Cannabinoid treatments in epilepsy and seizure disorders.

Cannabis has been used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized controlled clinical trials that led to US Food and Drug Administration approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.

The dietary sweetener sucralose is a negative modulator of T cell-mediated responses.

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years1. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners2-5. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8+ T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders.

Iron Is Critical for Mucosal-Associated Invariant T Cell Metabolism and Effector Functions.

Mucosal-Associated Invariant T (MAIT) cells are a population of innate T cells that play a critical role in host protection against bacterial and viral pathogens. Upon activation, MAIT cells can rapidly respond via both TCR-dependent and -independent mechanisms, resulting in robust cytokine production. The metabolic and nutritional requirements for optimal MAIT cell effector responses are still emerging. Iron is an important micronutrient and is essential for cellular fitness, in particular cellular metabolism. Iron is also critical for many pathogenic microbes, including those that activate MAIT cells. However, iron has not been investigated with respect to MAIT cell metabolic or functional responses. In this study, we show that human MAIT cells require exogenous iron, transported via CD71 for optimal metabolic activity in MAIT cells, including their production of ATP. We demonstrate that restricting iron availability by either chelating environmental iron or blocking CD71 on MAIT cells results in impaired cytokine production and proliferation. These data collectively highlight the importance of a CD71-iron axis for human MAIT cell metabolism and functionality, an axis that may have implications in conditions where iron availability is limited.

Glycogen-fuelled metabolism supports rapid mucosal-associated invariant T cell responses.

Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells which recognize a limited repertoire of ligands presented by the MHC class-I like molecule MR1. In addition to their key role in host protection against bacterial and viral pathogens, MAIT cells are emerging as potent anti-cancer effectors. With their abundance in human, unrestricted properties, and rapid effector functions MAIT cells are emerging as attractive candidates for immunotherapy. In the current study, we demonstrate that MAIT cells are potent cytotoxic cells, rapidly degranulating and inducing target cell death. Previous work from our group and others has highlighted glucose metabolism as a critical process for MAIT cell cytokine responses at 18 h. However, the metabolic processes supporting rapid MAIT cell cytotoxic responses are currently unknown. Here, we show that glucose metabolism is dispensable for both MAIT cell cytotoxicity and early (<3 h) cytokine production, as is oxidative phosphorylation. We show that MAIT cells have the machinery required to make (GYS-1) and metabolize (PYGB) glycogen and further demonstrate that that MAIT cell cytotoxicity and rapid cytokine responses are dependent on glycogen metabolism. In summary, we show that glycogen-fueled metabolism supports rapid MAIT cell effector functions (cytotoxicity and cytokine production) which may have implications for their use as an immunotherapeutic agent.

Redox status regulates autophagy in thymic stromal cells and promotes T cell tolerance.

Thymic stromal cells (TSCs) are critical regulators of T cell tolerance, but their basic biology has remained under-characterized because they are relatively rare and difficult to isolate. Recent work has revealed that constitutive autophagy in TSCs is required for self-antigen presentation and central T cell tolerance induction; however, the mechanisms regulating constitutive autophagy in TSCs are not well understood. Hydrogen peroxide has been shown to increase autophagy flux in other tissues, and we previously identified conspicuously low expression of the hydrogen peroxide-quenching enzyme catalase in TSCs. We investigated whether the redox status of TSCs established by low catalase expression regulates their basal autophagy levels and their capacity to impose central T cell tolerance. Transgenic overexpression of catalase diminished autophagy in TSCs and impaired thymocyte clonal deletion, concomitant with increased frequencies of spontaneous lymphocytic infiltrates in lung and liver and of serum antinuclear antigen reactivity. Effects on clonal deletion and autoimmune indicators were diminished in catalase transgenic mice when autophagy was rescued by expression of the Becn1F121A/F121A knock-in allele. These results suggest a metabolic mechanism by which the redox status of TSCs may regulate central T cell tolerance.

Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study.

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

Molecular ecology of microbiomes in the wild: Common pitfalls, methodological advances and future directions.

The study of microbiomes across organisms and environments has become a prominent focus in molecular ecology. This perspective article explores common challenges, methodological advancements, and future directions in the field. Key research areas include understanding the drivers of microbiome community assembly, linking microbiome composition to host genetics, exploring microbial functions, transience and spatial partitioning, and disentangling non-bacterial components of the microbiome. Methodological advancements, such as quantifying absolute abundances, sequencing complete genomes, and utilizing novel statistical approaches, are also useful tools for understanding complex microbial diversity patterns. Our aims are to encourage robust practices in microbiome studies and inspire researchers to explore the next frontier of this rapidly changing field.

Changes in UK price disparities between healthy and less healthy foods over 10 years: An updated analysis with insights in the context of inflationary increases in the cost-of-living from 2021.

Food prices and affordability play an important role in influencing dietary choices, which in turn have implications for public health. With inflationary increases in the cost-of-living in the UK since 2021, understanding the dynamics of food prices becomes increasingly important. In this longitudinal study, we aimed to examine changes in food prices from 2013 to 2023 by food group and by food healthiness. We established a dataset spanning the years 2013-2023 by combining price data from the UK Consumer Price Index for food and beverage items with nutrient and food data from the UK nutrient databank and UK Department of Health & Social Care's National Diet and Nutrition Survey data. We calculated the price (£/100 kcal) for each food item by year as well as before and during the period of inflationary pressure, and classified items into food groups according to the UK Eatwell Guide and as either "more healthy" or "less healthy" using the UK nutrient profiling score model. In 2023, bread, rice, potatoes and pasta was cheapest (£0.12/100 kcal) and fruit and vegetables most expensive (£1.01/100 kcal). Less healthy food was cheaper than more healthy food (£0.33/100 kcal versus £0.81/100 kcal). Before the inflationary pressure period (from 2013 to late 2021), the price of foods decreased by 3%. After this period, the price of food increased by 22%: relative increases were highest in the food group milk and dairy food (31%) and less healthy category (26%). While healthier foods saw smaller relative price increases since 2021, they remain more expensive, potentially exacerbating dietary inequalities. Policy responses should ensure food affordability and mitigate price disparities via, for example, healthy food subsidies.

A De Novo Whole Genome Assembly and Annotation of Parelaphostrongylus tenuis.

Parelaphostrongylus tenuis causes ungulate morbidity and mortality in eastern and central North America, but no reference genome sequence exists to facilitate research. Here, we present a P. tenuis genome assembly and annotation, generated with PacBio and Illumina technologies. The assembly is 491 Mbp, with 7285 scaffolds and 185 kb N50.

Functional traits explain waterbirds' host status, subtype richness, and community-level infection risk for avian influenza.

Species functional traits can influence pathogen transmission processes, and consequently affect species' host status, pathogen diversity, and community-level infection risk. We here investigated, for 143 European waterbird species, effects of functional traits on host status and pathogen diversity (subtype richness) for avian influenza virus at species level. We then explored the association between functional diversity and HPAI H5Nx occurrence at the community level for 2016/17 and 2021/22 epidemics in Europe. We found that both host status and subtype richness were shaped by several traits, such as diet guild and dispersal ability, and that the community-weighted means of these traits were also correlated with community-level risk of H5Nx occurrence. Moreover, functional divergence was negatively associated with H5Nx occurrence, indicating that functional diversity can reduce infection risk. Our findings highlight the value of integrating trait-based ecology into the framework of diversity-disease relationship, and provide new insights for HPAI prediction and prevention.

The spectral underpinnings of pathogen spread on animal networks.

Predicting what factors promote or protect populations from infectious disease is a fundamental epidemiological challenge. Social networks, where nodes represent hosts and edges represent direct or indirect contacts between them, are important in quantifying these aspects of infectious disease dynamics. However, how network structure and epidemic parameters interact in empirical networks to promote or protect animal populations from infectious disease remains a challenge. Here we draw on advances in spectral graph theory and machine learning to build predictive models of pathogen spread on a large collection of empirical networks from across the animal kingdom. We show that the spectral features of an animal network are powerful predictors of pathogen spread for a variety of hosts and pathogens and can be a valuable proxy for the vulnerability of animal networks to pathogen spread. We validate our findings using interpretable machine learning techniques and provide a flexible web application for animal health practitioners to assess the vulnerability of a particular network to pathogen spread.

Positive associations matter: Microbial relationships drive tick microbiome composition.

Untangling how factors such as environment, host, associations among bacterial species and dispersal predict microbial composition is a fundamental challenge. In this study, we use complementary machine-learning approaches to quantify the relative role of these factors in shaping microbiome variation of the blacklegged tick Ixodes scapularis. I. scapularis is the most important vector for Borrelia burgdorferi (the causative agent for Lyme disease) in the U.S. as well as a range of other important zoonotic pathogens. Yet the relative role of the interactions between pathogens and symbionts compared to other ecological forces is unknown. We found that positive associations between microbes where the occurrence of one microbe increases the probability of observing another, including between both pathogens and symbionts, was by far the most important factor shaping the tick microbiome. Microclimate and host factors played an important role for a subset of the tick microbiome including Borrelia (Borreliella) and Ralstonia, but for the majority of microbes, environmental and host variables were poor predictors at a regional scale. This study provides new hypotheses on how pathogens and symbionts might interact within tick species, as well as valuable predictions for how some taxa may respond to changing climate.

Automated Analysis of PD1 and PDL1 Expression in Lymph Nodes and the Microenvironment of Transmissible Tumors in Tasmanian Devils.

The wild Tasmanian devil (Sarcophilus harrisii) population has suffered a devastating decline due to two clonal transmissible cancers. The first devil facial tumor 1 (DFT1) was observed in 1996, followed by a second genetically distinct transmissible tumor, the devil facial tumor 2 (DFT2), in 2014. DFT1/2 frequently metastasize, with lymph nodes being common metastatic sites. MHC-I downregulation by DFT1 cells is a primary means of evading allograft immunity aimed at polymorphic MHC-I proteins. DFT2 cells constitutively express MHC-I, and MHC-I is upregulated on DFT1/2 cells by interferon gamma, suggesting other immune evasion mechanisms may contribute to overcoming allograft and anti-tumor immunity. Human clinical trials have demonstrated PD1/PDL1 blockade effectively treats patients showing increased expression of PD1 in tumor draining lymph nodes, and PDL1 on peritumoral immune cells and tumor cells. The effects of DFT1/2 on systemic immunity remain largely uncharacterized. This study applied the open-access software QuPath to develop a semiautomated pipeline for whole slide analysis of stained tissue sections to quantify PD1/PDL1 expression in devil lymph nodes. The QuPath protocol provided strong correlations to manual counting. PD-1 expression was approximately 10-fold higher than PD-L1 expression in lymph nodes and was primarily expressed in germinal centers, whereas PD-L1 expression was more widely distributed throughout the lymph nodes. The density of PD1 positive cells was increased in lymph nodes containing DFT2 metastases, compared to DFT1. This suggests PD1/PDL1 exploitation may contribute to the poorly immunogenic nature of transmissible tumors in some devils and could be targeted in therapeutic or prophylactic treatments.Abbreviations: PD1: programmed cell death protein 1; PDL1: programmed death ligand 1; DFT1: devil facial tumor 1; DFT2: devil facial tumor 2; DFTD: devil facial tumor disease; MCC: Matthew's correlation coefficient; DAB: diaminobenzidine; ROI: region of interest.

Mental Health of Royal Canadian Mounted Police at the Start of the Cadet Training Program.

OBJECTIVE: Serving Royal Canadian Mounted Police (RCMP) have screened positive for one or more mental disorders based on self-reported symptoms with substantial prevalence (i.e., 50.2%). Mental health challenges for military and paramilitary populations have historically been attributed to insufficient recruit screening; however, cadet mental health when starting the Cadet Training Program (CTP) was unknown. Our objective was to estimate RCMP Cadet mental health when starting the CTP and test for sociodemographic differences. METHOD: Cadets starting the CTP completed a survey assessing self-reported mental health symptoms (n = 772, 72.0% male) and a clinical interview (n = 736, 74.4% male) with a clinician or supervised trainee using the Mini-International Neuropsychiatric Interview to assess current and past mental health. RESULTS: The percentage of participants screening positive for one or more current mental disorders based on self-reported symptoms (15.0%) was higher than the diagnostic prevalence for the general population (10.1%); however, based on clinical interviews, participants were less likely to screen positive for any current mental disorder (6.3%) than the general population. Participants were also less likely to screen positive for any past mental disorder based on self-report (3.9%) and clinical interviews (12.5%) than the general population (33.1%). Females were more likely to score higher than males (all ps<.01; Cohen's ds .23 to .32) on several self-report mental disorder symptom measures. CONCLUSIONS: The current results are the first to describe RCMP cadet mental health when starting the CTP. The data evidenced a lower prevalence of anxiety, depressive, and trauma-related mental disorders than the general population based on clinical interviews, contrasting notions that more rigorous mental health screening would reduce the high prevalence of mental disorders among serving RCMP. Instead, protecting RCMP mental health may require ongoing efforts to mitigate operational and organizational stressors.

Maternal body mass index is associated with an altered immunological profile at 28 weeks of gestation.

Healthy pregnancy is accompanied by various immunological and metabolic adaptations. Maternal obesity has been implicated in adverse pregnancy outcomes such as miscarriage, preeclampsia, and gestational diabetes mellitus (GDM), while posing a risk to the neonate. There is a lack of knowledge surrounding obesity and the maternal immune system. The objective of this study was to consider if immunological changes in pregnancy are influenced by maternal obesity. Peripheral blood was collected from fasted GDM-negative pregnant women at 26-28 weeks of gestation. Analysis was done using immunoassay, flow cytometry, bioenergetics analysis, and cell culture. The plasma profile was significantly altered with increasing BMI, specifically leptin (r = 0.7635), MCP-1 (r = 0.3024), and IL-6 (r = 0.4985). Circulating leukocyte populations were also affected with changes in the relative abundance of intermediate monocytes (r = -0.2394), CD4:CD8 T-cell ratios (r = 0.2789), and NKT cells (r = -0.2842). Monocytes analysed in more detail revealed elevated CCR2 expression and decreased mitochondrial content with increased BMI. However, LPS-stimulated cytokine production and bioenergetic profile of PBMCs were not affected by maternal BMI. The Th profile skews towards Th17 with increasing BMI; Th2 (r = -0.3202) and Th9 (r = -0.3205) cells were diminished in maternal obesity, and CytoStim™-stimulation exacerbates IL-6 (r = 0.4166), IL-17A (r = 0.2753), IL-17F (r = 0.2973), and IL-22 (r = 0.2257) production with BMI, while decreasing IL-4 (r = -0.2806). Maternal obesity during pregnancy creates an inflammatory microenvironment. Successful pregnancy requires Th2-biased responses yet increasing maternal BMI favours a Th17 response that could be detrimental to pregnancy. Further research should investigate key populations of cells identified here to further understand the immunological challenges that beset pregnant women with obesity.

Temporal Patterns of High-Spend Subgroups Can Inform Service Strategy for Medicare Advantage Enrollees.

BACKGROUND: Most healthcare costs are concentrated in a small proportion of individuals with complex social, medical, behavioral, and clinical needs that are poorly met by a fee-for-service healthcare system. Efforts to reduce cost in the top decile have shown limited effectiveness. Understanding patient subgroups within the top decile is a first step toward designing more effective and targeted interventions. OBJECTIVE: Segment the top decile based on spending and clinical characteristics and examine the temporal movement of individuals in and out of the top decile. DESIGN: Retrospective claims data analysis. PARTICIPANTS: UnitedHealthcare Medicare Advantage (MA) enrollees (N = 1,504,091) continuously enrolled from 2016 to 2019. MAIN MEASURES: Medical (physician, inpatient, outpatient) and pharmacy claims for services submitted for third-party reimbursement under Medicare Advantage, available as International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) and National Drug Codes (NDC) claims. KEY RESULTS: The top decile was segmented into three distinct subgroups characterized by different drivers of cost: (1) Catastrophic: acute events (acute myocardial infarction and hip/pelvic fracture), (2) persistent: medications, and (3) semi-persistent chronic conditions and frailty indicators. These groups show different patterns of spending across time. Each year, 79% of the catastrophic group dropped out of the top decile. In contrast, 68-70% of the persistent group and 36-37% of the semi-persistent group remained in the top decile year over year. These groups also show different 1-year mortality rates, which are highest among semi-persistent members at 17.5-18.5%, compared to 12% and 13-14% for catastrophic and persistent members, respectively. CONCLUSIONS: The top decile consists of subgroups with different needs and spending patterns. Interventions to reduce utilization and expenditures may show more effectiveness if they account for the different characteristics and care needs of these subgroups.

Parasites as conservation tools.

Parasite success typically depends on a close relationship with one or more hosts; therefore, attributes of parasitic infection have the potential to provide indirect details of host natural history and are biologically relevant to animal conservation. Characterization of parasite infections has been useful in delineating host populations and has served as a proxy for assessment of environmental quality. In other cases, the utility of parasites is just being explored, for example, as indicators of host connectivity. Innovative studies of parasite biology can provide information to manage major conservation threats by using parasite assemblage, prevalence, or genetic data to provide insights into the host. Overexploitation, habitat loss and fragmentation, invasive species, and climate change are major threats to animal conservation, and all of these can be informed by parasites.

Los Parásitos como Herramienta de Conservación Resumen El éxito de los parásitos depende típicamente de la relación cercana con uno o más hospederos; por lo tanto, las características de la infección parasitaria tienen potencial para proporcionar detalles indirectos de la historia natural del hospedero y son biológicamente relevantes para la conservación animal. La caracterización de las infecciones parasitarias ha sido útil para definir a las poblaciones hospederas y ha servido como sustituto para la evaluación de la calidad ambiental. Los estudios innovadores de la biología de parásitos pueden proporcionar información para manejar las principales amenazas a la conservación mediante la información proporcionada por el conjunto de parásitos, su prevalencia o genética que proporciona conocimiento sobre el hospedero. La sobreexplotación, la pérdida del hábitat y la fragmentación, las especies invasoras y el cambio climático son las principales amenazas para la conservación animal y a todas pueden ser informadas mediante los parásitos.

Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella.

Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ-/- mice succumb rapidly to STm infections, T-bet-/- mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STm-infected IFN-γ-/- and T-bet-/- mice. In IFN-γ-/- mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-γ reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-γ. T-bet-/- mice induce significant levels of IFN-γ- after challenge. Moreover, T-bet-/- mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet-/- mice exhibit surprisingly wild-type-like immune cell organization postinfection, including extensive iNOS+ granuloma formation. In wild-type mice, most bacteria are within iNOS+ granulomas, but in T-bet-/- mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-γ-dependent iNOS+ granulomas and prevent dissemination.

Medication not accounted for in hospital electronic medication administration records: a retrospective observational study.

OBJECTIVE: To determine the nature, extent, and cost of discrepancies between the quantities of medications supplied to medical departments and administered to patients in public hospitals. DESIGN: Multicentre, retrospective observational study; analysis of electronic pharmacy drug management system (medication supply) and medication administration data for twenty frequently used medications. SETTING, PARTICIPANTS: Medical, surgical, and emergency department (ED) wards in each of four public hospitals in Melbourne, Victoria, during the 2019 calendar year. MAIN OUTCOME MEASURES: Discrepancy between the quantity of medication supplied and administered to patients (as proportion of medication supplied), overall and by hospital and ward type; direct cost to the hospitals of the discrepancies. RESULTS: The overall discrepancy rate (all medications, hospitals, ward types) was 19.2% (95% CI, 19.0-19.4%); overall rates by hospital ranged from 5.8% (95% CI, 5.7-5.9%) to 26.7% (95% CI, 26.6-26.9%). The discrepancies were largest for medications useful for self-treatment: oral antibiotics (eg, phenoxymethylpenicillin 250 mg capsule, 86.8%; 95% CI, 83.1-89.9%) and gastrointestinal medications (eg, ondansetron 4 mg tablet, 53.3%; 95% CI, 52.9-53.7%). Discrepancies were larger for oral than equivalent (or similar) parenteral formulations; they were generally low for controlled medications (temazepam, diazepam, oxycodone). Overall discrepancies were larger for EDs (32.3%; 95% CI, 32.2-32.5%) than for admitted patient wards, but differed between EDs (range: 25.7%; 95% CI, 25.5-26.0% to 39.5%; 95% CI, 39.2-39.7%). The estimated direct cost to hospitals of the discrepancies for the selected medications was $27 800. CONCLUSION: Substantial quantities of medications supplied to hospital wards and EDs are not accounted for in electronic administration records.

Long term trends in natriuretic peptide testing for heart failure in UK primary care: a cohort study.

AIMS: Heart failure (HF) is a malignant condition with poor outcomes and is often diagnosed on emergency hospital admission. Natriuretic peptide (NP) testing in primary care is recommended in international guidelines to facilitate timely diagnosis. We aimed to report contemporary trends in NP testing and subsequent HF diagnosis rates over time. METHODS AND RESULTS: Cohort study using linked primary and secondary care data of adult (≥45 years) patients in England 2004-18 (n = 7 212 013, 48% male) to report trends in NP testing (over time, by age, sex, ethnicity, and socioeconomic status) and HF diagnosis rates. NP test rates increased from 0.25 per 1000 person-years [95% confidence interval (CI) 0.23-0.26] in 2004 to 16.88 per 1000 person-years (95% CI 16.73-17.03) in 2018, with a significant upward trend in 2010 following publication of national HF guidance. Women and different ethnic groups had similar test rates, and there was more NP testing in older and more socially deprived groups as expected. The HF detection rate was constant over the study period (around 10%) and the proportion of patients without NP testing prior to diagnosis remained high [99.6% (n = 13 484) in 2004 vs. 76.7% (n = 12 978) in 2017]. CONCLUSION: NP testing in primary care has increased over time, with no evidence of significant inequalities, but most patients with HF still do not have an NP test recorded prior to diagnosis. More NP testing in primary care may be needed to prevent hospitalization and facilitate HF diagnosis at an earlier, more treatable stage.