines that are less susceptible to photoperiod but also provided a range of tools and approaches that are now being exploited in other crops such as winged bean (Psophocarpus tetragonolobus), amaranth (Amaranthus spp.), moringa (Moringa oleifera) and proso (Panicum miliaceum) and foxtail (Setaria italica) millets. CFF has developed and tested new food products and demonstrated that several crops can be used as feed for black soldier fly which can, in turn, be used to feed fish thereby reducing the need for fishmeal. Information about underutilised crops is widely dispersed; so, a major effort has been made to develop a knowledge base that can be interrogated and used to answer practical questions about potential exploitation of plant and nutritional characteristics. Future research will build on the success with Bambara groundnut and include topics such as urban agriculture, rural development and diversification, and the development of novel foods.

Metabolic markers of protein maldigestion after a 15N test meal in minipigs with pancreatic exocrine insufficiency.

The effect of pancreatic exocrine insufficiency (PEI) on protein malabsorption is little documented, partly due to methodological barriers. We aimed to validate biomarkers of protein malabsorption using a 15N test meal in a minipig model of PEI. Six pancreatic duct-ligated minipigs were used as a model of PEI and four nonoperated animals as a control. All animals were equipped with an ileocecal reentrant cannula. Minipigs were given a test meal containing [15N]casein. The PEI animals repeated the test three times, in the absence of any pancreatic enzymes, or after pancreatic substitution at two levels [ A or B: 7,500 or 75,000 (lipase) and 388 or 3881 (protease) FIP U]. Ileal chyme, urine, and blood were collected postprandially. Nitrogen and 15N were measured in digestive and metabolic pools. We obtained a gradient of ileal protein digestibility from 29 ± 11% in PEI to 89 ± 6% in the controls and a dose- dependent response of enzymes. Insulin and gastric inhibitory polypeptide secretions were decreased by PEI, an effect that was counteracted with the enzymes at level B. The total recovery of 15N in urinary urea and plasma proteins was 14 ± 5.1% in the control group and decreased to 5.5 ± 2.1% by PEI. It was dose dependently restored by the treatment. Both 15N recovery in plasma and urine were correlated to protein digestibility. We confirm that the 15N transfer in those pools is a sensitive marker of protein malabsorption. Nevertheless, an optimization of the test meal conditions would be necessary in the view of implementing a clinical test. NEW & NOTEWORTHY We designed an intervention study to create a gradient of ileal protein digestibility in minipigs with pancreatic exocrine insufficiency and to validate reliable metabolic markers using a 15N oral meal test. 15N recovery in plasma proteins and to a higher extent in urine was sensitive to protein malabsorption. This test is minimally invasive and could be used to reveal protein malabsorption in patients.

Hospitalizations due to self-poisoning at a Canadian paediatric hospital.

BACKGROUND: Adolescent self-harm by drug ingestion (i.e., self-poisoning) is a serious mental health issue. In Newfoundland and Labrador (NL), paediatricians suspected an increase in the number of adolescents hospitalized due to self-poisoning in the province. Our primary aim was to evaluate the number of hospital admissions of adolescents for self-poisoning between 2008 and 2013 to determine whether there was indeed an increase in hospitalizations. We also wanted to examine the characteristics of these admissions to better understand this patient population. METHOD: A retrospective chart review was conducted to identify cases of self-poisoning admitted to the only paediatric hospital in NL over a 6-year period. A data abstraction form was developed to collect patient demographic information and details about these incidences of self-poisoning. RESULTS: A total of 156 patient admissions were identified; 97 (62.2%) first time admissions and 59 (37.8%) recurrent admissions. The number of admissions for self-poisoning increased over the study period from 2.1% of total hospital admissions in 2008 to 6.5% in 2013. Mean (SD) age at the time of admission was 15.4 years, 122 patients (78.2%) were female and 86.5% had at least 1 previous mental health diagnosis. The most common drugs ingested were analgesics (38.0%) and antidepressants (32.2%), with 73 patients (48.7%) ingesting multiple drugs. CONCLUSIONS: The study contributes to the growing recognition of adolescent self-poisoning as a serious paediatric mental health issue. It also confirmed that an increase in adolescent hospitalizations due to self-poisoning has occurred in NL. Further research is warranted to identify effective prevention strategies for this serious problem.

Quantifying rooting at depth in a wheat doubled haploid population with introgression from wild emmer.

Background and Aims: The genetic basis of increased rooting below the plough layer, post-anthesis in the field, of an elite wheat line (Triticum aestivum 'Shamrock') with recent introgression from wild emmer (T. dicoccoides), is investigated. Shamrock has a non-glaucous canopy phenotype mapped to the short arm of chromosome 2B (2BS), derived from the wild emmer. A secondary aim was to determine whether genetic effects found in the field could have been predicted by other assessment methods. Methods: Roots of doubled haploid (DH) lines from a winter wheat ('Shamrock' × 'Shango') population were assessed using a seedling screen in moist paper rolls, in rhizotrons to the end of tillering, and in the field post-anthesis. A linkage map was produced using single nucleotide polymorphism markers to identify quantitative trait loci (QTLs) for rooting traits. Key Results: Shamrock had greater root length density (RLD) at depth than Shango, in the field and within the rhizotrons. The DH population exhibited diversity for rooting traits within the three environments studied. QTLs were identified on chromosomes 5D, 6B and 7B, explaining variation in RLD post-anthesis in the field. Effects associated with the non-glaucous trait on RLD interacted significantly with depth in the field, and some of this interaction mapped to 2BS. The effect of genotype was strongly influenced by the method of root assessment, e.g. glaucousness expressed in the field was negatively associated with root length in the rhizotrons, but positively associated with length in the seedling screen. Conclusions: To our knowledge, this is the first study to identify QTLs for rooting at depth in field-grown wheat at mature growth stages. Within the population studied here, our results are consistent with the hypothesis that some of the variation in rooting is associated with recent introgression from wild emmer. The expression of genetic effects differed between the methods of root assessment.

A new three-locus model for rootstock-induced dwarfing in apple revealed by genetic mapping of root bark percentage.

Rootstock-induced dwarfing of apple scions revolutionized global apple production during the twentieth century, leading to the development of modern intensive orchards. A high root bark percentage (the percentage of the whole root area constituted by root cortex) has previously been associated with rootstock-induced dwarfing in apple. In this study, the root bark percentage was measured in a full-sib family of ungrafted apple rootstocks and found to be under the control of three loci. Two quantitative trait loci (QTLs) for root bark percentage were found to co-localize to the same genomic regions on chromosome 5 and chromosome 11 previously identified as controlling dwarfing, Dw1 and Dw2, respectively. A third QTL was identified on chromosome 13 in a region that has not been previously associated with dwarfing. The development of closely linked sequence-tagged site markers improved the resolution of allelic classes, thereby allowing the detection of dominance and epistatic interactions between loci, with high root bark percentage only occurring in specific allelic combinations. In addition, we report a significant negative correlation between root bark percentage and stem diameter (an indicator of tree vigour), measured on a clonally propagated grafted subset of the mapping population. The demonstrated link between root bark percentage and rootstock-induced dwarfing of the scion leads us to propose a three-locus model that is able to explain levels of dwarfing from the dwarf 'M.27' to the semi-invigorating rootstock 'M.116'. Moreover, we suggest that the QTL on chromosome 13 (Rb3) might be analogous to a third dwarfing QTL, Dw3, which has not previously been identified.

Predictors of Failure in Fast-Track Cardiac Surgery.

OBJECTIVES: Fast-track (FT) management of cardiac surgery patients is associated with early extubation and reduced length of intensive care unit (ICU) stay, with potential benefit of reduced hospital costs. The authors examined perioperative factors and their influence on failure of FT and what implications this failure had. DESIGN: Prospective data collection from all adult cardiac surgeries between 2011 and 2013. SETTING: Single-institution study. PARTICIPANTS: The study included 2,770 consecutive adult cardiac surgery patients. INTERVENTIONS: All participants underwent adult cardiac surgeries. Of those, 451 (16.3%) patients were selected to undergo FT management. MEASUREMENTS AND MAIN RESULTS: Failure of FT was defined as early (admission to ICU on day of surgery) or late (patients later admitted to the ICU from the ward). Univariate and multivariate regression analyses were used to identify which variables predicted FT failure. Of the 451 patients included in this study, 138 (30.6%) failed the FT, with 115 (83.3%) early failures and 23 (16.7%) late failures. Predictors of failure were reduced renal function, hypertension, age, EuroSCORE, cardiopulmonary bypass time, first lactate or base deficit after surgery (all p<0.01), and cross-clamp time (p<0.05). Multivariate analysis showed that the strongest predictor of failure was glomerular filtration rate (GFR)<65 mL/min/BSA (sensitivity, 54%; specificity, 61%; likelihood ratio, 1.39; area under receiver operating characteristics curve, 0.59; 95% confidence interval, 0.53-0.64). Median length of hospital stay was longer for the failed group (5 v 7 days, p<0.001). There were no mortalities in any of the patients selected for FT. CONCLUSIONS: A number of perioperative factors are associated with failure to FT, the strongest predictor being GFR. Failure to FT can lead to significantly longer hospital stay.

Endogenous praecaecal and total tract losses of nitrogen in pancreatic duct-ligated minipigs.

The pancreatic duct-ligated minipig (PL) is an established model of pancreatic exocrine insufficiency (PEI) with a significant decrease of nutrient digestibility. This study aimed to quantify and compare endogenous losses of nitrogen (N) (ileal and faecal) in minipigs receiving an almost N-free diet. Altogether, 12 Göttingen minipigs (7 PL and 5 control animals) fitted with an re-entrant ileo-caecal fistula were used. In Study 1, ileal digesta was collected over a period of 12 h on seven consecutive days, including one 24 h collection, when animals were fed a diet containing 0.49 g N/kg dry matter (DM). In Study 2, faeces were collected for 10 consecutive days. In Group PL, the amount and DM content of ileal digesta were higher (p < 0.05), while N concentration was lower than in the Control. The ileo-caecal N flux [g/kg DM intake] was about 2.5 times higher in Group PL (5.47 ± 1.15) than in the Control (1.91 ± 0.59) (p < 0.05). The amount of faeces did not differ, but faecal N losses were higher in Group PL (p < 0.05). Endogenous faecal N losses [g N/kg DM intake] of the Control group (1.17 ± 0.72) were comparable with earlier studies, while those of Group PL were 2.6 times higher (3.09 ± 1.34). In contrast, urinary excretion of N did not differ between the Control and Group PL. In conclusion, PEI caused markedly increased endogenous N losses. Therefore, the impact of reduced digestibility of nutrients on endogenous N losses might be relevant for apparent protein digestibility rates and should be taken into account.

Impact of multidisciplinary team meetings on the management of patients with breast cancer in a large private healthcare facility.

AIMS: Multidisciplinary meetings (MDMs) play a crucial role in decision-making in breast cancer patient care. This study aimed to firstly assess the impact of breast cancer MDMs in decision-making for breast cancer patients and secondly to determine the concordance between MDM recommendations and implementation of clinical practice. METHODS: Patient cases to be presented at the weekly breast cancer MDMs were identified and prospectively enrolled. Management plans were predicted by the treating surgeon with the pre-MDM management plans then compared to MDM recommendations. Changes in decision-making were assessed in the following domains: further surgery, systemic therapy (endocrine, chemotherapy or targeted), radiotherapy, enrolment in a clinical trial, further investigations, and referral to other specialists or services. Patient records were subsequently reviewed at 3 months post-MDM to assess the rate of implementation of MDM recommendations and any reasons for discordance. RESULTS: Out of 50 cases, 66% (CI 53-79%; p < .005) experienced a change in management plan as a result of MDM discussion, with a total of 66 episodes of recorded change per decision-making domain affecting the following: further surgery (7.6%), endocrine therapy (4.5%), chemotherapy (19.7%), targeted therapy (4.5%), radiotherapy (18.2%), enrolment for a clinical trial (12.1%), additional investigations (22.7%), and further referrals (10.6%). MDM recommendations were implemented in 83.7% of cases. CONCLUSION: The breast cancer MDMs were found to substantially impact on the management plans for breast cancer patients, with 83.7% of MDM recommendations being implemented into clinical practice. This study reinforces the importance of MDMs in the management of these patients, as well as highlighting the need for further investigating and addressing the potential barriers to the implementation of MDM recommendations.

The Path to Diagnosis of Severe Asthma-A Qualitative Exploration.

Purpose: Severe asthma poses a significant health burden in those with the disease, therefore a timely diagnosis can ensure patients receive specialist care and appropriate medication management. This study qualitatively explored the patient experience of adult Australians with severe asthma regarding specialist referral, to identify potential opportunities to streamline the process of severe asthma diagnosis and treatment and optimise referral pathways. Patients and Methods: Adults currently being treated with medication for severe asthma were invited to participate in this study. Participants were interviewed and asked to describe initial diagnosis of their asthma or severe asthma, and how they came to be referred to secondary care. Interviews were transcribed verbatim, coded by two members of the research team and thematically analysed. Results: Thirty-two people completed the study; 72% were female. Mean interview length was 33 minutes. The major themes generated were patient-related factors contributing to seeking a severe asthma diagnosis; perceptions of health care provision; diagnosis of severe asthma and the referral journey. Key findings were that both patient and healthcare provider attitudes contributed to participants' willingness to seek or receive a referral, and referral to respiratory specialists was often delayed. Contributing factors included a mismatch between patient expectations and general practice, lack of continuity of primary care, and a lack of patient understanding of the role of the respiratory specialist. Conclusion: Timely severe asthma diagnosis in Australia appears to be hampered by an absence of a clear referral process, lack of general practitioner (GP) knowledge of additional treatment options, underutilisation of pharmacists, and multiple specialists treating patient comorbidities. Directions for future research might include interviewing healthcare providers regarding how well the referral process works for severe asthma patients, and researching the time between referral and when a patient sees the respiratory specialist.

Contributions of roots and rootstocks to sustainable, intensified crop production.

Sustainable intensification is seen as the main route for meeting the world's increasing demands for food and fibre. As demands mount for greater efficiency in the use of resources to achieve this goal, so the focus on roots and rootstocks and their role in acquiring water and nutrients, and overcoming pests and pathogens, is increasing. The purpose of this review is to explore some of the ways in which understanding root systems and their interactions with soils could contribute to the development of more sustainable systems of intensive production. Physical interactions with soil particles limit root growth if soils are dense, but root-soil contact is essential for optimal growth and uptake of water and nutrients. X-ray microtomography demonstrated that maize roots elongated more rapidly with increasing root-soil contact, as long as mechanical impedance was not limiting root elongation, while lupin was less sensitive to changes in root-soil contact. In addition to selecting for root architecture and rhizosphere properties, the growth of many plants in cultivated systems is profoundly affected by selection of an appropriate rootstock. Several mechanisms for scion control by rootstocks have been suggested, but the causal signals are still uncertain and may differ between crop species. Linkage map locations for quantitative trait loci for disease resistance and other traits of interest in rootstock breeding are becoming available. Designing root systems and rootstocks for specific environments is becoming a feasible target.

Matching roots to their environment.

BACKGROUND: Plants form the base of the terrestrial food chain and provide medicines, fuel, fibre and industrial materials to humans. Vascular land plants rely on their roots to acquire the water and mineral elements necessary for their survival in nature or their yield and nutritional quality in agriculture. Major biogeochemical fluxes of all elements occur through plant roots, and the roots of agricultural crops have a significant role to play in soil sustainability, carbon sequestration, reducing emissions of greenhouse gasses, and in preventing the eutrophication of water bodies associated with the application of mineral fertilizers. SCOPE: This article provides the context for a Special Issue of Annals of Botany on 'Matching Roots to Their Environment'. It first examines how land plants and their roots evolved, describes how the ecology of roots and their rhizospheres contributes to the acquisition of soil resources, and discusses the influence of plant roots on biogeochemical cycles. It then describes the role of roots in overcoming the constraints to crop production imposed by hostile or infertile soils, illustrates root phenotypes that improve the acquisition of mineral elements and water, and discusses high-throughput methods to screen for these traits in the laboratory, glasshouse and field. Finally, it considers whether knowledge of adaptations improving the acquisition of resources in natural environments can be used to develop root systems for sustainable agriculture in the future.

Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels.

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg⁻¹·day⁻¹) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 µM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K(ATP) KCOs where rimonabant and ibipinabant allosterically regulated ³H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K(ATP) channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.

Datasets for the development of hemp (Cannabis sativa L.) as a crop for the future in tropical environments (Malaysia).

An evidence base was developed to facilitate adoption of hemp (Cannabis sativa L.) in tropical environments (Wimalasiri et al. (2021)). Agro-ecological requirements data of hemp were acquired from international databases and was contrasted against local climate and soil conditions using an augmented species ecological niche modeling. The outputs were then used to map the suitability for all locations for 12 possible calendar-year seasons within peninsular Malaysia. The most probable seasonal map was then used to generate a land suitability map for agricultural areas across 5 standard land suitability categories. Having developed the general suitability maps of hemp in Malaysia, detailed crop growth data were collected from literature and was then used to simulate an ideotype crop model (for both seed and fiber) for selected locations across Malaysia, where detailed daily climate data and soil information were available. Following the development of a downscaled future climate dataset, a simulated dataset of yield for the future conditions were also developed. Next, the simulated seed and fiber yield data were used to create yield maps for hemp across peninsular Malaysia. An economic value and cost-benefit analyses were also carried out using data that were collected from literature and local sources to simulate the true cost and benefit of growing hemp both for now and future conditions. This data provides the first ever evidence base for an underutilized crop in Southeast Asia. All data that was generated using the proposed published framework for the adoption of hemp in the future are stored in their original format in an online repository and is described in this article. The data can be used to map the suitability at finer scales, analyze and re-calibrate a yield model using any climate scenario and evaluate the economics of production using the standard methodology described in the above-mentioned publication.

Feeding nine billion: the challenge to sustainable crop production.

In the recent past there was a widespread working assumption in many countries that problems of food production had been solved, and that food security was largely a matter of distribution and access to be achieved principally by open markets. The events of 2008 challenged these assumptions, and made public a much wider debate about the costs of current food production practices to the environment and whether these could be sustained. As in the past 50 years, it is anticipated that future increases in crop production will be achieved largely by increasing yields per unit area rather than by increasing the area of cropped land. However, as yields have increased, so the ratio of photosynthetic energy captured to energy expended in crop production has decreased. This poses a considerable challenge: how to increase yield while simultaneously reducing energy consumption (allied to greenhouse gas emissions) and utilizing resources such as water and phosphate more efficiently. Given the timeframe in which the increased production has to be realized, most of the increase will need to come from crop genotypes that are being bred now, together with known agronomic and management practices that are currently under-developed.

Crop model ideotyping for agricultural diversification.

Evidence based crop diversification requires modelling for crops that are currently neglected or underutilised. Crop model calibration is a lengthy and resource consuming effort that is typically done for a particular variety or a set of varieties of a crop. Whilst calibration data are widely available for major crops, such data are rarely available for underutilised crops due to limited funding for detailed field data collection and model calibration. Subsequently, the lack of evidence on their performance will lead to the lack of interest from the policy and regulatory communities to include these crops in the agricultural development plans. In order to motivate further research into the use of state of the art techniques in modelling for less known crops, we have developed and validated an ideotyping technique that approximates the crop modelling parameters based on already calibrated crops of different lineage. The method has been successfully tested for hemp (Cannabis sativa L.) based on a well-known crop model. In this paper we present the method and provide an impetus on the way forward to further develop such methods for modelling the performance of minor crops and their varieties.•The approach works based on modelling the performance of hemp using the knowledge from an existing model that was developed for sugar cane.•The customisation uses one of the most prominent models (AquaCrop) to approximate growth coefficients for hemp (Cannabis sativa L.).•A sequential procedure was used to approximate the phenological stages in the growth model that performs well in the calibration and validation steps.