Validation of an automated, end-to-end metagenomic sequencing assay for agnostic detection of respiratory viruses.

BACKGROUND: Current molecular diagnostics are limited in the number and type of detectable pathogens. Metagenomic next generation sequencing (mNGS) is an emerging, and increasingly feasible, pathogen-agnostic diagnostic approach. Translational barriers prohibit the widespread adoption of this technology in clinical laboratories. We validate an end-to-end mNGS assay for detection of respiratory viruses. Our assay is optimized to reduce turnaround time, lower cost-per-sample, increase throughput, and deploy secure and actionable bioinformatic results. METHODS: We validated our assay using residual nasopharyngeal swab specimens from Vancouver General Hospital (n = 359), RT-PCR-positive, or negative for Influenza, SARS-CoV-2, and RSV. We quantified sample stability, assay precision, the effect of background nucleic acid levels, and analytical limits of detection. Diagnostic performance metrics were estimated. RESULTS: We report that our mNGS assay is highly precise, semi-quantitative, with analytical limits of detection ranging from 103-104 copies/mL. Our assay is highly specific (100%) and sensitive (61.9% Overall: 86.8%; RT-PCR Ct < 30). Multiplexing capabilities enable processing of up to 55-specimens simultaneously on an Oxford Nanopore GridION device, with results reported within 12-hours. CONCLUSIONS: This study outlines the diagnostic performance and feasibility of mNGS for respiratory viral diagnostics, infection control, and public health surveillance. We addressed translational barriers to widespread mNGS adoption.

Socio-economic inequalities in the breadth of internet use before and during the COVID-19 pandemic among older adults in England.

Understanding digital exclusion in older adults during the COVID-19 pandemic could help tailor responses to future outbreaks. This cohort study used data from older adults aged 60+ years in England who participated in wave nine (2018/2019) of the main English Longitudinal Study of Ageing (ELSA) survey, and/or wave one of the ELSA COVID-19 sub-study (June/July 2020). Using latent class analysis and latent transition analysis, we aimed to identify distinct subgroups of older adults characterised by different patterns of internet use pre- and intra-pandemic, explore the extent to which individuals remained in the same subgroup or transitioned to a different subgroup during the COVID-19 pandemic, and examine longitudinal associations of socio-economic factors (education, occupational class, and wealth) with latent class membership. Preliminary tests showed that the types of internet activities differed between men and women; therefore, subsequent analyses were stratified by biological sex. Three clusters (low, medium, and high) were identified in male participants at both timepoints. Among female participants, three clusters were distinguished pre-pandemic and two (low versus high) during the pandemic. The latent classes were characterised by participants' breadth of internet use. Higher education, occupational class, and wealth were associated with greater odds of membership in the medium and/or high classes, versus the low class, in men and women. A high degree of stability in latent class membership was observed over time. However, men experienced a stark decrease in online health information-seeking. Our results highlight that inequality regarding the range of functional and social opportunities provided by the internet prevailed during the pandemic. Policymakers should ensure that digital access and upskilling initiatives are equitable for all.

Hypoxic pulmonary vasoconstriction does not limit maximal exercise capacity in healthy volunteers breathing 12% oxygen at sea level.

Maximal exercise capacity is reduced at altitude or during hypoxia at sea level. It has been suggested that this might reflect increased right ventricular afterload due to hypoxic pulmonary vasoconstriction. We have shown previously that the pulmonary vascular sensitivity to hypoxia is enhanced by sustained isocapnic hypoxia, and inhibited by intravenous iron. In this study, we tested the hypothesis that elevated pulmonary artery pressure contributes to exercise limitation during acute hypoxia. Twelve healthy volunteers performed incremental exercise tests to exhaustion breathing 12% oxygen, before and after sustained (8-h) isocapnic hypoxia at sea level. Intravenous iron sucrose (n = 6) or saline placebo (n = 6) was administered immediately before the sustained hypoxia. In the placebo group, there was a substantial (12.6 ± 1.5 mmHg) rise in systolic pulmonary artery pressure (SPAP) during sustained hypoxia, but no associated fall in maximal exercise capacity breathing 12% oxygen. In the iron group, the rise in SPAP during sustained hypoxia was markedly reduced (3.4 ± 1.0 mmHg). There was a small rise in maximal exercise capacity following sustained hypoxia within the iron group, but no overall effect of iron, compared with saline. These results do not support the hypothesis that elevated SPAP inhibits maximal exercise capacity during acute hypoxia in healthy volunteers.

Searching new targets for the control of Black Rot: following the role of host factors modulating the infection process of Phyllosticta ampelicida.

Black Rot is a grapevine disease caused by the ascomycete Phyllosticta ampelicida. Neglected so far, this is developing into a pertinent problem in organic viticulture as resistant varieties are still lacking. Here, we follow cellular details of the infection process in the susceptible vinifera variety Müller-Thurgau and screen the ancestral European wild grapevine (V. vinifera sylvestris) for resistance to Black Rot. Using a standardized infection assay, we follow fungal development using LTSEM and quantify key stages on different hosts using fluorescence microscopy. There is considerable variation in susceptibility, which is associated with more rapid leaf maturation. Hyphal growth on different carbon sources shows a preference for pectins over starch, cellulose or xylans. In the resistant sylvestris genotypes Ketsch 16 and Ketsch 18 we find that neither spore attachment nor appressorium formation, but hyphal elongation is significantly inhibited as compared to Müller-Thurgau. Moreover, defence-related oxidative burst and accumulation of phenolic compounds is stimulated in the resistant genotypes. We arrive at a model, where more rapid maturation of the cell wall in these sylvestris genotypes sequesters pectins as major food source and thus block hyphal elongation. This paves the way for introgression of genetic factors responsible for cell wall maturation into V. vinifera to develop Black Rot-resistant varieties of grapevine.

Learning to navigate uncertainty in primary care: a scoping literature review.

BACKGROUND: Clinical practice occurs in the context of uncertainty. Primary care is a clinical environment that accepts and works with uncertainty differently from secondary care. Recent literature reviews have contributed to understanding how clinical uncertainty is taught in educational settings and navigated in secondary care, and, to a lesser extent, by experienced GPs. We do not know how medical students and doctors in training learn to navigate uncertainty in primary care. AIM: To explore what is known about primary care as an opportunity for learning to navigate uncertainty. DESIGN & SETTING: Scoping review of articles written in English. METHOD: Using a scoping review methodology, Embase, MEDLINE, and Web of Science databases were searched, with additional articles obtained through citation searching. Studies were included in this review if they: (a) were based within populations of medical students and/or doctors in training; and (b) considered clinical uncertainty or ambiguity in primary care or a simulated primary care setting. Study findings were analysed thematically. RESULTS: Thirty-six studies were included from which the following three major themes were developed: uncertainty contributes to professional identity formation (PIF); adaptive responses; and maladaptive behaviours. Relational and social factors that influence PIF were identified. Adaptive responses included adjusting epistemic expectations and shared decision making (SDM). CONCLUSION: Educators can play a key role in helping learners navigate uncertainty through socialisation, discussing primary care epistemology, recognising maladaptive behaviours, and fostering a culture of constructive responses to uncertainty.

Distinct effects of AMPAR subunit depletion on spatial memory.

Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3ΔFb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3-/- mice showed premature mortality. Gria1/3ΔFb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3ΔFb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1-/- and Gria3-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.

A 2D model to study how secondary growth affects the self-supporting behaviour of climbing plants.

Climbing plants exhibit specialized shoots, called "searchers", to cross spaces and alternate between spatially discontinuous supports in their natural habitats. To achieve this task, searcher shoots combine both primary and secondary growth processes of their stems in order to support, orientate and explore their extensional growth into the environment. Currently, there is an increasing interest in developing models to describe plant growth and posture. However, the interactions between the sensing activity (e.g. photo-, gravi-, proprioceptive sensing) and the elastic responses are not yet fully understood. Here, we aim to model the extension and rigidification of searcher shoots. Our model defines variations in the radius (and consequently in mass distribution) along the shoot based on experimental data collected in natural habitats of two climbing species: Trachelospermum jasminoides (Lindl.) Lem. and Condylocarpon guianense Desf.. Using this framework, we predicted the sensory aspect of a plant, that is, the plant's response to external stimuli, and the plant's proprioception, that is, the plant's "self-awareness". The results suggest that the inclusion of the secondary growth in a model is fundamental to predict the postural development and self-supporting growth phase of shoots in climbing plants.

Severe falciparum malaria in pregnancy in Southeast Asia: a multi-centre retrospective cohort study.

BACKGROUND: Severe malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy. METHODS: A retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality. RESULTS: We included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio [aOR], 7.18, 95% CI 2.01-25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27-98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13-22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit < 20%) only. In the SMRU prospective cohort, in which the pregnant women were followed up until delivery, the risks of foetal loss (23.3% by Kaplan-Meier estimator, 25/117) and small-for-gestational-age (38.3%, 23/60) after severe malaria were high. Maternal death, foetal loss and preterm birth occurred commonly within a week of diagnosis of severe malaria. CONCLUSIONS: Vital organ dysfunction in pregnant women with severe malaria was associated with a very high maternal and foetal mortality whereas severe anaemia or hyperparasitaemia alone were not associated with poor prognosis, which may explain the variation of reported mortality from severe malaria in pregnancy. Access to antenatal care must be promoted to reduce barriers to early diagnosis and treatment of both malaria and anaemia.

Is there ever a single best answer (SBA): assessment driving certainty in the uncertain world of GP?

Uncertainty is inherent in all areas of medical practice, not least in primary care, which is defined by its acceptance of uncertainty and complexity. Single best answer (SBA) questions are a ubiquitous assessment tool in undergraduate medical assessments; however clinical practice, particularly in primary care, challenges the supposition that a single best answer exists for all clinical encounters and dilemmas. In this article, we seek to highlight several aspects of the relationship between this assessment format and clinical uncertainty by considering its influence on medical students' views of uncertainty in the contexts of their medical education, personal epistemology, and clinical expectations.

Impact of heat on emergency hospital admission in Texas: geographic and racial/ethnic disparities.

BACKGROUND: Studies exploring the racial/ethnicity disparity of the impact of heat on hospital admission are notably limited, especially in Texas, a state with a diverse population and consistently ranking among the top ten U.S. states for heat-related deaths per capita from 2018 to 2020. OBJECTIVE: Our objective is to determine the correlation between elevated temperatures and emergency hospital admissions for various causes and age groups across 12 Metropolitan Statistical Areas(MSAs) in Texas. Additionally, we aim to investigate health inequalities in the five largest MSAs in Texas between 2004 and 2013. METHODS: We used MSA-level hospital admission and weather data to estimate the relationship between heat and emergency hospital admissions. We applied a Generalized Additive Model and random effects meta-analysis to calculate MSA-specific associations and overall correlation, repeating the analysis for age groups and specific causes of admission. We also investigated health disparities across racial and ethnic groups and performed a sensitivity analysis. RESULTS: The results showed that a 1 °C increase in temperature was associated with a 0.50% (95% CI [0.38%, 0.63%]) increase in all-cause emergency hospital admissions. Heat's impact on hospital admissions varied among age groups and causes, with children under 6 years showing the highest effect estimate (0.64% (95% CI [0.32%,0.96%])). Statistically significant associations were found for Cardiovascular Diseases (0.27% (95% CI [0.07%,0.47%])), Ischemic Heart Diseases (0.53% (95% CI [0.15%,0.92%])), Pneumonia (0.70% (95% CI [0.25%,1.16%])), and Respiratory Diseases (0.67% (95% CI [0.18%,1.17%])). Health disparities were found among racial and ethnic groups in the five largest MSAs. IMPACT STATEMENT: Studies exploring the impact of heat on hospital admission in Texas are notably limited. Our research provided a comprehensive examination of the connection between heat and emergency hospital admissions throughout Texas. Furthermore, we are the first to examine racial/ethnic disparities, identifying African American and Hispanic groups as disproportionately affected. These insights provide valuable insights for policymakers to allocate resources and implement strategies to mitigate the negative consequences of rising temperatures.

Single cell RNA sequencing unravels mechanisms underlying senescence-like phenotypes of alveolar macrophages.

Alveolar macrophages (AMs) are resident innate immune cells that play vital roles in maintaining lung physiological functions. However, the effects of aging on their dynamics, heterogeneity, and transcriptional profiles remain to be fully elucidated. Through single cell RNA sequencing (scRNA-seq), we identified CBFß as an indispensable transcription factor that ensures AM self-renewal. Intriguingly, despite transcriptome similarities of proliferating cells, AMs from aged mice exhibited reduced embryonic stem cell-like features. Aged AMs also displayed compromised DNA repair abilities, potentially leading to obstructed cell cycle progression and an elevation of senescence markers. Consistently, AMs from aged mice exhibited impaired self-renewal ability and reduced sensitivity to GM-CSF. Decreased CBFß was observed in the cytosol of AMs from aged mice. Similar senescence-like phenotypes were also found in human AMs. Taken together, these findings suggest that AMs in aged hosts demonstrate senescence-like phenotypes, potentially facilitated by the abrogated CBF ß activity.

Senescent alveolar macrophages promote early-stage lung tumorigenesis.

Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease.

Computed cardiopulmonography and the idealized lung clearance index, iLCI2.5, in early-stage cystic fibrosis.

This study explored the use of computed cardiopulmonography (CCP) to assess lung function in early-stage cystic fibrosis (CF). CCP has two components. The first is a particularly accurate technique for measuring gas exchange. The second is a computational cardiopulmonary model where patient-specific parameters can be estimated from the measurements of gas exchange. Twenty-five participants (14 healthy controls, 11 early-stage CF) were studied with CCP. They were also studied with a standard clinical protocol to measure the lung clearance index (LCI2.5). Ventilation inhomogeneity, as quantified through CCP parameter σlnCl, was significantly greater (P < 0.005) in CF than in controls, and anatomical deadspace relative to predicted functional residual capacity (DS/FRCpred) was significantly more variable (P < 0.002). Participant-specific parameters were used with the CCP model to calculate idealized values for LCI2.5 (iLCI2.5) where extrapulmonary influences on the LCI2.5, such as breathing pattern, had all been standardized. Both LCI2.5 and iLCI2.5 distinguished clearly between CF and control participants. LCI2.5 values were mostly higher than iLCI2.5 values in a manner dependent on the participant's respiratory rate (r = 0.46, P < 0.05). The within-participant reproducibility for iLCI2.5 appeared better than for LCI2.5, but this did not reach statistical significance (F ratio = 2.2, P = 0.056). Both a sensitivity analysis on iLCI2.5 and a regression analysis on LCI2.5 revealed that these depended primarily on an interactive term between CCP parameters of the form σlnCL*(DS/FRC). In conclusion, the LCI2.5 (or iLCI2.5) probably reflects an amalgam of different underlying lung changes in early-stage CF that would require a multiparameter approach, such as potentially CCP, to resolve.NEW & NOTEWORTHY Computed cardiopulmonography is a new technique comprising a highly accurate sensor for measuring respiratory gas exchange coupled with a cardiopulmonary model that is used to identify a set of patient-specific characteristics of the lung. Here, we show that this technique can improve on a standard clinical approach for lung function testing in cystic fibrosis. Most particularly, an approach incorporating multiple model parameters can potentially separate different aspects of pathological change in this disease.

Failure without Tears: Two-Step Attachment in a Climbing Cactus.

Climbing plants can be extremely adaptable to diverse habitats and capable of colonising perturbed, unstructured, and even moving environments. The timing of the attachment process, whether instantaneous (e.g., a pre-formed hook) or slow (growth process), crucially depends on the environmental context and the evolutionary history of the group concerned. We observed how spines and adhesive roots develop and tested their mechanical strength in the climbing cactus Selenicereus setaceus (Cactaceae) in its natural habitat. Spines are formed on the edges of the triangular cross-section of the climbing stem and originate in soft axillary buds (areoles). Roots are formed in the inner hard core of the stem (wood cylinder) and grow via tunnelling through soft tissue, emerging from the outer skin. We measured maximal spine strength and root strength via simple tensile tests using a field measuring Instron device. Spine and root strengths differ, and this has a biological significance for the support of the stem. Our measurements indicate that the measured mean strength of a single spine could theoretically support an average force of 2.8 N. This corresponds to an equivalent stem length of 2.62 m (mass of 285 g). The measured mean strength of root could theoretically support an average of 13.71 N. This corresponds to a stem length of 12.91 m (mass of 1398 g). We introduce the notion of two-step attachment in climbing plants. In this cactus, the first step deploys hooks that attach to a substrate; this process is instantaneous and is highly adapted for moving environments. The second step involves more solid root attachment to the substrate involving slower growth processes. We discuss how initial fast hook attachment can steady the plant on supports allowing for the slower root attachment. This is likely to be important in wind-prone and moving environmental conditions. We also explore how two-step anchoring mechanisms are of interest for technical applications, particularly for soft-bodied artefacts, which must safely deploy hard and stiff materials originating from a soft compliant body.

Genetic characterization of Macaca arctoides: A highlight of key genes and pathways.

When compared to the approximately 22 other macaque species, Macaca arctoides has many unique phenotypes. These traits fall into various phenotypic categories, including genitalia, coloration, mating, and olfactory traits. Here we used a previously identified whole genome set of 690 outlier genes to look for possible genetic explanations of these unique traits. Of these, 279 genes were annotated miRNAs, which are non-coding. Patterns within the remaining outliers in coding genes were investigated using GO (n = 370) and String (n = 383) analysis, which showed many interconnected immune-related genes. Further, we compared the outliers to candidate pathways associated with M. arcotides' unique phenotypes, revealing 10/690 outlier genes that overlapped these four pathways: hedgehog signaling, WNT signaling, olfactory, and melanogenesis. Of these, genes in all pathways except olfactory had higher FST values than the rest of the genes in the genome based on permutation tests. Overall, our results point to many genes each having a small impact on phenotype, working in tandem to cause large systemic changes. Additionally, these results may indicate pleiotropy. This seems to be especially true with the development and coloration of M. arctoides. Our results highlight that development, melanogenesis, immune function, and miRNAs may be heavily involved in M. arctoides' evolutionary history.

A neural basis of choking under pressure.

Incentives tend to drive improvements in performance. But when incentives get too high, we can "choke under pressure" and underperform when it matters most. What neural processes might lead to choking under pressure? We studied Rhesus monkeys performing a challenging reaching task in which they underperform when an unusually large "jackpot" reward is at stake. We observed a collapse in neural information about upcoming movements for jackpot rewards: in the motor cortex, neural planning signals became less distinguishable for different reach directions when a jackpot reward was made available. We conclude that neural signals of reward and motor planning interact in the motor cortex in a manner that can explain why we choke under pressure. One-Sentence Summary: In response to exceptionally large reward cues, animals can "choke under pressure", and this corresponds to a collapse in the neural information about upcoming movements.

Coupling machine learning and epidemiological modelling to characterise optimal fungicide doses when fungicide resistance is partial or quantitative.

Increasing fungicide dose tends to lead to better short-term control of plant diseases. However, high doses select more rapidly for fungicide resistant strains, reducing long-term disease control. When resistance is qualitative and complete-i.e. resistant strains are unaffected by the chemical and resistance requires only a single genetic change-using the lowest possible dose ensuring sufficient control is well known as the optimal resistance management strategy. However, partial resistance (where resistant strains are still partially suppressed by the fungicide) and quantitative resistance (where a range of resistant strains are present) remain ill-understood. Here, we use a model of quantitative fungicide resistance (parametrized for the economically important fungal pathogen Zymoseptoria tritici) which handles qualitative partial resistance as a special case. Although low doses are optimal for resistance management, we show that for some model parametrizations the resistance management benefit does not outweigh the improvement in control from increasing doses. This holds for both qualitative partial resistance and quantitative resistance. Via a machine learning approach (a gradient-boosted trees model combined with Shapley values to facilitate interpretability), we interpret the effect of parameters controlling pathogen mutation and characterising the fungicide, in addition to the time scale of interest.

[A male with a pulsating ear drum]. / Een man met een kloppend trommelvlies.

A 28-year-old male presented with non-pulsatile tinnitus, rightsided hearing loss and an ipsilateral pulsating ear drum. A CT-scan revealed an aberrant internal carotid artery in the middle ear. This is an uncommon finding. Recognition of this birth analomy is important since ear manipulation or surgery can lead to life-threatening complications.

Modelling quantitative fungicide resistance and breakdown of resistant cultivars: Designing integrated disease management strategies for Septoria of winter wheat.

Plant pathogens respond to selection pressures exerted by disease management strategies. This can lead to fungicide resistance and/or the breakdown of disease-resistant cultivars, each of which significantly threaten food security. Both fungicide resistance and cultivar breakdown can be characterised as qualitative or quantitative. Qualitative (monogenic) resistance/breakdown involves a step change in the characteristics of the pathogen population with respect to disease control, often caused by a single genetic change. Quantitative (polygenic) resistance/breakdown instead involves multiple genetic changes, each causing a smaller shift in pathogen characteristics, leading to a gradual alteration in the effectiveness of disease control over time. Although resistance/breakdown to many fungicides/cultivars currently in use is quantitative, the overwhelming majority of modelling studies focus on the much simpler case of qualitative resistance. Further, those very few models of quantitative resistance/breakdown which do exist are not fitted to field data. Here we present a model of quantitative resistance/breakdown applied to Zymoseptoria tritici, which causes Septoria leaf blotch, the most prevalent disease of wheat worldwide. Our model is fitted to data from field trials in the UK and Denmark. For fungicide resistance, we show that the optimal disease management strategy depends on the timescale of interest. Greater numbers of fungicide applications per year lead to greater selection for resistant strains, although over short timescales this can be oset by the increased control oered by more sprays. However, over longer timescales higher yields are attained using fewer fungicide applications per year. Deployment of disease-resistant cultivars is not only a valuable disease management strategy, but also oers the secondary benefit of protecting fungicide effectiveness by delaying the development of fungicide resistance. However, disease-resistant cultivars themselves erode over time. We show how an integrated disease management strategy with frequent replacement of disease-resistant cultivars can give a large improvement in fungicide durability and yields.