Synthesis of Membrane-Permeable Macrocyclic Peptides via Imidazopyridinium Grafting.

Macrocyclic peptides (MPs) are a class of compounds that have been shown to be particularly well suited for engaging difficult protein targets. However, their utility is limited by their generally poor cell permeability and bioavailability. Here, we report an efficient solid-phase synthesis of novel MPs by trapping a reversible intramolecular imine linkage with a 2-formyl- or 2-keto-pyridine to create an imidazopyridinium (IP+)-linked ring. This chemistry is useful for the creation of macrocycles of different sizes and geometries, including head-to-side and side-to-side chain configurations. Many of the IP+-linked MPs exhibit far better passive membrane permeability than expected for "beyond Rule of 5" molecules, in some cases exceeding that of much lower molecular weight, traditional drug molecules. We demonstrate that this chemistry is suitable for the creation of libraries of IP+-linked MPs and show that these libraries can be mined for protein ligands.

Translational or translationable? A call for ethno-immersion in (empirical) bioethics research.

The shift towards "empirical bioethics" was largely triggered by a recognition that stakeholders' views and experiences are vital in ethical analysis where one hopes to produce practicable recommendations. Such perspectives can provide a rich resource in bioethics scholarship, perhaps challenging the researcher's perspective. However, overreliance on a picture painted by a group of research participants-or on pre-existing literature in that field-can lead to a biased view of a given context, as the subjectivity of data generated in these ways cannot (and should not wholly) be escaped. In response, we propose the implementation of a complementary approach of ethno-immersion in bioethics research. By positioning oneself in the context being researched, the researcher can better understand the realities of that context. The researcher's understanding will, naturally, be subjective too. However, it will act as a better developed and more informed outsider view, when considering the picture painted by participants and previous studies, thus enabling the researcher to introduce more nuance when analysing data. We introduce this approach after examining what we call the context detachment problem, whereby some bioethics scholarship-empirical or otherwise-fails to reflect the reality of the healthcare setting it concerns. Our proposed ethno-immersion (which differs from formal ethnography) is then explored as a response, highlighting its benefits, and answering the question of timing within a research project. Finally, we reflect on the applicability of our proposal to non-empirical bioethics scholarship, concluding that it remains important but may require some adjustments.

Snakes on a plain: biotic and abiotic factors determine venom compositional variation in a wide-ranging generalist rattlesnake.

BACKGROUND: Snake venoms are trophic adaptations that represent an ideal model to examine the evolutionary factors that shape polymorphic traits under strong natural selection. Venom compositional variation is substantial within and among venomous snake species. However, the forces shaping this phenotypic complexity, as well as the potential integrated roles of biotic and abiotic factors, have received little attention. Here, we investigate geographic variation in venom composition in a wide-ranging rattlesnake (Crotalus viridis viridis) and contextualize this variation by investigating dietary, phylogenetic, and environmental variables that covary with venom. RESULTS: Using shotgun proteomics, venom biochemical profiling, and lethality assays, we identify 2 distinct divergent phenotypes that characterize major axes of venom variation in this species: a myotoxin-rich phenotype and a snake venom metalloprotease (SVMP)-rich phenotype. We find that dietary availability and temperature-related abiotic factors are correlated with geographic trends in venom composition. CONCLUSIONS: Our findings highlight the potential for snake venoms to vary extensively within species, for this variation to be driven by biotic and abiotic factors, and for the importance of integrating biotic and abiotic variation for understanding complex trait evolution. Links between venom variation and variation in biotic and abiotic factors indicate that venom variation likely results from substantial geographic variation in selection regimes that determine the efficacy of venom phenotypes across populations and snake species. Our results highlight the cascading influence of abiotic factors on biotic factors that ultimately shape venom phenotype, providing evidence for a central role of local selection as a key driver of venom variation.

Barriers to green inhaler prescribing: ethical issues in environmentally sustainable clinical practice.

The National Health Service (NHS) was the first healthcare system globally to declare ambitions to become net carbon zero. To achieve this, a shift away from metered-dose inhalers which contain powerful greenhouse gases is necessary. Many patients can use dry powder inhalers which do not contain greenhouse gases and are equally effective at managing respiratory disease. This paper discusses the ethical issues that arise as the NHS attempts to mitigate climate change. Two ethical issues that pose a barrier to moving away from metered-dose inhalers are considered: patients who decline an inhaler with a smaller carbon footprint and increased cost. I argue that while a patient is not morally justified in refusing a more environmentally sustainable inhaler due to the expected harms, a doctor may still prescribe a metered-dose inhaler if they believe that switching without consent might undermine trust or substantially worsen the patient's health. Turning to cost, I argue that the imperative to combat climate change means the NHS should accept small increased financial costs for lower carbon inhalers, even though this provides no additional direct benefit for the patient. I then go on to consider the implications of the preceding analysis for policy and practice. I argue for a policy that minimises the impact of inhalers on the climate by advocating for a principle of environmental prescribing and explore decision-making in practice. While the arguments here pertain primarily to inhalers, the discussion has broader implications for debates around healthcare's responsibility to be environmentally sustainable.

How should institutions help clinicians to practise greener anaesthesia: first-order and second-order responsibilities to practice sustainably.

There is a need for all industries, including healthcare, to reduce their greenhouse gas emissions. In anaesthetic practice, this not only requires a reduction in resource use and waste, but also a shift away from inhaled anaesthetic gases and towards alternatives with a lower carbon footprint. As inhalational anaesthesia produces greenhouse gas emissions at the point of use, achieving sustainable anaesthetic practice involves individual practitioner behaviour change. However, changing the practice of healthcare professionals raises potential ethical issues. The purpose of this paper is twofold. First, we discuss what moral duties anaesthetic practitioners have when it comes to practices that impact the environment. We argue that behaviour change among practitioners to align with certain moral responsibilities must be supplemented with an account of institutional duties to support this. In other words, we argue that institutions and those in power have second-order responsibilities to ensure that practitioners can fulfil their first-order responsibilities to practice more sustainably. The second goal of the paper is to consider not just the nature of second-order responsibilities but the content. We assess four different ways that second-order responsibilities might be fulfilled within healthcare systems: removing certain anaesthetic agents, seeking consensus, education and methods from behavioural economics. We argue that, while each of these are a necessary part of the picture, some interventions like nudges have considerable advantages.

Doctors as Appointed Fiduciaries: A Supplemental Model for Medical Decision-Making.

How should we respond to patients who do not wish to take on the responsibility and burdens of making decisions about their own care? In this paper, we argue that existing models of decision-making in modern healthcare are ill-equipped to cope with such patients and should be supplemented by an "appointed fiduciary" model where decision-making authority is formally transferred to a medical professional. Healthcare decisions are often complex and for patients can come at time of vulnerability. While this does not undermine their capacity, it can be excessively burdensome. Most existing models of decision-making mandate that patients with capacity must retain ultimate responsibility for decisions. An appointed fiduciary model provides a formalized mechanism through which those few patients who wish to defer responsibility can hand over decision-making authority. By providing a formal structure for deferring to an appointed fiduciary, the confusions and risks of the informal transfers that can occur in practice are avoided. Finally, we note how appropriate governance and law can provide safeguards against risks to the welfare of patients and medical professionals.

Terrible choices in the septic child: a response to the PALOH trial round table authors.

In this response article, we challenge a core assumption that lies at the centre of a round table discussion regarding the Pharmacogenetics to Avoid Loss of Hearing trial. The round table regards a genetic test for a variant (mt.1555A>G) that increases the risk of deafness if a carrier is given the antibiotic gentamicin. The idea is that rapid testing can identify neonates at risk, providing an opportunity to prevent giving an antibiotic that might cause deafness. We challenge the assumption that a positive test unequivocally guides antibiotic choice because, aside from the risk of deafness, all antibiotics for neonatal sepsis are equivalent. We argue that this assumption is faulty and has particularly troubling moral consequences. We claim that giving an alternative to gentamicin is potentially providing inferior treatment and thereby may increase the risk of death. Parents and doctors are faced with a terrible choice as a result of positive point-of-care testing (POCT): give gold-standard treatment and risk deafness or give second line care and risk death. While we do not indicate an answer to this choice, what we do argue is that such a deep and difficult choice is one that may make parents wish genetic testing was never undertaken, and therefore, contra some authors in the round table, provides a reason to gain specific consent for POCT.

Postmortem non-directed sperm donation: quality matters.

In our paper 'The ethical case for non-directed postmortem sperm donation' we argued that it would be ethical for men to donate sperm after death for use by strangers. In their thoughtful response Fredrick and Ben Kroon lay out practical concerns regarding our proposal. They raise issues regarding the quality of sperm collected postmortem based on empirical studies. Second, they claim that concerns about quality would make women unlikely to use sperm collected after death. In this response we explore issues of sperm quality in both living and dead donors. We consider whether there might be ways to ensure quality in both. Finally, we question whether quality should be a barrier to women choosing to use sperm donated after death.

The ethical case for non-directed postmortem sperm donation.

In this article we outline and defend the concept of voluntary non-directed postmortem sperm donation. This approach offers a potential means of increasing the quantity and heterogeneity of donor sperm. This is pertinent given the present context of a donor sperm shortage in the UK. Beyond making the case that it is technically feasible for dead men to donate their sperm for use in reproduction, we argue that this is ethically permissible. The inability to access donor sperm and the suffering this causes, we argue, justifies allowing access to sperm donated after death. Moreover, it is known that individuals and couples have desires for certain sperm donor characteristics which may not be fulfilled when numbers of sperm donors are low. Enacting these preferences contributes significantly to the well-being of intended parents, so we argue that this provides a pro tanto reason for respecting them. Finally, we explore the benefits and possible disadvantages of such a system for the various parties affected.

No Blame No Gain? From a No Blame Culture to a Responsibility Culture in Medicine.

Healthcare systems need to consider not only how to prevent error, but how to respond to errors when they occur. In the United Kingdom's National Health Service, one strand of this latter response is the 'No Blame Culture', which draws attention from individuals and towards systems in the process of understanding an error. Defences of the No Blame Culture typically fail to distinguish between blaming someone and holding them responsible. This article argues for a 'responsibility culture', where healthcare professionals are held responsible in cases of foreseeable and avoidable errors. We demonstrate how healthcare professionals can justifiably be held responsible for their errors even though they work in challenging circumstances. We then review the idea of 'responsibility without blame', applying this to cases of error in healthcare. Sensitive to the undesirable effects of blaming healthcare professionals and to the moral significance of holding individuals accountable, we argue that a responsibility culture has significant advantages over a No Blame Culture due to its capacity to enhance patient safety and support medical professionals in learning from their mistakes, while also recognising and validating the legitimate sense of responsibility that many medical professionals feel following avoidable error, and motivating medical professionals to report errors.

Too much medicine: not enough trust? A response.

In their paper 'Too much medicine: not enough trust?' Zoë Fritz and Richard Holton explore the connection between trust and overtreatment and overinvestigation. Whilst their paper is insightful, here I argue that much more could be made of a doctor's (mis)trust and how this exacerbates overtreatment and overinvestigation. By taking Fritz and Holton's view of trust as having 'our best interests at heart' as my starting point, I argue that doctor's do not always trust that patients or the system has their interests at heart and so use overtreatment and overinvestigation to protect themselves. I also point to the tensions created by a lack of trust on the doctor's part as a focal point for much needed sustained ethical analysis.

Junior doctors and moral exploitation.

In this paper I argue that junior doctors are morally exploited. Moral exploitation occurs where an individual's vulnerability is used to compel them to take on additional moral burdens. These might include additional moral responsibility, making weighty moral decisions and shouldering the consequent emotions. Key to the concept of exploitation is vulnerability and here I build on Rosalind McDougall's work on the key roles of junior doctors to show how these leave them open to moral exploitation by restricting their reasonable options. I argue that there are a number of ways junior doctors are morally exploited. First, their seniors can leverage their position to force a junior to take on some discreet decision. More common is the second type of moral exploitation where rota gaps and staffing issues means junior doctors take on more than their fair share of the moral burdens of practice. Third, I discuss structural moral exploitation where the system offloads moral burdens onto healthcare professionals. Not every instance of exploitation is wrongful and so I conclude by exploring the ways that moral exploitation wrongs junior doctors.

Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αß and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology.

Targeting soluble acid hydrolases to lysosomes requires the addition of mannose 6-phosphate residues on their N-glycans. This process is initiated by GlcNAc-1-phosphotransferase, a multi-subunit enzyme encoded by the GNPTAB and GNPTG genes. The GNPTAB gene products (the α and ß subunits) are responsible for recognition and catalysis of hydrolases whereas the GNPTG gene product (the γ subunit) enhances mannose phosphorylation of a subset of hydrolases. Here we identify and characterize a zebrafish gnptg insertional mutant and show that loss of the gamma subunit reduces mannose phosphorylation on a subset glycosidases but does not affect modification of several cathepsin proteases. We further show that glycosidases, but not cathepsins, are hypersecreted from gnptg(-/-) embryonic cells, as evidenced by reduced intracellular activity and increased circulating serum activity. The gnptg(-/-) embryos lack the gross morphological or craniofacial phenotypes shown in gnptab-deficient morphant embryos to result from altered cathepsin activity. Despite the lack of overt phenotypes, decreased fertilization and embryo survival were noted in mutants, suggesting that gnptg associated deposition of mannose 6-phosphate modified hydrolases into oocytes is important for early embryonic development. Collectively, these findings demonstrate that loss of the zebrafish GlcNAc-1-phosphotransferase γ subunit causes enzyme-specific effects on mannose phosphorylation. The finding that cathepsins are normally modified in gnptg(-/-) embryos is consistent with data from gnptab-deficient zebrafish suggesting these proteases are the key mediators of acute pathogenesis. This work also establishes a valuable new model that can be used to probe the functional relevance of GNPTG mutations in the context of a whole animal.

Adenylyl cyclase mRNA localizes to the posterior of polarized DICTYOSTELIUM cells during chemotaxis.

BACKGROUND: In Dictyostelium discoideum, vesicular transport of the adenylyl cyclase A (ACA) to the posterior of polarized cells is essential to relay exogenous 3',5'-cyclic adenosine monophosphate (cAMP) signals during chemotaxis and for the collective migration of cells in head-to-tail arrangements called streams. RESULTS: Using fluorescence in situ hybridization (FISH), we discovered that the ACA mRNA is asymmetrically distributed at the posterior of polarized cells. Using both standard estimators and Monte Carlo simulation methods, we found that the ACA mRNA enrichment depends on the position of the cell within a stream, with the posterior localization of ACA mRNA being strongest for cells at the end of a stream. By monitoring the recovery of ACA-YFP after cycloheximide (CHX) treatment, we observed that ACA mRNA and newly synthesized ACA-YFP first emerge as fluorescent punctae that later accumulate to the posterior of cells. We also found that the ACA mRNA localization requires 3' ACA cis-acting elements. CONCLUSIONS: Together, our findings suggest that the asymmetric distribution of ACA mRNA allows the local translation and accumulation of ACA protein at the posterior of cells. These data represent a novel functional role for localized translation in the relay of chemotactic signal during chemotaxis.

Analysis of microtubule growth dynamics arising from altered actin network structure and contractility in breast tumor cells.

The periphery of epithelial cells is shaped by opposing cytoskeletal physical forces generated predominately by two dynamic force generating systems-growing microtubule ends push against the boundary from the cell center, and the actin cortex contracts the attached plasma membrane. Here we investigate how changes to the structure and dynamics of the actin cortex alter the dynamics of microtubules. Current drugs target actin polymerization and contraction to reduce cell division and invasiveness; however, the impacts on microtubule dynamics remain incompletely understood. Using human MCF-7 breast tumor cells expressing GFP-tagged microtubule end-binding-protein-1 (EB1) and coexpression of cytoplasmic fluorescent protein mCherry, we map the trajectories of growing microtubule ends and cytoplasmic boundary respectively. Based on EB1 tracks and cytoplasmic boundary outlines, we calculate the speed, distance from cytoplasmic boundary, and straightness of microtubule growth. Actin depolymerization with Latrunculin-A reduces EB1 growth speed as well as allows the trajectories to extend beyond the cytoplasmic boundary. Blebbistatin, a direct myosin-II inhibitor, reduced EB1 speed and yielded less straight EB1 trajectories. Inhibiting signaling upstream of myosin-II contractility via the Rho-kinase inhibitor, Y-27632, altered EB1 dynamics differently from Blebbistatin. These results indicate that reduced actin cortex integrity can induce distinct alterations in microtubule dynamics. Given recent findings that tumor stem cell characteristics are increased by drugs which reduce actin contractility or stabilize microtubules, it remains important to clearly define how cytoskeletal drugs alter the interactions between these two filament systems in tumor cells.

Variants in CCL16 are associated with blood plasma and cerebrospinal fluid CCL16 protein levels.

BACKGROUND: CCL16 is a chemokine predominantly expressed in the liver, but is also found in the blood and brain, and is known to play important roles in immune response and angiogenesis. Little is known about the gene's regulation. METHODS: Here, we test for potential causal SNPs that affect CCL16 protein levels in both blood plasma and cerebrospinal fluid in a genome-wide association study across two datasets. We then use METAL to performed meta-analyses with a significance threshold of p < 5x10(-8). We removed SNPs where the direction of the effect was different between the two datasets. RESULTS: We identify 10 SNPs associated with increased CCL16 protein levels in both biological fluids. CONCLUSIONS: Our results will help understand CCL16's regulation, allowing researchers to better understand the gene's effects on human health.

Videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation.

BACKGROUND: Successful tracheal intubation during general anaesthesia traditionally requires a line of sight to the larynx attained by positioning the head and neck and using a laryngoscope to retract the tongue and soft tissues of the floor of the mouth. Difficulties with intubation commonly arise, and alternative laryngoscopes that use digital and/or fibreoptic technology have been designed to improve visibility when airway difficulty is predicted or encountered. Among these devices, a rigid videolaryngoscope (VLS) uses a blade to retract the soft tissues and transmits a lighted video image to a screen. OBJECTIVES: Our primary objective was to assess whether use of videolaryngoscopy for tracheal intubation in adults requiring general anaesthesia reduces risks of complications and failure compared with direct laryngoscopy. Our secondary aim was to assess the benefits and risks of these devices in selected population groups, such as adults with obesity and those with a known or predicted difficult airway. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase on 10 February 2015. Our search terms were relevant to the review question and were not limited by outcomes. We carried out clinical trials register searches and forward and backward citation tracking. We reran the search on 12 January 2016; we added potential new studies of interest from the 2016 search to a list of 'Studies awaiting classification', and we will incorporate these studies into the formal review during the review update. SELECTION CRITERIA: We considered all randomized controlled trials and quasi-randomized studies with adult patients undergoing laryngoscopy performed with a VLS or a Macintosh laryngoscope in a clinical, emergency or out-of-hospital setting. We included parallel and cross-over study designs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data, consulting a third review author to resolve disagreements. We used standard Cochrane methodological procedures, including assessment of risk of bias. MAIN RESULTS: We included 64 studies identified during the 2015 search that enrolled 7044 adult participants and compared a VLS of one or more designs with a Macintosh laryngoscope. We identified 38 studies awaiting classification and seven ongoing studies. Of the 64 included studies, 61 included elective surgical patients, and three were conducted in an emergency setting. Among 48 studies that included participants without a predicted difficult airway, 15 used techniques to simulate a difficult airway. Seven recruited participants with a known or predicted difficult airway, and the remaining studies did not specify or included both predicted and not predicted difficult airways. Only two studies specifically recruited obese participants. It was not possible to blind the intubator to the device, and we noted a high level of inevitable heterogeneity, given the large number of studies.Statistically significantly fewer failed intubations were reported when a VLS was used (Mantel-Haenszel (M-H) odds ratio (OR), random-effects 0.35, 95% confidence Interval (CI) 0.19 to 0.65; 38 studies; 4127 participants), and fewer failed intubations occurred when a VLS was used in participants with an anticipated difficult airway (M-H OR, random-effects 0.28, 95% CI 0.15 to 0.55; six studies; 830 participants). We graded the quality of this evidence as moderate on the basis of the GRADE system. Failed intubations were fewer when a VLS was used in participants with a simulated difficult airway (M-H OR, random-effects 0.18, 95% CI 0.04 to 0.77; nine studies; 810 participants), but groups with no predicted difficult airway provided no significant results (M-H OR, random-effects 0.61, 95% CI 0.22 to 1.67; 19 studies; 1743 participants).Eight studies reported on hypoxia, and only three of these described any events; results showed no differences between devices for this outcome (M-H OR, random-effects 0.39, 95% CI 0.10 to 1.44; 1319 participants). Similarly, few studies reported on mortality, noting no differences between devices (M-H OR, fixed-effect 1.09, 95% CI 0.65 to 1.82; two studies; 663 participants), and only one study reporting on the occurrence of respiratory complications (78 participants); we graded these three outcomes as very low quality owing to lack of data. We found no statistically significant differences between devices in the proportion of successful first attempts (M-H OR, random-effects 1.27, 95% CI 0.77 to 2.09; 36 studies; 4731 participants) nor in those needing more than one attempt. We graded the quality of this evidence as moderate. Studies reported no statistically significant differences in the incidence of sore throat in the postanaesthesia care unit (PACU) (M-H OR, random-effects 1.00 (95% CI 0.73 to 1.38); 10 studies; 1548 participants) nor at 24 hours postoperatively (M-H OR random-effects 0.54, 95% CI 0.27 to 1.07; eight studies; 844 participants); we graded the quality of this evidence as moderate. Data combined to include studies of cross-over design revealed statistically significantly fewer laryngeal or airway traumas (M-H OR, random-effects 0.68, 95% CI 0.48 to 0.96; 29 studies; 3110 participants) and fewer incidences of postoperative hoarseness (M-H OR, fixed-effect 0.57, 95% CI 0.36 to 0.88; six studies; 527 participants) when a VLS was used. A greater number of laryngoscopies performed with a VLS achieved a view of most of the glottis (M-H OR, random-effects 6.77, 95% CI 4.17 to 10.98; 22 studies; 2240 participants), fewer laryngoscopies performed with a VLS achieved no view of the glottis (M-H OR, random-effects 0.18, 95% CI 0.13 to 0.27; 22 studies; 2240 participants) and the VLS was easier to use (M-H OR, random-effects 7.13, 95% CI 3.12 to 16.31; seven studies; 568 participants).Although a large number of studies reported time required for tracheal intubation (55 studies; 6249 participants), we did not present an effects estimate for this outcome owing to the extremely high level of statistical heterogeneity (I2 = 96%). AUTHORS' CONCLUSIONS: Videolaryngoscopes may reduce the number of failed intubations, particularly among patients presenting with a difficult airway. They improve the glottic view and may reduce laryngeal/airway trauma. Currently, no evidence indicates that use of a VLS reduces the number of intubation attempts or the incidence of hypoxia or respiratory complications, and no evidence indicates that use of a VLS affects time required for intubation.

Deference or critical engagement: how should healthcare practitioners use clinical ethics guidance?

Healthcare practitioners have access to a range of ethical guidance. However, the normative role of this guidance in ethical decision-making is underexplored. This paper considers two ways that healthcare practitioners could approach ethics guidance. We first outline the idea of deference to ethics guidance, showing how an attitude of deference raises three key problems: moral value; moral understanding; and moral error. Drawing on philosophical literature, we then advocate an alternative framing of ethics guidance as a form of moral testimony by colleagues and suggest that a more promising attitude to ethics guidance is to approach it in the spirit of 'critical engagement' rather than deference.

Large Left Ventricular Pseudoaneurysm Presenting as an Embolic Stroke After a "Silent" Myocardial Infarction.

A 72-year-old woman with no history of coronary artery disease presented with an acute left middle cerebral artery stroke and was found to have a large left ventricular pseudoaneurysm measuring 8.7 × 7.6 cm and 2 large left ventricular thrombi, the source of her systemic embolization. Despite initial medical management, she developed refractory New York Heart Association functional class III heart failure, uncontrolled atrial fibrillation, and further enlargement of her pseudoaneurysm to 5.5 × 10.6 × 9.2 cm. She underwent urgent aneurysmectomy. Left ventricular pseudoaneurysms are rare and most commonly occur following an acute myocardial infarction when a ventricular free-wall rupture is contained by pericardium or thrombi. Historically, left ventricular angiography displaying a lack of an overlying coronary artery was the gold standard for diagnosis. Now, noninvasive imaging such as computed tomography, magnetic resonance imaging, and echocardiogram with ultrasound-enhancing agent, are reliable diagnostic tools. They can distinguish a pseudoaneurysm from a true left ventricular aneurysm using characteristic findings such as a narrow aneurysm neck, bidirectional doppler flow between the pseudoaneurysm and the left ventricle, and abrupt changes in the cardiac wall structures. Progressive dilation, wall thinning, and dyskinesis can result in refractory heart failure, arrhythmias, and thrombi formation from venous stasis. Pseudoaneurysms have a 30% to 45% risk of rupture and can be treated with left ventricular aneurysmectomy.