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Zymoseptoria tritici is the most economically significant fungal pathogen of wheat in Europe. However, despite the importance of this pathogen, the molecular interactions between pathogen and host during infection are not well understood. Herein, we describe the use of two libraries of cloned Z. tritici effectors that were screened to identify effector candidates with putative pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI)-suppressing activity. The effectors from each library were transiently expressed in Nicotiana benthamiana, and expressing leaves were treated with bacterial or fungal PAMPs to assess the effectors ability to suppress reactive oxygen species (ROS) production. From these screens, numerous effectors were identified with PTI-suppressing activity. In addition, some effectors were able to suppress cell death responses induced by other Z. tritici secreted proteins. We used structural prediction tools to predict the putative structures of all of the Z. tritici effectors and used these predictions to examine whether there was enrichment of specific structural signatures among the PTI-suppressing effectors. From among the libraries, multiple members of the killer protein-like 4 (KP4) and killer protein-like 6 (KP6) effector families were identified as PTI suppressors. This observation is intriguing, as these protein families were previously associated with antimicrobial activity rather than virulence or host manipulation. This data provides mechanistic insight into immune suppression by Z. tritici during infection and suggests that, similar to biotrophic pathogens, this fungus relies on a battery of secreted effectors to suppress host immunity during early phases of colonization.

Abstract Background Inappropriate prescribing (IP) is common in hospitalised older adults with frailty. However, it is not known whether the presence of frailty confers an increased risk of mortality and readmissions from IP nor whether rectifying IP reduces this risk. This review was conducted to determine whether IP increases the risk of adverse outcomes in hospitalised middle-aged and older adults with frailty. Methods A systematic review was conducted on IP in hospitalised middle-aged (45–64 years) and older adults (≥ 65 years) with frailty. This review considered multiple types of IP including potentially inappropriate medicines, prescribing omissions and drug interactions. Both observational and interventional studies were included. The outcomes were mortality and hospital readmissions. The databases searched included MEDLINE, CINAHL, EMBASE, World of Science, SCOPUS and the Cochrane Library. The search was updated to 12 July 2024. Meta-analysis was performed to pool risk estimates using the random effects model. Results A total of 569 studies were identified and seven met the inclusion criteria, all focused on the older population. One of the five observational studies found an association between IP and emergency department visits and readmissions at specific time points. Three of the observational studies were amenable to meta-analysis which showed no significant association between IP and hospital readmissions (OR 1.08, 95% CI 0.90–1.31). Meta-analysis of the subgroup assessing Beers criteria medicines demonstrated that there was a 27% increase in the risk of hospital readmissions (OR 1.27, 95% CI 1.03–1.57) with this type of IP. In meta-analysis of the two interventional studies, there was a 37% reduced risk of mortality (OR 0.63, 95% CI 0.40-1.00) with interventions that reduced IP compared to usual care but no difference in hospital readmissions (OR 0.83, 95% CI 0.19–3.67). Conclusions Interventions to reduce IP were associated with reduced risk of mortality, but not readmissions, compared to usual care in older adults with frailty. The use of Beers criteria medicines was associated with hospital readmissions in this group. However, there was limited evidence of an association between IP more broadly and mortality or hospital readmissions. Further high-quality studies are needed to confirm these findings.

Abstract Background and Objective Multimorbidity is common in hospitalised adults who are at increased risk of inappropriate prescribing including drug–disease interactions. These interactions occur when a medicine being used to treat one condition exacerbates a concurrent medical condition and may lead to adverse health outcomes. The aim of this review was to examine the association between drug–disease interactions and the risk of mortality and readmission in hospitalised middle-aged and older adults. Methods A systematic review was conducted on drug–disease interactions in hospitalised middle-aged (45–64 years) and older adults (≥65 years). The study protocol was prospectively registered with PROSPERO (Registration Number: CRD42022341998). Drug–disease interactions were defined as a medicine being used to treat one condition with the potential to exacerbate a concurrent medical condition or that were inappropriate based on a comorbid medical condition. Both observational and interventional studies were included. The outcomes of interest were mortality and readmissions. The databases searched included MEDLINE, CINAHL, EMBASE, Web of Science, SCOPUS and the Cochrane Library from inception to 12 July, 2022. A meta-analysis was performed to pool risk estimates using the random-effects model. Results A total of 563 studies were identified and four met the inclusion criteria. All were observational studies in older adults, with no studies identified in middle-aged adults. Most of the studies were at risk of bias because of an inadequate adjustment for covariates and a lack of clarity around individuals lost to follow-up. There were various definitions of drug–disease interactions within these four studies. Two studies assessed drugs that were contraindicated based on renal function, one assessed an individual drug–disease combination, and one was based on the clinical judgement of a pharmacist. There were two studies that showed an association between drug–disease interactions and the outcomes of interest. One reported that the use of diltiazem in patients with heart failure was associated with an increased risk of readmissions. The second reported that the use of medicines contraindicated according to renal function were associated with increased risk of all-cause mortality and a composite of mortality and readmission. Three of the studies (total study population = 5705) were amenable to a meta-analysis, which showed no significant association between drug–disease interactions and readmissions (odds ratio = 1.0, 95% confidence interval 0.80–1.38). Conclusions Few studies were identified examining the risk of drug–disease interactions and mortality and readmission in hospitalised adults. Most of the identified studies were at risk of bias. There is no universal accepted definition of drug–disease interactions in the literature. Further studies are needed to develop a standardised and accepted definition of these interactions to guide further research in this area.

Ruthless Times: Songs of Care /Armotonta menoa – Hoivatyön laulujaan (Helke 2002) is an acclaimed musical documentary about the privatization of elderly care. I explore how the film was framed by the director Susanna Helke, in written articles and in an interview, as artistic research, and consider how this research engages with the question of knowledge production in terms of the director’s stated aims and reference points, particularly Bertolt Brecht and Jacques Rancière. I analyse to what extent, as Helke suggests, it can be seen as creating a “rupture”, in Rancière’s sense, in relation to previous documentary forms and languages. I argue that while the film faces some of the same issues that critical art often confronts in terms of spectator address, its process of working with its topic and its participants nonetheless embodies a progressive model of feminist witnessing.

Abstract Hypoxia is mainly caused by cardiopulmonary disease or high‐altitude exposure. We used a driving simulator to investigate whether breathing hypoxic gas influences driving behaviors in healthy subjects. Fifty‐two healthy subjects were recruited in this study, approved by the Science and Engineering Ethical Committee. During simulated driving experiments, driving behaviors, breathing frequency, oxygen saturation (SpO2), and heart rate variability (HRV) were analyzed. Each subject had four driving sessions; a 10‐min practice and three 20‐min randomized interventions: normoxic room air (21% FIO2) and medical air (21% FIO2) and hypoxic air (equal to 15% FIO2), analyzed by repeated measures ANOVA. Driving behaviors and HRV frequency domains showed no significant change. Heart rate (HR; p

Abstract Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.

Background. Local health services make limited use of economic evaluation to inform decisions to fund new health service interventions. One barrier is the relevance of published intervention effects to the local setting, given these effects can strongly reflect the original evaluation context. Expert elicitation methods provide a structured approach to explicitly and transparently adjust published effect estimates, which can then be used in local-level economic evaluations to increase their local relevance. Expert elicitation was used to adjust published effect estimates for 2 interventions targeting the prevention of inpatient hypoglycemia. Methods. Elicitation was undertaken with 6 clinical experts. They were systematically presented with information regarding potential differences in patient characteristics and quality of care between the published study and local contexts, and regarding the design and application of the published study. The experts then assessed the intervention effects and provided estimates of the most realistic, most pessimistic, and most optimistic intervention effect sizes in the local context. Results. The experts estimated both interventions would be less effective in the local setting compared with the published effect estimates. For one intervention, the experts expected the lower complexity of admitted patients in the local setting would reduce the intervention’s effectiveness. For the other intervention, the reduced effect was largely driven by differences in the scope of implementation (hospital-wide in the local setting compared with targeted implementation in the evaluation). Conclusions. The pragmatic elicitation methods reported in this article provide a feasible and acceptable approach to assess and adjust published intervention effects to better reflect expected effects in the local context. Further development and application of these methods is proposed to facilitate the use of local-level economic evaluation. Highlights Local health services make limited use of economic evaluation to inform their decisions on the funding of new health service interventions. One barrier to use is the relevance of published intervention evaluations to the local setting. Expert elicitation methods provide a structured way to consider differences between the evaluation and local settings and to explicitly and transparently adjust published effect estimates for use in local economic evaluations. The pragmatic elicitation methods reported in this article offer a feasible and acceptable approach to adjusting published intervention effects to better reflect the effects expected in the local context. This increases the relevance of economic evaluations for local decision makers.

Abstract Background Maximal inspiratory pressure (MIP) is currently the most commonly used measure for respiratory muscle strength (RMS) estimation, however, requires significant effort. Falsely low values are therefore common, especially in fatigue-prone subjects, such as neuromuscular disorder patients. In contrast, sniff nasal inspiratory pressure (SNIP) requires a short, sharp sniff; this is a natural manoeuvre, decreasing required effort. Consequently, it has been suggested that use of SNIP could confirm the accuracy of MIP measurements. However, no recent guidelines regarding the optimal method of SNIP measurement exist, and varied approaches have been described. Objectives We compared SNIP values from three conditions, namely with 30, 60 or 90 s time intervals between repeats, the right (SNIPR) and left (SNIPL) nostril, and the contralateral nostril occluded (SNIPO) or non-occluded (SNIPNO). Additionally, we determined the optimal number of repeats for accurate SNIP measurement. Method 52 healthy subjects (23 males) were recruited for this study, of which a subset of 10 subjects (5 males) completed tests comparing the time interval between repeats. SNIP was measured from functional residual capacity via a probe in one nostril, while MIP was measured from residual volume. Results There was no significant difference in SNIP depending on the interval between repeats (P = 0.98); subjects preferred the 30 s. SNIPO was significantly higher than SNIPNO (P

BackgroundSelf-harm is complex, multifaceted, and dynamic, typically starts in adolescence, and is prevalent in young people. A novel research tool (the Card Sort Task for Self-harm; CaTS) offers a systematic approach to understanding this complexity by charting the dynamic interplay between multidimensional factors in the build-up to self-harm. Sequential analysis of CaTS has revealed differences in key factors between the first and the most recent episode of self-harm in adolescence. Rates of self-harm typically decline post-adolescence, but self-harm can continue into adulthood. A comparison between factors linked to self-harm in young people vs. adults will inform an understanding of how risk unfolds over time and clarify age-specific points for intervention. A pilot online adaptation (CaTS-online) and a new method (Indicator Wave Analysis; IWA) were used to assess key factors in the build-up to self-harm.MethodsCommunity-based young people (n = 66; 18–25 years, M = 21.4; SD = 1.8) and adults (n = 43; 26–57 years, M = 35; SD = 8.8) completed CaTS-online, documenting thoughts, feelings, events, and behaviours over a 6-month timeline for the first ever and most recent self-harm. A notable interdependence between factors and time points was identified using IWA.ResultsPositive emotion at and immediately after self-harm exceeded the threshold for both groups for both episodes. Feeling better following self-harm was more pronounced for the first-ever episodes. Impulsivity was an important immediate antecedent to self-harm for both groups at both episodes but most markedly for young people. Acquired capability was notable for adults’ most recent episodes, suggesting this develops over time. Burdensomeness was only more notable for adults and occurred 1 week prior to a recent episode. Both groups revealed patterns of accessing support that were helpful and unhelpful.ConclusionCommonalities and differences in the temporal organisation of factors leading to and following self-harm were identified in young people and adult pathways which shed light on age-specific factors and possible points of intervention. This has implications for clinical support and services around approaches to positive feelings after self-harm (especially for first-ever self-harm), feeling of burdensomeness, impulsivity, and acquired capability leading up to self-harm. Support is provided for card-sort approaches that enable the investigation of the complex and dynamic nature of pathways to self-harm.

Abstract Background The goal of the Global Health in Preconception, Pregnancy and Postpartum (HiPPP) Alliance, comprising consumers and leading international multidisciplinary academics and clinicians, is to generate research and translation priorities and build international collaboration around healthy lifestyle and obesity prevention among women across the reproductive years. In doing so, we actively seek to involve consumers in research, implementation and translation initiatives. There are limited frameworks specifically designed to involve women across the key obesity prevention windows before (preconception), during and after pregnancy (postpartum). The aim of this paper is to outline our strategy for the development of the HiPPP Consumer and Community (CCI) Framework, with consumers as central to co-designed, co-implemented and co-disseminated research and translation. Method The development of the framework involved three phases: In Phase 1, 21 Global HiPPP Alliance members participated in a CCI workshop to propose and discuss values and approaches for framework development; Phase 2 comprised a search of peer-reviewed and grey literature for existing CCI frameworks and resources; and Phase 3 entailed collaboration with consumers (i.e., members of the public with lived experience of weight/lifestyle issues in preconception, pregnancy and postpartum) and international CCI experts to workshop and refine the HiPPP CCI Framework (guided by Phases 1 and 2). Results The HiPPP CCI Framework’s values and approaches identified in Phases 1–2 and further refined in Phase 3 were summarized under the following five key principles: 1. Inclusive, 2. Flexible, 3. Transparent, 4. Equitable, and 5. Adaptable. The HiPPP Framework describes values and approaches for involving consumers in research initiatives from design to translation that focus on improving healthy lifestyles and preventing obesity specifically before, during and after pregnancy; importantly it takes into consideration common barriers to partnering in obesity research during perinatal life stages, such as limited availability associated with family caregiving responsibilities. Conclusion The HiPPP CCI Framework aims to describe approaches for implementing meaningful CCI initiatives with women in preconception, pregnancy and postpartum periods. Evaluation of the framework is now needed to understand how effective it is in facilitating meaningful involvement for consumers, researchers and clinicians, and its impact on research to improve healthy lifestyle outcomes.

An editorial is presented on the evolution of type 2 diabetes management over 32 years, and it highlights the impact of an aging population on healthcare systems. It reports that advancements in diabetes pathophysiology and trials have led to new drugs with cardiovascular, renal, and heart failure benefits. It emphasizes the challenges, like multimorbidity and polypharmacy, and it reports the importance of individualized management.

A reverse genetics approach was used to investigate the role of γ-aminobutyric acid metabolism in the wheat pathogenic fungus Stagonospora nodorum. The creation of mutants lacking Sdh1, the gene encoding succinic semialdehyde dehydrogenase, resulted in strains that grew poorly on γ-aminobutyric acid as a nitrogen source. The sdh1 mutants were more susceptible to reactive oxygen stress but were less affected by increased growth temperatures. Pathogenicity assays revealed that the metabolism of γ-aminobutyric acid is required for complete pathogenicity. Growth assays of the wild-type and mutant strains showed that the inclusion of γ-aminobutyric acid as a supplement in minimal media (i.e., not as a nitrogen or carbon source) resulted in restricted growth but increased sporulation. The addition of glutamate, the precursor to GABA, had no effect on either growth or sporulation. The γ-aminobutyric acid effect on sporulation was found to be dose dependent and not restricted to Stagonospora nodorum with a similar effect observed in the dothideomycete Botryosphaeria sp. The positive effect on sporulation was assayed using isomers of γ-aminobutyric acid and other metabolites known to influence asexual development in Stagonospora nodorum but no effect was observed. These data demonstrate that γ-aminobutyric acid plays an important role in Stagonospora nodorum in responding to environmental stresses while also having a positive effect on asexual development.

Traditional treatment options for type 2 diabetes mellitus (T2DM) target the primary pathophysiological defects of increased insulin resistance, hepatic glucose overproduction and progressive pancreatic beta-cell dysfunction. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the newest class of medication for T2DM and provide an alternative, insulin-independent, pathway for addressing hyperglycaemia, by reducing renal glucose reabsorption. SGLT2 inhibitors are associated with a low risk of hypoglycaemia and recent trials have indicated, for empagliflozin at least, reductions in cardiovascular morbidity and mortality and a slower progression of kidney disease. These characteristics make SGLT2 inhibitors attractive second-line agents. Adverse effects include an increased risk of genitourinary tract infections, hypotension, fractures and acute renal impairment. Common events in hospitalised older patients, such as volume depletion, indwelling catheter use, potential renal insults (e.g. aminoglycosides or intravenous contrast administration) and unpredictable haemodynamics, may exacerbate these adverse effects, suggesting SGLT2 inhibitors may be best avoided in this setting. Clinical heterogeneity of the older patient cohort calls for individualised management. As there is a lack of evidence to guide diabetes management in older people, this review aims to summarise the available evidence from clinical trials and meta-analyses and provide a practical perspective on how best to use SGLT2 inhibitors in older patients. [ABSTRACT FROM AUTHOR]

This synthesis concludes this Special Issue (II) by revisiting and extending the synthesis which concluded Special Issue (I) in December 2015. The focus is again on instrument-action alignments in governance in terms of their nature, pervasiveness and warranting. Of particular interest are inherent challenges of diversity, interconnection and responsibility which require appreciative, integrative and legitimation capacities. These challenges and capacities, involving their form, significance and intertwining, are central to the thematic interests and concerns of the Special Issues. [ABSTRACT FROM AUTHOR]

This synthesis begins with propositions concerning instrument-action alignments in governance which underpin the Special Issue and companion Special Issue in March 2016. Thereafter, instrument choices and efficacy are considered with reference to how the alignments are crafted, as influenced by their nature, pervasiveness and warranting. An appreciation of these matters assists in understanding important thematic interests and concerns of the Special Issues. [ABSTRACT FROM AUTHOR]

The symposium is introduced here as heralding the beginning of a new era for the journal. Significant aspects of public administration are addressed concerning power as its lifeblood and basis of its institutional-organisational configurations, roles, responsibilities, control and legitimacy. The discussion of these matters sets the scene for the analyses in the following articles. [ABSTRACT FROM AUTHOR]