Risk of sudden cardiac death:Are coronary chronic total occlusions an additional risk factor?

Sudden arrhythmic cardiac death remains a significant, potentially reversible, cardiological challenge in terms of creating accurate risk prediction models. The current guidelines for implantable cardioverter defibrillator (ICD) therapy are mainly based on left ventricular ejection fraction despite its low sensitivity and specificity in predicting sudden cardiac death (SCD). Chronic total occlusions have been associated with increased mortality but further research is required to clarify if they should be incorporated in a risk model predicting SCD aiming to identify patients that would benefit from ICD therapy even with preserved ejection fraction

Percutaneous Coronary Intervention in the Elderly: Are Drug-coated Balloons the Future?

Balloon angioplasty revolutionised percutaneous treatment for coronary artery disease four decades ago, but vessel-threatening dissections, elastic recoil and restenosis were major drawbacks to an otherwise successful long-lasting intervention. Subsequent advances with bare metal stents and then drug eluting stents followed, aiming to mitigate the risks of acute vessel closure and restenosis. However, stent implantation often necessitates dual antiplatelet therapy for a prolonged period of time, which in itself can lead to adverse outcomes, especially in the frail elderly population at higher risk of bleeding. More recently, bioabsorbable stents have been implemented in clinical practice enabling earlier intimal coverage of the stent and apposition. However, another addition to the armamentarium of percutaneous coronary intervention is the use of drug-coated balloons without the need for deploying any coronary stents or scaffolds. Drug-coated balloons are semi-compliant balloons coated with an antiproliferative agent that is rapidly released on contact with the vessel intima exerting an anti-restenotic effect. The absence of a metallic scaffold means that the need for antiplatelet therapy can potentially be negated in the longer term if required. In this article, we will review the history of percutaneous coronary intervention and the available evidence for the appropriate use of drug-coated balloons especially in the elderly population. We will conclude this review by demonstrating the potential use of drug-coated balloon rather percutaneous stenting through case examples

PIM kinases in luminal A breast cancer: A study of three novel substrates

The PIM kinase family comprises three constitutively active serine/threonine kinases that affect cell proliferation, survival, and motility, especially when upregulated in hematological malignancies or solid tumors, such as breast cancer. Furthermore, in estrogen receptor α (ERα)-expressing (ER+) breast cancer cells, PIM expression is upregulated in response to estrogen stimulation. The aim of this PhD project was to explore the physiological roles of PIM kinases (PIMs) and their substrates in ER+ luminal A breast cancer. A variety of pharmacological PIM inhibitors and genetically modified cell lines were used in experiments, where the effects of phosphorylation on the activity of three novel PIM substrates (Notch3, LKB1, and ERα) were investigated. In study I, PIM-catalyzed phosphorylation of Notch3 was shown to inhibit Notch canonical signaling by disrupting interaction with CSL, a crucial component of the Notch transcriptional complex. Despite this, phosphorylated Notch3 supported tumor growth in the chick chorioallantoic membrane (CAM) xenograft model, hinting at an oncogenic CSLindependent Notch3 signaling mechanism. In study II, PIMs were shown to phosphorylate the tumor suppressor LKB1, and in doing so, reduce its catalytic capacity. Moreover, the growth of CAM tumors was slower when the xenografted cells lacked both LKB1 and PIMs, suggesting that PIMs could be a promising therapeutic target for cancer patients with LKB1-deficient tumors. Study III demonstrated that PIMs phosphorylate ERα and play a key role in regulating Erα signaling. While PIMs are known to contribute to resistance against various cancer therapies, we found no evidence that they are involved in endocrine therapy resistance in breast cancer. Collectively, these study results provide further insight into how PIMs impact breast cancer cell signaling mechanisms.PIM kinaasit luminaali A rintasyövässä PIM-kinaasiperheeseen kuuluu kolme konstitutiivisesti aktiivista seriini/treoniinikinaasia, jotka vaikuttavat solujen proliferaatioon, elinkykyyn ja liikkuvuuteen etenkin silloin, kun niitä ilmennetään liiallisesti hematologissa tai kiinteissä kasvaimissa, kuten rintasyövässä. Estrogeenireseptoria α (ERα) ilmentävissä (ER+) rintasyöpäsoluissa PIM-kinaasien ilmentyminen lisääntyy estrogeenistimulaation seurauksena. Tämän väitöskirjaprojektin tavoitteena oli tutkia PIM-kinaasien ja niiden substraattien fysiologista merkitystä luminaalisissa A-tyypin rintasyöpäsoluissa. Erilaisia farmakologisia PIM-inhibiittoreita sekä geneettisesti muokattuja solulinjoja käytettiin kokeissa, joissa tutkittiin fosforylaation vaikutuksia kolmen uuden PIMsubstraatin (Notch3, LKB1 ja ERα) aktiivisuuteen. Tutkimuksessa I osoitettiin, että PIM-kinaasien katalysoima Notch3-fosforylaatio estää Notch-välitteistä kanonista viestintää häiritsemällä Notch3:n vuorovaikutusta CSL:n kanssa, joka on keskeinen komponentti Notch-transkriptiokompleksissa. Tästä huolimatta fosforyloitu Notch3 edisti kasvaimen kasvua kanan korioallantoiskalvon (CAM) siirrännäismallissa, mikä viittaa CSL-riippumattomaan viestintämekanismiin. Tutkimuksessa II PIMkinaasien osoitettiin fosforyloivan tuumorisuppressiivisen LKB1-kinaasin ja siten vähentävän sen katalyyttistä aktiivisuutta. Lisäksi CAM-kasvainten kasvu oli hitaampaa, kun siirretyistä soluista puuttuivat LKB1:n lisäksi myös PIM-kinaasit. Tämä viittaa siihen, että PIM-kinaasit voisivat olla mahdollinen terapeuttinen kohde syöpäpotilaille, joiden kasvaimista LKB1 puuttuu. Tutkimuksessa III PIM-kinaasien osoitettiin fosforyloivan ERα:n ja olevansa keskeisessä roolissa ERα-signaloinnin säätelyssä. Vaikka PIM-kinaasien tiedetään suojaavan syöpäsoluja erilaisia hoitoja vastaan, emme löytäneet näyttöä siitä, että ne osallistuisivat endokriinisen hoitoresistenssin kehittymiseen rintasyövässä. Kaiken kaikkiaan tämän tutkimuksen tulokset antavat uutta lisätietoa niistä mekanismeista, joilla PIM-kinaasit voivat vaikuttaa rintasyöpäsolujen viestintään

Occupational therapy in Oman: the impact of cultural dissonance

Occupational therapy theory and philosophy are broadly considered to be based on Western cultural values. In contrast, the application of theory and practice in the Sultanate of Oman, historically based on traditional Middle Eastern and Islamic cultural values, provides a case exemplar, which highlights both paradigmatic differences andcultural dissonance. Drawing on the experiences of occupational therapists working in Oman, this study found that the application of therapeutic goals aimed at patient independence and autonomy were difficult to achieve in an environment where family duty and responsibility for care were highly prized. Dressing and cooking assessments werechallenging, and issues related to gender proved problematic. Therapists found the need to adapt practice to acknowledge these differences, and to adopt pragmatic problem-solving strategies, without resolving the underpinning philosophical contradictions. Occupational therapy in Oman is under-researched; further work is needed to confirm the cross-cultural validity of specific assessments and practice models

Cardiovascular magnetic resonance: Stressing the future

Non-invasive cardiac stress imaging plays a central role in the assessment of patients with known or suspected coronary artery disease. The current guidelines suggest estimation of the myocardial ischaemic burden as a criterion for revascularisation on prognostic grounds despite the lack of standardised reporting of the magnitude of ischaemia on various non-invasive imaging methods. Future studies should aim to accurately describe the relationship between myocardial ischaemic burden as assessed by cardiovascular magnetic resonance imaging and mortality

A modified hyperbolic tangent equation to determine equilibrium shape of headland bay beaches

When designing any artificial beach, it’s desirable to avoid (or minimise) future maintenance commitments by arranging the initial beach planshape so that it remains in equilibrium given the incident wave climate. Headlands bays, or embayments, where a sandy beach is held between two erosion resistant headlands, tend to evolve to a stable beach planshape with little movement of the beach contours over time. Several empirical bay shape equations have been derived to fit curves to the shoreline of headland bay beaches. One of the most widely adopted empirical equations is the parabolic bay shape equation, as it is the only equation that directly links the shoreline positions to the predominant wave direction and the point of diffraction. However, the main limitation with the application of the parabolic bay shape equation is locating the downcoast control point. As a result of research presented in this paper a new equation, based on the hyperbolic tangent shape equation was developed, which eliminates the requirement of placing the down coast control point and relies on defining a minimum beach width instead. This modified equation was incorporated into a new ArcGIS tool

Reiterative drawing as translation : Making, resistance, and the negotiated encounter.

Reiterative art, art that remakes art, is a significant strand of twentieth and twenty-first century practice, encompassing the work of artists as diverse as Marcel Duchamp, Elaine Sturtevant, Kate Davis, and Yann Serandour. Prevailing discourses on such works often focus on replication and appropriation as the source of their critique while overlooking what might be understood by exploring their making. Founded in an examination of my own work -predominantly drawings of extant works by others - this doctoral project frames reiterative art in terms of translation and its attendant theory, transforming the act of making into a close reading of its source, and following up on the implications of that reframing.Translations plot trajectories away from their sources and towards specific targets, exposing the space, conceptual and actual, between precursor and product as one of making through remaking and where 'an extended apprenticeship' occurs (Briggs, 2013). An expanded description of translation is proposed encompassing visual and literary forms, incorporating the importance of resistance in complex making processes through the generation of sites of negotiated encounter (Sennett, 2008). Negotiation is considered here as a variant of the ongoing and contingent 'figuring out' of interlocutors, described by Jacques Ranciere as a hallmark of emancipation, and predicated on a striving for an understanding that 'must be understood in its true sense: not the decisive power to unveil things, but the power of translation that makes one speaker confront another' (The Ignorant Schoolmaster, 1991). In translation, as in the drawings produced for this research, negotiation is verifiable and tripartite: occurring between translator, source, and target works. Antoine Berman's analytic, the 'twelve deforming tendencies of translation' (found in his essay Translation and Trials of the Foreign, 1985), when deployed to analyse visual rather than linguistic reiteration, facilitates this verifiability. Berman's tendencies are revealed as a regulation of the maker's voice, allowing the artist to understand how works of art are deformed even as they are made, and furthermore providing a new vocabulary for understanding works of art, particularly those founded on reiteration

Day case discharge of patients treated with drug coated balloon only angioplasty for de novo coronary artery disease:A single center experience

Objective: To report our initial experience with Drug Coated Balloon (DCB) only angioplasty and propose a protocol to achieve this safely. Background: There are no articles published in the literature currently regarding the safety of same day discharge in patients treated with DCB-only angioplasty. Methods: Retrospective review of all our patients treated with DCB-only angioplasty from Sept 2017 to April 2018 with identification of potential complications relating to same day discharge. Results: A total of 100 consecutive patients who underwent elective DCB-only angioplasty for de novo coronary artery disease and were discharged on the same day as the procedure were included. In 99% no cardiac symptoms relating to the procedure requiring urgent hospitalisation or urgent investigations were identified. One patient was readmitted the next day requiring stenting of the previously treated lesion. Our 30 day mortality was zero. Some 97 hospital bed days were saved with 100 patients treated. Conclusion: Elective day-case DCB-only angioplasty according to our local protocol is safe and cost-effective and should be considered for the majority of the patients

Duration of dual antiplatelet therapy in elective drug coated balloon angioplasty

Objectives: We sought to answer whether 1-month duration of dual antiplatelet therapy (DAPT) is safe after elective drug-coated balloon only (DCB) angioplasty. Background: The duration of DAPT after elective DCB was called into question after the ESC Focused DAPT Update of 2017. Until then, a 1-month duration of DAPT was considered safe by national consensus groups (German, Italian, and Chinese) supported by data from prospective worldwide registries. The ESC Guidelines recommended a 6-month duration of DAPT based on evidence from in-stent restenosis randomized controlled trials only. Methods: Retrospective, real-world population, single-center analysis conducted from January 1, 2012 to March 31, 2017 in a high-volume, tertiary PCI center. Consecutive patients receiving 1-month duration of DAPT after elective DCB angioplasty were included. We identified a primary composite outcome of cardiac death, myocardial infarction and target lesion revascularization at 6-months. Results: A total of 303 patients (78.5% male) with mean age of 67 ± 12.5 were included. This incorporated 86.1% de novo lesions and 56.5% nonsmall (≥3 mm diameter) coronary arteries treated. There were no reported outcomes of lesion thrombosis, target vessel MI, target lesion revascularization or cardiac death at 6-months. There were two (0.6%) nontarget vessel MIs and one (0.3%) noncardiac death. Conclusion: One-month duration of DAPT appears safe after elective DCB-only angioplasty, highlighting this strategy for patients at high-risk of bleeding. These results also show favorable clinical outcomes for de novo coronary artery disease and nonsmall coronary arteries treated with DCB-only angioplasty. A 1-month duration of DAPT appears a safe and attractive option

Erosion and the sediment conveyor in central Australia

Why are the Neogene sedimentary fills across central Australia generally thin and discontinuous? One long-standing explanation is that sluggish tectonism and intensified aridity have combined to suppress rates of erosion and sediment production yielding a landscape crowded with inherited, preMiocene forms. Quantifying rates of sediment production, residence time and transport is possible with numerous methods, but the recent growth of cosmogenic nuclide (CN) analysis has provided unprecedented quantitative insights to rates of landscape evolution. Measurements of in situ produced cosmogenic 10Be and 26Al integrate rates of surface processes over million-year timescales—the last part of the Neogene in which aridity has strengthened across the continental interior. We present a compilation of ~600 published and unpublished 10Be and 26Al measurements from central Australia with a focus on the Neogene Eyre Basin and its periphery. Outlying and inlying bedrock uplands serve as engines of sediment production via erosion of bedrock. Surrounding the bedrock outcrops are vast sediment conveyors of varying efficiency and tempo: hillslopes, pediments, and alluvial fans are interim storage/burial zones for sediment in transit to the network of low-gradient rivers, dunes, and playas towards base level. Interactions between fluvial and aeolian processes are especially pertinent to sediment flux in the Eyre Basin. Major rivers such as the Cooper and Finke traverse dunefields in their lower reaches where quantities of alluvia are recirculated into dunes and vice versa. Tracking the trajectories of sediment from source-to-sink (including aeolian recirculation) remains a major challenge, but is central to unravelling the sedimentary dynamics of central Australia's Neogene basins. Based on the CN compilation we estimate 1) spatially averaged erosion rates at the scale of a hillslope or river catchment; 2) pointbased erosion rates on bedrock surfaces; 3) residence time of sediment in hillslope regolith and alluvial fans; and 4) cumulative burial history of sediments in transit. Catchment-scale erosion rates (n~100) are consistently low (<10 m/Myr) and include some of the lowest rates ever measured (~0.3 m/Myr); however, a small group of catchments in the Flinders Ras yield higher erosion rates (~30–60 m/Myr). Bedrock hillslopes (n~200) tend to erode even slower (<5 m/Myr), with a subset of Flinders Ras sites again being the exception (~10–30 m/Myr) and suggesting the influence of recent tectonism. Several CN depth-profiles measured on hillslopes and alluvial fans indicate sediment residence times >0.5 Myr, and high-resolution sampling along three hillslopes with differing morphology (linear, convex, and concave) reveals major variations in sediment production and transport rates that hint at the long-term evolution. In the rivers, fluvial sediments show a weak tendency to increase cumulative burial history downstream (1–2 Myr), consistent with the expanding accommodation space for storage and burial. Dune sediments sampled in the Simpson and Tirari dunefields (n~16) contain cumulative burial histories (up to 1.5 Myr) similar to that of the intersecting rivers. This points to an intimate mix of fluvial and aeolian processes in areas approaching base level. Curiously, these sediments occur in the lowest part of the continent and contain the longest histories of cumulative burial, yet do not form part of the thickest sedimentary fills in the Eyre Basin