Contemporary Management of Secondary Mitral Regurgitation

Secondary mitral regurgitation (SMR) is a common occurrence in patients with heart failure with reduced ejection fraction. Moderate-severe or severe SMR is associated with increased mortality and hospitalisations from heart failure. Medical and cardiac resynchronisation therapies have been the only treatments proven to improve prognosis in this patient population. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) and the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) RCTs evaluated transcatheter mitral valve repair with MitraClip for treatment of SMR in addition to medical therapy and they had divergent results. The COAPT trial demonstrated that a reduction in SMR with MitraClip resulted in reduced mortality and heart failure hospitalisations along with improved symptoms and quality of life in appropriately selected patients. The MITRA-FR trial did not show any benefit from using MitraClip for patients with SMR. This article summarises the differences in these two trials and suggests a contemporary approach to the management of SMR

Adjunctive Techniques for Repair of Ischaemic Mitral Regurgitation

Ischaemic mitral regurgitation is a complex process with debate in the literature as to the optimal treatment pathway. Multiple therapies are available to alleviate mitral regurgitation including medical management, transcatheter edge-to-edge repair, mitral valve repair and mitral valve replacement. Medical management with goal-directed therapy should be utilised in patients with heart failure and mild-to-moderate regurgitation. Transcatheter approaches are typically used in patients with prohibitive operative risk, although their use is expanding, especially in those with functional mitral regurgitation who are not responding to goal-directed medical therapy. It is generally accepted that patients with mild-to-moderate disease can avoid valve intervention if successful revascularisation is performed. A higher consideration should be given to valve replacement over repair in patients with severe mitral regurgitation in the setting of myocardial ischaemia. Operative course must be personalised to each patient, and continues to develop with improving technologies and ongoing research into optimal treatment

Don’t turn your back on the symptoms of psychosis : the results of a proof-of-principle, quasi-experimental intervention to reduce duration of untreated psychosis

Background No evidence based approach to reduce duration of untreated psychosis (DUP) has been effective in the UK. Existing interventions have many components and have been difficult to replicate. The majority of DUP in Birmingham, UK is accounted for by delays within mental health services (MHS) followed by help-seeking delay and, we hypothesise, these require explicit targeting. This study examined the feasibility and impact of an intervention to reduce DUP, targeting help-seeking and MHSs delays. Methods A dual-component intervention, comprising a direct care pathway, for 16-25 year olds, and a community psychosis awareness campaign, using our youth-friendly website as the central hub, was implemented, targeting the primary sources of care pathway delays experienced by those with long DUP. Evaluation, using a quasi-experimental, design compared DUP of cases in two areas of the city receiving early detection vs detection as usual, controlling for baseline DUP in each area. Results DUP in the intervention area was reduced from a median 71 days (mean 285) to 39 days (mean 104) following the intervention, with no change in the control area. Relative risk for the reduction in DUP was 0.74 (95 % CI 0.35 to 0.89; p = .004). Delays in MHSs and help-seeking were also reduced. Conclusions Our targeted approach appears to be successful in reducing DUP and could provide a generalizable methodology applicable in a variety of healthcare contexts with differing sources of delay. More research is needed, however, to establish whether our approach is truly effective

Outcomes of Transcatheter Aortic Valve Replacement in Patients With Cardiogenic Shock

AIMS: The safety and efficacy of transcatheter aortic valve replacement (TAVR) with contemporary balloon expandable transcatheter valves in patients with cardiogenic shock (CS) remain largely unknown. In this study, the TAVRs performed for CS between June 2015 and September 2022 using SAPIEN 3 and SAPIEN 3 Ultra bioprosthesis from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry were analysed. METHODS AND RESULTS: CS was defined as: (i) coding of CS within 24 h on Transcatheter Valve Therapy Registry form; and/or (ii) pre-procedural use of inotropes or mechanical circulatory support devices and/or (iii) cardiac arrest within 24 h prior to TAVR. The control group was comprised of all the other patients undergoing TAVR. Baseline characteristics, all-cause mortality, and major complications at 30-day and 1-year outcomes were reported. Landmark analysis was performed at 30 days post-TAVR. Cox-proportional multivariable analysis was performed to determine the predictors of all-cause mortality at 1 year. A total of 309 505 patients underwent TAVR with balloon-expandable valves during the study period. Of these, 5006 patients presented with CS prior to TAVR (1.6%). The mean Society of Thoracic Surgeons score was 10.76 ± 10.4. The valve was successfully implanted in 97.9% of patients. Technical success according to Valve Academic Research Consortium-3 criteria was 94.5%. In a propensity-matched analysis, CS was associated with higher in-hospital (9.9% vs. 2.7%), 30-day (12.9% vs. 4.9%), and 1-year (29.7% vs. 22.6%) mortality compared to the patients undergoing TAVR without CS. In the landmark analysis after 30 days, the risk of 1-year mortality was similar between the two groups [hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.95-1.21]. Patients who were alive at 1 year noted significant improvements in functional class (Class I/II 89%) and quality of life (ΔKCCQ score +50). In the multivariable analysis, older age (HR 1.02, 95% CI 1.02-1.03), peripheral artery disease (HR 1.25, 95% CI 1.06-1.47), prior implantation of an implantable cardioverter-defibrillator (HR 1.37, 95% CI 1.07-1.77), patients on dialysis (HR 2.07, 95% CI 1.69-2.53), immunocompromised status (HR 1.33, 95% CI 1.05-1.69), New York Heart Association class III/IV symptoms (HR 1.50, 95% CI 1.06-2.12), lower aortic valve mean gradient, lower albumin levels, lower haemoglobin levels, and lower Kansas City Cardiomyopathy Questionnaire scores were independently associated with 1-year mortality. CONCLUSION: This large observational real-world study demonstrates that the TAVR is a safe and effective treatment for aortic stenosis patients presenting with CS. Patients who survived the first 30 days after TAVR had similar mortality rates to those who were not in CS

Prehospital 12-Lead Electrocardiogram within 60 Minutes Differentiates Proximal versus Nonproximal Left Anterior Descending Artery Myocardial Infarction

<p>Introduction: Acute anterior myocardial infarctions caused by proximal left anterior descending (LAD) artery occlusions are associated with a higher morbidity and mortality. Early identification of high-risk patients via the 12-lead electrocardiogram (ECG) could assist physicians and emergency response teams in providing early and aggressive care for patients with anterior ST-elevation myocardial infarctions (STEMI). Approximately 25% of US hospitals have primary percutaneous coronary intervention (PCI) capability for the treatment of acute myocardial infarctions. Given the paucity of</p> <p>hospitals capable of PCI, early identification of more severe myocardial infarction may prompt</p> <p>emergency medical service routing of these patients to PCI-capable hospitals. We sought to determine if the 12 lead ECG is capable of predicting proximal LAD artery occlusions.</p> <p>Methods: In a retrospective, post-hoc analysis of the Pre-Hospital Administration of Thrombolytic Therapy with Urgent Culprit Artery Revascularization pilot trial, we compared the ECG findings of</p> <p>proximal and nonproximal LAD occlusions for patients who had undergone an ECG within 180 minutes of symptom onset.</p> <p>Results: In this study, 72 patients had anterior STEMIs, with ECGs performed within 180 minutes of symptom onset. In patients who had undergone ECGs within 60 minutes (n¼35), the mean sum of ST elevation (STE) in leads V1 through V6 plus ST depression (STD) in leads II, III, and aVF was 19.2 mm for proximal LAD occlusions and 11.7 mm for nonproximal LAD occlusions (P¼0.007). A sum STE in V1 through V6 plus STD in II, III, and aVF of at least 17.5 mm had a sensitivity of 52.3%, specificity of 92.9%, positive predictive value of 91.7%, and negative predictive value of 56.5% for proximal LAD occlusions. When the ECG was performed more than 60 minutes after symptom onset (n¼37), there was no significant difference in ST-segment deviation between the 2 groups.</p> <p>Conclusion: The sum STE (V1-V6) and STD (II, III, aVF) on a 12-lead ECG can be used to predict proximal LAD occlusions if performed within the first hour of symptom onset. This should be considered a high-risk finding and may prompt prehospital direction of such patients to PCI-capable hospitals. [West J Emerg Med. 2011;12(4):408–413.]</p

Physiological strength electric fields modulate human T cell activation and polarisation

Acknowledgements: This work was supported by grants from an NHS Grampian Endowment Fund (Grant number 10/19). C.E.A was supported by an Institution of Medical Science University studentship. The authors acknowledge and are grateful to all volunteers for donating blood for T cell isolation. The authors also thank the University of Aberdeen Iain Fraser Cytometry Centre for their assistance.Peer reviewedPublisher PD

Volcanic glass from the 1.8 ka Taupō eruption (New Zealand) detected in Antarctic ice at ~ 230 CE.

Chemical anomalies in polar ice core records are frequently linked to volcanism; however, without the presence of (crypto)tephra particles, links to specific eruptions remain speculative. Correlating tephras yields estimates of eruption timing and potential source volcano, offers refinement of ice core chronologies, and provides insights into volcanic impacts. Here, we report on sparse rhyolitic glass shards detected in the Roosevelt Island Climate Evolution (RICE) ice core (West Antarctica), attributed to the 1.8 ka Taupō eruption (New Zealand)-one of the largest and most energetic Holocene eruptions globally. Six shards of a distinctive geochemical composition, identical within analytical uncertainties to proximal Taupō glass, are accompanied by a single shard indistinguishable from glass of the ~25.5 ka Ōruanui supereruption, also from Taupō volcano. This double fingerprint uniquely identifies the source volcano and helps link the shards to the climactic phase of the Taupō eruption. The englacial Taupō-derived glass shards coincide with a particle spike and conductivity anomaly at 278.84 m core depth, along with trachytic glass from a local Antarctic eruption of Mt. Melbourne. The assessed age of the sampled ice is 230 ± 19 CE (95% confidence), confirming that the published radiocarbon wiggle-match date of 232 ± 10 CE (2 SD) for the Taupō eruption is robust

Initial Results from the LIGO Newtonian Calibrator

The precise calibration of the strain readout of the LIGO gravitational wave observatories is paramount to the accurate interpretation of gravitational wave events. This calibration is traditionally done by imparting a known force on the test masses of the observatory via radiation pressure. Here we describe the implementation of an alternative calibration scheme: the Newtonian Calibrator. This system uses a rotor consisting of both quadrupole and hexapole mass distributions to apply a time-varying gravitational force on one of the observatory's test masses. The force produced by this rotor can be predicted to $<1\%$ relative uncertainty and is well-resolved in the readout of the observatory. This system currently acts as a cross-check of the existing absolute calibration system

The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme

Deregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor—antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen.Output Status: Forthcoming/Available Onlin

What lies beneath? Reconstructing the primitive magmas fueling voluminous silicic volcanism using olivine-hosted melt inclusions

Understanding the origins of the mantle melts that drive voluminous silicic volcanism is challenging because primitive magmas are generally trapped at depth. The central Taupō Volcanic Zone (TVZ; New Zealand) hosts an extraordinarily productive region of rhyolitic caldera volcanism. Accompanying and interspersed with the rhyolitic products, there are traces of basalt to andesite preserved as enclaves or pyroclasts in caldera eruption products and occurring as small monogenetic eruptive centers between calderas. These mafic materials contain MgO-rich olivines (Fo79–86) that host melt inclusions capturing the most primitive basaltic melts fueling the central TVZ. Olivine-hosted melt inclusion compositions associated with the caldera volcanoes (intracaldera samples) contrast with those from the nearby, mafic intercaldera monogenetic centers. Intracaldera melt inclusions from the modern caldera volcanoes of Taupō and Okataina have lower abundances of incompatible elements, reflecting distinct mantle melts. There is a direct link showing that caldera-related silicic volcanism is fueled by basaltic magmas that have resulted from higher degrees of partial melting of a more depleted mantle source, along with distinct subduction signatures. The locations and vigor of Taupō and Okataina are fundamentally related to the degree of melting and flux of basalt from the mantle, and intercaldera mafic eruptive products are thus not representative of the feeder magmas for the caldera volcanoes. Inherited olivines and their melt inclusions provide a unique “window” into the mantle dynamics that drive the active TVZ silicic magmatic systems and may present a useful approach at other volcanoes that show evidence for mafic recharge