Editorial: Advances in breeding for wheat disease resistance

Wheat is the most widely planted crop on the planet and contributes up to 20% of total calorie intake for humankind. Maintaining wheat yields is crucial to feeding the world’s people, especially as climate models suggest that rising global temperatures will negatively affect wheat production (Asseng et al., 2015). Diseases of wheat take an important toll, annually robbing humanity of 20% or more of the crop on a global basis (Savary et al., 2019; Savary and Willocquet, 2021). Changes in weather patterns may accelerate pathogen life cycles and escalate shifts in pathogen populations and virulence, posing significant challenges to disease resistance breeding. As well, global trade may increase the chances for a pathogen to spread rapidly and adapt to novel environments and even hosts, leading to emerging diseases. The release and use of wheat cultivars with effective and durable disease resistance is more important now than ever. This is so for multiple reasons. First, disease resistance stabilizes yields and reduces economic losses, saving money for producers who are already facing major challenges due to rising temperatures, more frequent and unpredictable natural disasters, and high and rising costs of inputs such as pesticides (FAO, 2021; Lüttringhaus et al., 2021; Miedaner and Juroszek, 2021). Second, greater reliance on disease resistance can slow pathogen spread and multiplication, prolonging the useful life of available pesticide chemistries so they will be effective when needed to manage severe epidemics (Brent et al., 2007). Third, the growing use of conservation tillage, which is vital for soil health and stabilization, has elevated the importance of diseases such as Fusarium head blight that cannot be completely managed with fungicides (Aboukhaddour et al., 2020). Breeding for disease resistance in wheat has made major technological advances, but still faces important challenges. Prominent among those challenges is the need to develop cultivars for a tremendous diversity of agro-ecological environments, production practices, and discrete market classes (Cowger, 2021). Another challenge is that major genes such as those traditionally deployed to manage wheat rust diseases are often rapidly overcome. This requires a focus on quantitative and race non-specific resistance that may be harder to introgress, select for, and retain in a multi-trait context (Cowger and Brown, 2019; van Esse et al., 2020). The more genes are identified and their mechanisms of action elucidated, the more tools will be available to researchers and breeders to assemble genetically novel germplasm with improved and more durable resistance. The authors who have contributed to this Research Topic tackle those challenges by providing new resources and tools to aid wheat breeders across the globe. The 18 original articles cover a good sample of the world’s most important wheat diseases and the state-of-the-art techniques applied by researchers to identify and evaluate the relevant disease resistance traits. For example, wheat blast is an emergent and damaging disease that has jumped continents from Latin America to Asia, as explained in a comprehensive review by Singh et al., 2021. A team of blast researchers has compared marker-assisted and genomic selection using precision phenotyping of blast resistance conferred by the 2NS translocation (Juliana et al., 2022), which is partial and sometimes background-dependent. Another major threat to global wheat production is Fusarium head blight. Three articles in this Research Topic offer important new resources for breeding cultivars with effective FHB resistance. The Brazilian spring cultivar Surpresa provides a new source of resistance not currently used (Poudel et al. 2022). Three resistance loci (Fhb1, Fhb4, and Fhb5) were introgressed as a pyramid into desirable Chinese white and red semi-winter wheat lines (Zhang et al., 2021). And a novel technique could speed up the development of FHB-resistant winter wheat germplasm, increasing breeding generations from two to three per year (Zakieh et al. 2021). Researchers used various approaches to identify new sources of resistance to the three wheat rusts (stem, stripe, and leaf). A new stem rust resistance gene was mapped in the durum wheat variety Kronos and introgressed into common wheat using co-segregating DNA markers (Li et al., 2021). The effects of combinations of leaf rust resistance genes were investigated in a Canadian wheat double-haploid population (McCallum and Hiebert, 2022) and in a durably resistant Canadian wheat cultivar (Bokore et al., 2022). A multi-parent advanced generation intercross (MAGIC) wheat population was used to map adult-plant and seedling resistance to stripe rust in Germany (Rollar et al., 2021). A genome-wide association study was used to identify stripe rust resistance loci in a panel of Chinese wheat landraces (Yao et al., 2021). And QTL mapping led to identification of stripe and leaf rust loci in an Afghan landrace (Zhang et al., 2022), a Chinese landrace (Wang et al., 2022), and the CIMMYT wheat line “Mucuy” (Lan et al., 2022; so far this is an abstract, need the URL to the full article when it’s available). Breeding wheat cultivars with resistance to powdery mildew requires a constant stream of new resistance sources, thanks to the pathogen’s ability to rapidly overcome host resistance through adaptation. The efficacy of a set of new resistance genes introgressed from Middle Eastern wild wheat relatives was measured using powdery mildew populations from various wheat growing regions affected by the disease (Kloppe et al., 2022). A more unusual wild relative of wheat, Psathyrostachys huashanica, which is found only in the Huashan Mountains of China, also furnished novel resistance to wheat powdery mildew (Liu et al., 2021). A previously unidentified source of resistance to Hessian fly was identified in spring wheat cultivars of the U.S. Pacific Northwest (Prather et al., 2022). And in a twist, a locus conferring not resistance but susceptibility, in this case to tan spot, was identified in U.S. bi-parental spring wheat mapping populations and narrowed to a region encompassing seven candidate genes (Running et al., 2022). Last but not least, an interesting look under the ground revealed that rhizosphere microbiomes differed among wheat genotypes and had an impact on pathogenicity of Rhizoctonia solani, suggesting the potential to manage Rhizoctonia root rot with wheat genotypes that recruit microbiomes associated with improved plant fitness and suppression of the fungal pathogen (Dilla-Ermita et al., 2021). For this Research Topic, we have collected articles that demonstrate how cutting-edge approaches to breeding are being brought to bear on some of the chief diseases threatening the world’s wheat production systems. The authors’ contributions are of the highest quality, and illustrate the strong international interest in this topic. These reports help breeders everywhere assess and employ novel and potentially durable resistance to wheat diseases. They will make a practical difference in helping safeguard global wheat yields in the challenging years to come

Protective effects of carbonic anhydrase inhibition in brain ischaemia in vitro and in vivo models

Ischaemic stroke is a leading cause of death and disability. One of the major pathogenic mechanisms after ischaemia includes the switch to the glycolytic pathway, leading to tissue acidification. Carbonic anhydrase (CA) contributes to pH regulation. A new generation of CA inhibitors, AN11-740 and AN6-277 and the reference compound acetazolamide (ACTZ) were investigated in two models of brain ischaemia: in rat hippocampal acute slices exposed to severe oxygen, glucose deprivation (OGD) and in an in vivo model of focal cerebral ischaemia induced by permanent occlusion of the middle cerebral artery (pMCAo) in the rat. In vitro, the application of selective CAIs significantly delayed the appearance of anoxic depolarisation induced by OGD. In vivo, sub-chronic systemic treatment with AN11-740 and ACTZ significantly reduced the neurological deficit and decreased the infarct volume after pMCAo. CAIs counteracted neuronal loss, reduced microglia activation and partially counteracted astrocytes degeneration inducing protection from functional and tissue damage

Multicentre translational Trial of Remote Ischaemic Conditioning in Acute Ischaemic Stroke (TRICS): Protocol of multicentre, parallel group, randomised, preclinical trial in female and male rat and mouse from the Italian Stroke Organization (ISO) Basic Science network

INTRODUCTION: Multicentre preclinical randomised controlled trials (pRCT) are emerging as a necessary step to confirm efficacy and improve translation into the clinic. The aim of this project is to perform two multicentre pRCTs (one in rats and one in mice) to investigate the efficacy of remote ischaemic conditioning (RIC) in an experimental model of severe ischaemic stroke. METHODS AND ANALYSIS: Seven research laboratories within the Italian Stroke Organization (ISO) Basic Science network will participate in the study. Transient endovascular occlusion of the proximal right middle cerebral artery will be performed in two species (rats and mice) and in both sexes. Animals will be randomised to receive RIC by transient surgical occlusion of the right femoral artery, or sham surgery, after reperfusion. Blinded outcome assessment will be performed for dichotomised functional neuroscore (primary endpoint) and infarct volume (secondary endpoint) at 48 hours. A sample size of 80 animals per species will yield 82% power to detect a significant difference of 30% in the primary outcome in both pRCTs. Analyses will be performed in a blind status and according to an intention-to-treat paradigm. The results of this study will provide robust, translationally oriented, high-quality evidence on the efficacy of RIC in multiple species of rodents with large ischaemic stroke. ETHICS AND DISSEMINATION: This is approved by the Animal Welfare Regulatory Body of the University of Milano Bicocca, under project license from the Italian Ministry of Health. Trial results will be subject to publication according to the definition of the outcome presented in this protocol. TRIAL REGISTRATION NUMBER: PCTE0000177

How can advance care planning support hope in patients with advanced cancer and their families: a qualitative study as part of the international ACTION trial

Objective Clinicians' fears of taking away patients' hope is one of the barriers to advance care planning (ACP). Research on how ACP supports hope is scarce. We have taken up the challenge to specify ways in which ACP conversations may potentially support hope. Methods In an international qualitative study, we explored ACP experiences of patients with advanced cancer and their personal representatives (PRs) within the cluster-randomised control ACTION trial. Using deductive analysis of data obtained in interviews following the ACP conversations, this substudy reports on a theme of hope. A latent thematic analysis was performed on segments of text relevant to answer the research question. Results Twenty patients with advanced cancer and 17 PRs from Italy, the Netherlands, Slovenia, and the United Kingdom were participating in post-ACP interviews. Three themes reflecting elements that provide grounds for hope were constructed. ACP potentially supports hope by being (I) a meaningful activity that embraces uncertainties and difficulties; (II) an action towards an aware and empowered position; (III) an act of mutual care anchored in commitments. Conclusion Our findings on various potentially hope supporting elements of ACP conversations provide a constructive way of thinking about hope in relation to ACP that could inform practice

Advance care planning in patients with advanced cancer: A 6-country, cluster-randomised clinical trial

Background Advance care planning (ACP) supports individuals to define, discuss, and record goals and preferences for future medical treatment and care. Despite being internationally recommended, randomised clinical trials of ACP in patients with advanced cancer are scarce. Methods and findings To test the implementation of ACP in patients with advanced cancer, we conducted a cluster-randomised trial in 23 hospitals across Belgium, Denmark, Italy, Netherlands, Slovenia, and United Kingdom in 2015–2018. Patients with advanced lung (stage III/IV) or colorectal (stage IV) cancer, WHO performance status 0–3, and at least 3 months life expectancy were eligible. The ACTION Respecting Choices ACP intervention as offered to patients in the intervention arm included scripted ACP conversations between patients, family members, and certified facilitators; standardised leaflets; and standardised advance directives. Control patients received care as usual. Main outcome measures were quality of life (operationalised as European Organisation for Research and Treatment of Cancer [EORTC] emotional functioning) and symptoms. Secondary outcomes were coping, patient satisfaction, shared decision-making, patient involvement in decision-making, inclusion of advance directives (ADs) in hospital files, and use of hospital care. In all, 1,117 patients were included (442 intervention; 675 control), and 809 (72%) completed the 12-week questionnaire. Patients’ age ranged from 18 to 91 years, with a mean of 66; 39% were female. The mean number of ACP conversations per patient was 1.3. Fidelity was 86%. Sixteen percent of patients found ACP conversations distressing. Mean change in patients’ quality of life did not differ between intervention and control groups (T-score −1.8 versus −0.8, p = 0.59), nor did changes in symptoms, coping, patient satisfaction, and shared decision-making. Specialist palliative care (37% versus 27%, p = 0.002) and AD inclusion in hospital files (10% versus 3%, p < 0.001) were more likely in the intervention group. A key limitation of the study is that recruitment rates were lower in intervention than in control hospitals. Conclusions Our results show that quality of life effects were not different between patients who had ACP conversations and those who received usual care. The increased use of specialist palliative care and AD inclusion in hospital files of intervention patients is meaningful and requires further study. Our findings suggest that alternative approaches to support patient-centred end-of-life care in this population are needed

Advance care planning, a multi-centre cluster randomised clinical trial: the research protocol of the ACTION study

Background: Awareness of preferences regarding medical care should be a central component of the care of patients with advanced cancer. Open communication can facilitate this but can occur in an ad hoc or variable manner. Advance care planning (ACP) is a formalized process of communication between patients, relatives and professional caregivers about patients’ values and care preferences. It raises awareness of the need to anticipate possible future deterioration of health. ACP has the potential to improve current and future healthcare decision making, provide patients with a sense of control, and improve their quality of life. Methods/Design: We will study the effects of the ACP program Respecting Choices on the quality of life of patients with advanced lung or colorectal cancer. In a phase III multicenter cluster randomised controlled trial, 22 hospitals in 6 countries will be randomised. In the intervention sites, patients will be offered interviews with a trained facilitator. In the control sites, patients will receive care as usual. In total, 1360 patients will be included. All participating patients will be asked to complete questionnaires at inclusion, and again after 2.5 and 4.5 months. If a patient dies within a year after inclusion, a relative will be asked to complete a questionnaire on end-of-life care. Use of medical care will be assessed by checking medical files. The primary endpoint is patients’ quality of life at 2.5 months ost-inclusion. Secondary endpoints are the extent to which care as received is aligned with patients’ preferences, patients’ evaluation of decision-making processes, quality of end-of-life care and cost-effectiveness of the intervention. A complementary qualitative study will be carried out to explore the lived experience of engagement with the Respecting Choices program from the perspectives of patients, their Personal Representatives, healthcare providers and facilitators. Discussion: Transferring the concept of ACP from care of the elderly to patients with advanced cancer, who on average are younger and retain their mental capacity for a larger part of their disease trajectory, is an important next step in an era of increased focus on patient centered healthcare and shared decision-making. Trial registration: International Standard Randomised Controlled Trial Number: ISRCTN63110516. Date of registration: 10/3/2014. Keywords: Advance care planning, Oncology, Quality of life, Medical decision-makin

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

Trained facilitators’ experiences with structured advance care planning conversations in oncology : an international focus group study within the ACTION trial

Background In oncology, Health Care Professionals often experience conducting Advance Care Planning (ACP) conversations as difficult and are hesitant to start them. A structured approach could help to overcome this. In the ACTION trial, a Phase III multi-center cluster-randomized clinical trial in six European countries (Belgium, Denmark, Italy, the Netherlands, Slovenia, United Kingdom), patients with advanced lung or colorectal cancer are invited to have one or two structured ACP conversations with a trained facilitator. It is unclear how trained facilitators experience conducting structured ACP conversations. This study aims to understand how facilitators experience delivering the ACTION Respecting Choices (RC) ACP conversation. Methods A qualitative study involving focus groups with RC facilitators. Focus group interviews were recorded, transcribed, anonymized, translated into English, and thematically analysed, supported by NVivo 11. The international research team was involved in data analysis from initial coding and discussion towards final themes. Results Seven focus groups were conducted, involving 28 of in total 39 trained facilitators, with different professional backgrounds from all participating countries. Alongside some cultural differences, six themes were identified. These reflect that most facilitators welcomed the opportunity to participate in the ACTION trial, seeing it as a means of learning new skills in an important area. The RC script was seen as supportive to ask questions, including those perceived as difficult to ask, but was also experienced as a barrier to a spontaneous conversation. Facilitators noticed that most patients were positive about their ACTION RC ACP conversation, which had prompted them to become aware of their wishes and to share these with others. The facilitators observed that it took patients substantial effort to have these conversations. In response, facilitators took responsibility for enabling patients to experience a conversation from which they could benefit. Facilitators emphasized the need for training, support and advanced communication skills to be able to work with the script. Conclusions Facilitators experienced benefits and challenges in conducting scripted ACP conversations. They mentioned the importance of being skilled and experienced in carrying out ACP conversations in order to be able to explore the patients’ preferences while staying attuned to patients’ needs