Sex Differences in the Inflammatory Response: Pharmacological Opportunities for Therapeutics for Coronary Artery Disease.

Coordinated molecular responses are key to effective initiation and resolution of both acute and chronic inflammation. Vascular inflammation plays an important role in initiating and perpetuating atherosclerotic disease, specifically at the site of plaque and subsequent fibrous cap rupture. Both men and women succumb to this disease process, and although management strategies have focused on revascularization and pharmacological therapies in the acute situation to reverse vessel closure and prevent thrombogenesis, data now suggest that regulation of host inflammation may improve both morbidity and mortality, thus supporting the notion that prevention is better than cure. There is a clear sex difference in the incidence of vascular disease, and data confirm biological differences in inflammatory initiation and resolution between men and women. This article reviews contemporary opinions describing the sex difference in the initiation and resolution of inflammatory responses, with a view to explore potential targets for pharmacological intervention.

Invasive evaluation of coronary microvascular dysfunction.

Coronary microvascular dysfunction (CMD) is a prevalent cause of ischemic heart disease and is associated with poorer quality of life and worse patient outcomes. Both functional and structural abnormalities of the microcirculation can generate ischemia in the absence of epicardial stenosis or worsen concomitant obstructive coronary artery disease (CAD). The invasive assessment of CMD allows for the evaluation of the entirety of the coronary vascular tree, from the large epicardial vessels to the microcirculation, and enables the study of vasomotor function through vasoreactivity testing. The standard evaluation of CMD includes vasomotor assessment with acetylcholine, as well as flow- and resistance-derived indices calculated with either thermodilution or Doppler guidewires. Tailored treatment based upon the information gathered from the invasive evaluation of CMD has been demonstrated to reduce the burden of angina; therefore, a thorough understanding of these procedures is warranted with the aim of improving the quality of life of the patient. This review summarizes the most widespread approaches for the invasive evaluation of CMD, with a focus on patients with ischemia and non-obstructive CAD.

Insect-fungal-interactions: A detailed review on entomopathogenic fungi pathogenicity to combat insect pests.

Global food security is threatened by insect pests of economically important crops. Chemical pesticides have been used frequently for the last few decades to manage insect pests throughout the world. However, these chemicals are hazardous for human health as well as the ecosystem. In addition, several pests have evolved resistance to many chemicals. Finding environment friendly alternatives lead the researchers to introduce biocontrol agents such as entomopathogenic fungi (EPF). These fungi include various genera that can infect and kill insects efficiently. Moreover, EPFs have considerable host specificity with a mild effect on non-target organisms and can be produced in bulk quantity quickly. However, insights into the biology of EPF and mechanism of action are of prime significance for their efficient utilization as a biocontrol agent. This review focuses on EPF-mediated insect management by explaining particular EPF strains and their general mode of action. We have comprehensively discussed which criteria should be used for the selection of pertinent EPF, and which aspects can impact the EPF efficiency. Finally, we have outlined various advantages of EPF and their limitations. The article summarizes the prospects related to EPF utilization as biocontrol agents. We hope that future strategies for the management of insects will be safer for our planet.

Parthenium hysterophorus: A tale of global invasion over two centuries, spread and prevention measures.

Ever since parthenium weed (Parthenium hysterophorus L.) first left its native range more than two centuries ago, this noxious herb has now invaded 46 countries and territories. The weed has expanded its range from a couple of islands in 18th Century through 11 minor and eight major introductions around the world. Segmented regression analyses confirmed introductions and revealed that the weed has spread fastest in developing countries, especially after the 1950s in Asia and Africa. A review of historical records, research papers and reports suggests that while border traffic (36%) and unchecked imports (seeds 16%, other commodities 17%) have resulted in the majority of international introductions, local spread has been achieved through multiple pathways, including roads and vehicles, by water and wind, through contaminated seed feed lots and floral bouquets. The high proportion of adjacent counties (51%) and oversea islands (5%) over the unknown origins (32%) or directly from the native range (12%) reveal a steady and predictable international spread pattern. Prevention of spread by management was first practised in Australia, then followed by other five countries. Containment barriers were set up, legislation on biosecurity imposed, and management plans based on early detection and eradication were executed; and these measures have been effective. Awareness within international research groups is raising, however, insufficient coordination between invaded countries has occurred to date, with policies yet to be formalised and executed to prevent the spread and impact of this weed.

Reducing the fitness of an invasive weed, Parthenium hysterophorus: Complementing biological control with plant competition.

We studied the effects of a biological control agent, Epiblema strenuana Walker (Lepidoptera: Tortricidae) alone and together with a sown native grass, Astrebla squarrosa C.E. Hubb. and an introduced pasture plant, Clitoria ternatea L. on growth and seed production of Parthenium hysterophorus L. Astrebla squarrosa and C. ternatea individually reduced shoot dry biomass of P. hysterophorus by 30 and 42%, respectively; and by 48 and 70%, respectively in the presence of biological control agent, E. strenuana. Similarly, A. squarrosa and C. ternatea individually reduced weed seed production up to 48 and 64%, respectively; and by 73 and 81%, respectively in the presence of E. strenuana. In the presence of E. strenuana, the biomass of A. squarrosa and C. ternatea was increased by 13 and 10%, respectively. The biological control agent induced more galls per P. hysterophorus plant when either of the competing plants were present than when grown alone. The abundance of galls increased with pasture competition, but only for C. ternatea, and not for A. squarrosa. The biological control agent worked synergistically with the two competitive plants to reduce the growth and production of viable seed, which should lead to a decrease in the P. hysterophorus soil seed banks in the field, and eventually seedling recruitment in future generations of P. hysterophorus.

Plant defense against fungal pathogens by antagonistic fungi with Trichoderma in focus.

Fungal diseases cause considerable damage to the economically important crops worldwide thus posing continuous threat to global food security. Management of these diseases is normally done via utilization of chemicals that have severe negative impact upon human health and surrounding ecosystems. Finding eco-friendly alternatives has led the researchers to focus towards biological control of fungal diseases through biocontrol agents such as antagonistic fungi (AF) and other microorganisms. AF include various genera of fungi that cure the fungal diseases on plants effectively. Furthermore, they play a regulatory role in various plant physiological pathways and interactions. AF are highly host specific having negligible effects on non-target organisms and have fast mass production capability. However, understanding the mechanisms of the effects of AF on plant diseases is a prerequisite for their effective utilization as biocontrol agent. Trichoderma is one of the most important fungal genera known for its antagonistic activity against disease causing fungal pathogens. Therefore, in this review, we have focused upon Trichoderma-mediated fungal diseases management via illustrating its taxonomy, important strains, biodiversity and mode of action. Furthermore, we have assessed the criteria to be followed for selection of AF and the factors influencing their efficiency. Finally, we evaluated the advantages and limitations of Trichoderma as AF. We conclude that effective AF utilization against fungal pathogens can serve as a safe strategy for our Planet.

What do we really know about alien plant invasion? A review of the invasion mechanism of one of the world's worst weeds.

MAIN CONCLUSION: This review provides an insight into alien plant invasion taking into account the invasion mechanism of parthenium weed ( Parthenium hysterophorus L.). A multi-lateral understanding of the invasion biology of this weed has pragmatic implications for weed ecology and management. Biological invasions are one of the major drivers of restructuring and malfunctioning of ecosystems. Invasive plant species not only change the dynamics of species composition and biodiversity but also hinder the system productivity and efficiency in invaded regions. Parthenium weed, a well-known noxious invasive species, has invaded diverse climatic and biogeographic regions in more than 40 countries across five continents. Efforts are under way to minimize the parthenium weed-induced environmental, agricultural, social, and economic impacts. However, insufficient information regarding its invasion mechanism and interference with ecosystem stability is available. It is hard to devise effective management strategies without understanding the invasion process. Here, we reviewed the mechanism of parthenium weed invasion. Our main conclusions are: (1) morphological advantages, unique reproductive biology, competitive ability, escape from natural enemies in non-native regions, and a C3/C4 photosynthesis are all likely to be involved in parthenium weed invasiveness. (2) Tolerance to abiotic stresses and ability to grow in wide range of edaphic conditions are thought to be additional invasion tools on a physiological front. (3) An allelopathic potential of parthenium weed against crop, weed and pasture species, with multiple modes of allelochemical expression, may also be responsible for its invasion success. Moreover, the release of novel allelochemicals in non-native environments might have a pivotal role in parthenium weed invasion. (4) Genetic diversity found among different populations and biotypes of parthenium weed, based on geographic, edaphic, climatic, and ecological ranges, might also be a strong contributor towards its invasion success. (5) Rising temperatures and atmospheric carbon dioxide (CO2) concentrations and changing rainfall patterns, all within the present day climate change prediction range are favorable for parthenium weed growth, its reproductive output, and therefore its future spread and infestation. (6) Parthenium weed invasion in South Asia depicts the relative and overlapping contribution of all the above-mentioned mechanisms. Such an understanding of the core phenomena regulating the invasion biology has pragmatic implications for its management. A better understanding of the interaction of physiological processes, ecological functions, and genetic makeup within a range of environments may help to devise appropriate management strategies for parthenium weed.

Angiography-versus wire-based microvascular resistance index to detect coronary microvascular obstruction associated with ST-segment elevation myocardial infarction.

BACKGROUND: Microvascular obstruction (MVO) measured by cardiac magnetic resonance (CMR) after ST-segment elevation myocardial infarction (STEMI) has important prognostic implications. While invasive index of microvascular resistance (IMR) have been shown to predict the occurrence and extent of MVO, the role of the angiography-based microvascular resistance (Angio-IMR) for this purpose remains unknown. The present study aims to perform a head-to-head comparison of wire-based and angiography-derived microcirculatory resistance (IMR and Angio-IMR, respectively) for the detection of MVO. METHODS: Patients with a first STEMI and multivessel disease underwent CMR for detection of MVO, and angio-IMR and IMR measurements during PPCI and at 30 day follow up, both in STEMI culprit and non-culprit vessels. RESULTS: 58 patients were included (mean age 60.7 ± 9.9 years, 82% male). At the time of PPCI, angio-IMR and IMR exhibited significant correlation (r = 0.70, P < 0.001), and agreement (coefficient of agreement 0.58). Both indices showed good predictive value of MVO [Angio IMR: AUC 0.79 (95% CI: 0.667-0.928); IMR: AUC 0.70 (95% CI: 0.539-0.853); p = 0.15]. Angio-IMR 40 U and IMR 34 U were identified as best cut-offs for prediction of MVO. In non-culprit vessels, angio-IMR and IMR also correlated well (rho = 0.59, p < 0.001), with overall lower mean values compared to culprit vessels (Angio-IMR: 36 vs. 23; IMR: 39 vs. 22, p < 0.001 for both comparisons). CONCLUSION: Angio-IMR constitutes a valid alternative to wire-based IMR in predicting MVO in STEMI. Angio-IMR and IMR show a good correlation in the acute and subacute STEMI phases, both in culprit and non-culprit vessels.

Extraction of an entangled coronary guidewire using the balloon trapping technique.

A 74-year-old man who previously underwent percutaneous coronary intervention (PCI) for a right coronary non-ST-segment elevation myocardial infarction was scheduled for physiology-guided PCI to a left main stem (LMS)/left anterior descending (LAD) lesion.

Procedural and Technological Innovations Facilitating Ultra-low Contrast Percutaneous Coronary Interventions.

Ultra-low-dose contrast percutaneous coronary intervention (PCI) is a valuable approach in selected complex high-risk patients with renal failure. One of the objectives of ultra-low contrast PCI is to decrease the probability of developing postprocedural contrast-induced nephropathy (CIN), which predominately affects patients with baseline renal dysfunction. CIN is associated with poor clinical outcomes and increased healthcare-related costs. Another two clinical scenarios in which reduced dependence on contrast administration by the operator may contribute to improved safety are PCI in complex, high-risk indicated patients and in shock. In this review, we discuss the procedural techniques and recent technological innovations that enable ultra-low-dose contrast PCI to be performed in the cardiac cath lab.

The Current and Potential Distribution of Parthenium Weed and Its Biological Control Agent in Pakistan.

Parthenium hysterophorus L. (Asteraceae), commonly known as parthenium weed, is a highly invasive weed spreading rapidly from northern to southern parts of Pakistan. The persistence of parthenium weed in the hot and dry southern districts suggests that the weed can survive under more extreme conditions than previously thought. The development of a CLIMEX distribution model, which considered this increased tolerance to drier and warmer conditions, predicted that the weed could still spread to many other parts of Pakistan as well as to other regions of south Asia. This CLIMEX model satisfied the present distribution of parthenium weed within Pakistan. When an irrigation scenario was added to the CLIMEX program, more parts of the southern districts of Pakistan (Indus River basin) became suitable for parthenium weed growth, as well as the growth of its biological control agent, Zygogramma bicolorata Pallister. This expansion from the initially predicted range was due to irrigation producing extra moisture to support its establishment. In addition to the weed moving south in Pakistan due to irrigation, it will also move north due to temperature increases. The CLIMEX model indicated that there are many more areas within South Asia that are suitable for parthenium weed growth, both under the present and a future climate scenario. Most of the south-western and north-eastern parts of Afghanistan are suitable under the current climate, but more areas are likely to become suitable under climate change scenarios. Under climate change, the suitability of southern parts of Pakistan is likely to decrease.

Coronary Physiology as Part of a State-of-the-Art Percutaneous Coronary Intervention Strategy: Lessons from SYNTAX II and Beyond.

The use of coronary physiology allows for rational decision making at the time of PCI, contributing to better patient outcomes. Yet, coronary physiology is only one aspect of optimal revascularization. State-of-the-art PCI must also consider other important aspects such as intracoronary imaging guidance and specific procedural expertise, as tested in the SYNTAX II study. In this review, we highlight the technical aspects pertaining to the use of physiology as used in that trial and offer a glimpse into the future with emerging physiologic metrics, including functional coronary angiography, which have already established themselves as useful indices to guide decision making.

Functional coronary angiography for the assessment of the epicardial vessels and the microcirculation.

Over the last decade, steady progress has been made in the ability to assess coronary stenosis relevance by merging computerised analyses of angiograms with fluid dynamic modelling. The new field of functional coronary angiography (FCA) has attracted the attention of both clinical and interventional cardiologists as it anticipates a new era of facilitated physiological assessment of coronary artery disease, without the need for intracoronary instrumentation or vasodilator drug administration, and an increased adoption of ischaemia-driven revascularisation. This state-of-the-art review performs a deep dive into the foundations and rationale behind FCA indices derived from either invasive or computed angiograms. We discuss the currently available FCA systems, the evidence supporting their use, and the specific clinical scenarios in which FCA might facilitate patient management. Finally, the rapidly growing application of FCA to the diagnosis of coronary microvascular dysfunction is discussed. Overall, we aim to provide a state-of-the-art review not only to digest the achievements made so far in FCA, but also to enable the reader to follow the many publications and developments in this field that will likely take place in years to come.

A double-blind, randomised, placebo-controlled parallel study to investigate the effect of sex and dietary nitrate on COVID-19 vaccine-induced vascular dysfunction in healthy men and women: protocol of the DiNOVasc-COVID-19 study.

BACKGROUND: Cardiovascular events, driven by endothelial dysfunction, are a recognised complication of COVID-19. SARS-CoV-2 infections remain a persistent concern globally, and an understanding of the mechanisms causing endothelial dysfunction, particularly the role of inflammation, nitric oxide, and whether sex differences exist in this response, is lacking. We have previously demonstrated important sex differences in the inflammatory response and its impact on endothelial function and separately that the ingestion of inorganic nitrate can protect the endothelium against this dysfunction. In this study, we will investigate whether sex or a dietary inorganic nitrate intervention modulates endothelial function and inflammatory responses after the COVID-19 vaccine. METHODS: DiNOVasc-COVID-19 is a double-blind, randomised, single-centre, placebo-controlled clinical trial. A total of 98 healthy volunteers (49 males and 49 females) will be recruited. Participants will be randomised into 1 of 2 sub-studies: part A or part B. Part A will investigate the effects of sex on vascular and inflammatory responses to the COVID-19 vaccine. Part B will investigate the effects of sex and dietary inorganic nitrate on vascular and inflammatory responses to the COVID-19 vaccine. In part B, participants will be randomised to receive 3 days of either nitrate-containing beetroot juice (intervention) or nitrate-deplete beetroot juice (placebo). The primary outcome for both sub-studies is a comparison of the change in flow-mediated dilatation (FMD) from baseline after COVID-19 vaccination. The study has a power of > 80% to assess the primary endpoint. Secondary endpoints include change from baseline in inflammatory and leukocyte counts and in pulse wave analysis (PWA) and pulse wave velocity (PWV) following the COVID-19 vaccination. DISCUSSION: This study aims to evaluate whether sex or dietary influences endothelial function and inflammatory responses in healthy volunteers after receiving the COVID-19 vaccine. TRIAL REGISTRATION: ClinicalTrials.gov NCT04889274. Registered on 5 May 2023. The study was approved by the South Central - Oxford C Research Ethics Committee (21/SC/0154).

Treatment with SGLT2 Inhibitors in Patients with Diabetes Mellitus and Extensive Coronary Artery Disease: Mortality and Cardiovascular Outcomes.

INTRODUCTION: Sodium-glucose type 2 cotransporter inhibitors (SGLT2-I) have shown solid benefits in reducing cardiovascular mortality and admissions for heart failure in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease. However, no specific studies exist in patients with high-risk coronary artery disease (CAD). METHODS: Single-center, retrospective, observational study including patients with T2DM and a new diagnosis of extensive CAD (defined as left main disease or three main coronary vessel disease). Patients were recruited from 2015 until 2020, with a follow-up of at least 12 months. The primary outcome was to compare all-cause mortality in patients treated with or without SGLT2-I at discharge and adjusted by inverse probability of treatment weighting (IPTW) propensity score. RESULTS: A total of 420 patients were included: 104 (24.7%) were treated with SGLT2-I and 316 (75.3%) were not (non-SGLT2-I group). The presentation was acute coronary syndrome in 44.3%. The mean age was 71.2 ± 10.5 years. The mean left ventricular ejection fraction was 51.5 ± 12.5%, and the mean estimated glomerular filtration rate was 73.9 ± 22 ml/min. After a mean follow-up of 3 ± 1.6 years, all-cause mortality was 16.4%, and cardiovascular mortality was 9.5%. After IPTW, the risk of all-cause death was lower in the SGLT2-I group with a hazard ratio of 0.32 (95% confidence interval 0.12-0.81), p = 0.016. With regard to secondary outcomes, patients in the SGLT2-I group were associated with less renal function deterioration but an increase in unplanned revascularizations. CONCLUSIONS: In patients with T2DM and extensive CAD, treatment with SGLT2-I after discharge was associated with a reduced risk of all-cause death.

Comprehensive Assessment of Myocardial Ischemia Mechanisms in the Catheterization Laboratory: Design and Rationale of the Advanced Invasive Diagnosis Strategy for Patients with Stable Coronary Syndromes Undergoing Coronary ANGIOgraphy - the AID-ANGIO Study.

BACKGROUND: The diagnostic yield of invasive coronary angiography (ICA) to identify obstructive coronary artery disease in the context of chronic coronary syndromes (CCS) is very low. Furthermore, myocardial ischemia may have a non-obstructive origin, which cannot be detected by ICA. METHODS: AID-ANGIO is an observational, prospective, single-cohort, multicenter study, intended to evaluate the diagnostic yield of adopting a hierarchical strategy to assess obstructive and non-obstructive causes of myocardial ischemia in an all-comers population of patients with CCS at the time of ICA. The primary endpoint will investigate the additional diagnostic value of such strategy over angiography alone regarding the identification of ischemia-generating mechanisms. SUMMARY: An estimated sample of consecutive 260 patients with CCS referred by their clinicians to ICA, will be enrolled. In a stepwise manner, a conventional ICA will be performed as the initial diagnostic tool. Those patients with severe-grade stenosis will not undergo further assessment and an obstructive origin for myocardial ischemia will be assumed. Subsequently, the remainder with intermediate-grade stenosis will be assessed with pressure guidewires. Those with a negative result from physiological evaluation and those without epicardial coronary stenosis will be further studied for ischemia of non-obstructive origin, including microvascular dysfunction and vasomotor disorders. The study will be conducted in two steps. Firstly, ICA images will be displayed to patient's referring clinicians, who will be asked to identify the existent epicardial stenosis, their angiographic severity and probable physiological relevance, together with a tentative therapeutic approach. Then, the diagnostic algorithm will continue to be applied and, considering the whole gathered information, a definite therapeutic plan will be consensually established by the interventional cardiologist and patient's referring clinicians. CONCLUSION: The AID-ANGIO study will assess the additional diagnostic yield of a hierarchical strategy over ICA alone to identify ischemia-generating mechanisms in patients with CCS and its impact on therapeutic approach. Positive results of the study might support a streamlined invasive diagnostic process for patients with CCS.

The Incidence, Impact, and Techniques of Commissural Alignment in Transcatheter Aortic Valve Implantation: A Review.

In current clinical practice, commissural alignment of the transcatheter heart valve (THV) during transcatheter aortic valve implantation (TAVI) is seldom achieved. Orientation of the THV within the aortic root and the subsequent influence upon leaflet haemodynamic function, coronary blood flow, and ease of access to the coronary ostia are gaining significant interest. Herein, we review the incidence and clinical implications of commissural misalignment in TAVI and offer thorough descriptions of how optimal alignment can be achieved with several different contemporary THV devices.

Applied coronary physiology for planning and guidance of percutaneous coronary interventions. A clinical consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the European Society of Cardiology.

The clinical value of fractional flow reserve and non-hyperaemic pressure ratios are well established in determining an indication for percutaneous coronary intervention (PCI) in patients with coronary artery disease (CAD). In addition, over the last 5 years we have witnessed a shift towards the use of physiology to enhance procedural planning, assess post-PCI functional results, and guide PCI optimisation. In this regard, clinical studies have reported compelling data supporting the use of longitudinal vessel analysis, obtained with pressure guidewire pullbacks, to better understand how obstructive CAD contributes to myocardial ischaemia, to establish the likelihood of functionally successful PCI, to identify the presence and location of residual flow-limiting stenoses and to predict long-term outcomes. The introduction of new functional coronary angiography tools, which merge angiographic information with fluid dynamic equations to deliver information equivalent to intracoronary pressure measurements, are now available and potentially also applicable to these endeavours. Furthermore, the ability of longitudinal vessel analysis to predict the functional results of stenting has played an integral role in the evolving field of simulated PCI. Nevertheless, it is important to have an awareness of the value and challenges of physiology-guided PCI in specific clinical and anatomical contexts. The main aim of this European Association of Percutaneous Cardiovascular Interventions clinical consensus statement is to offer up-to-date evidence and expert opinion on the use of applied coronary physiology for procedural PCI planning, disease pattern recognition and post-PCI optimisation.

Estimating the economic cost of one of the world's major insect pests, Plutella xylostella (Lepidoptera: Plutellidae): just how long is a piece of string?

Since 1993, the annual worldwide cost of diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), control has been routinely quoted to be US$1 billion. This estimate requires updating and incorporation of yield losses to reflect current total costs of the pest to the world economy. We present an analysis that estimates what the present costs are likely to be based on a set of necessary, but reasoned, assumptions. We use an existing climate driven model for diamondback moth distribution and abundance, the Food and Agriculture Organization country Brassica crop production data and various management scenarios to bracket the cost estimates. The "length of the string" is somewhere between US$1.3 billion and US$2.3 billion based on management costs. However, if residual pest damage is included then the cost estimates will be even higher; a conservative estimate of 5% diamondback moth-induced yield loss to all crops adds another US$2.7 billion to the total costs associated with the pest. A conservative estimate of total costs associated with diamondback moth management is thus US$4 billion-US$5 billion. The lower bound represents rational decision making by pest managers based on diamondback moth abundance driven by climate only. The upper estimate is due to the more normal practice of weekly insecticide application to vegetable crops and the assumption that canola (Brassica napus L.) is treated with insecticide at least once during the crop cycle. Readers can decide for themselves what the real cost is likely to be because we provide country data for further interpretation. Our analysis suggests that greater efforts at implementation of even basic integrated pest management would reduce insecticide inputs considerably, reducing negative environmental impacts and saving many hundreds of millions of dollars annually.

Acute neurological deficit with submassive pulmonary emboli.

Pulmonary embolism (PE) is frequently encountered in the emergency department. Syncope, often as a consequence of impending haemodynamic collapse, is associated with increased mortality. While loss of consciousness owing to cerebral hypoperfusion and reduced left ventricular preload is a common cause of collapse with large volume PE, other syndromes can also cause neurological deficit in thromboembolic disease. Here, we describe a case of a woman in her 60s, presenting to the emergency department with features of high-risk PE. During clinical examination, the patient collapsed and became unresponsive with a Glasgow Coma Scale of 4/15 despite normal haemodynamics. Neurological signs were noted and CT revealed evidence of a large territory cerebral infarction. Further cardiovascular investigations identified a grade 4 patent foramen ovale. We describe a challenging case of established venous thromboembolism complicated by paradoxical embolism, highlighting the importance of thorough clinical examination and investigation and discuss the current evidence base of treatments.