A woman with recent personalized external aortic root support implant presented in cardiogenic shock with bilateral coronary ostial occlusion and aortic inflammation requiring emergency coronary angioplasty. Subsequent computed tomography with positron emission tomography scanning demonstrated aortitis with extensive inflammation adjacent to the personalized external aortic root support mesh, the first report of this important complication.
Synthetic chromosome engineering is a complex process due to the need to identify and repair growth defects and deal with combinatorial gene essentiality when rearranging chromosomes. To alleviate these issues, we have demonstrated novel approaches for repairing and rearranging synthetic Saccharomyces cerevisiae genomes. We have designed, constructed, and restored wild-type fitness to a synthetic 753,096-bp version of S. cerevisiae chromosome XIV as part of the Synthetic Yeast Genome project. In parallel to the use of rational engineering approaches to restore wild-type fitness, we used adaptive laboratory evolution to generate a general growth-defect-suppressor rearrangement in the form of increased TAR1 copy number. We also extended the utility of the synthetic chromosome recombination and modification by loxPsym-mediated evolution (SCRaMbLE) system by engineering synthetic-wild-type tetraploid hybrid strains that buffer against essential gene loss, highlighting the plasticity of the S. cerevisiae genome in the presence of rational and non-rational modifications.
Adaptive Laboratory Evolution (ALE) is a powerful tool for engineering and understanding microbial physiology. ALE relies on the selection and enrichment of mutations that enable survival or faster growth under a selective condition imposed by the experimental setup. Phenotypic fitness landscapes are often underpinned by complex genotypes involving multiple genes, with combinatorial positive and negative effects on fitness. Such genotype relationships result in mutational fitness landscapes with multiple local fitness maxima and valleys. Traversing local maxima to find a global maximum often requires an individual or sub-population of cells to traverse fitness valleys. Traversing involves gaining mutations that are not adaptive for a given local maximum but are necessary to 'peak shift' to another local maximum, or eventually a global maximum. Despite these relatively well understood evolutionary principles, and the combinatorial genotypes that underlie most metabolic phenotypes, the majority of applied ALE experiments are conducted using constant selection pressures. The use of constant pressure can result in populations becoming trapped within local maxima, and often precludes the attainment of optimum phenotypes associated with global maxima. Here, we argue that oscillating selection pressures is an easily accessible mechanism for traversing fitness landscapes in ALE experiments, and provide theoretical and practical frameworks for implementation.
Background: Efforts to maintain sinus rhythm in patients with persistent atrial fibrillation (PsAF) remain challenging, with suboptimal long-term outcomes. Methods: All patients undergoing convergent PsAF ablation at our centre were retrospectively analysed. The Atricure Epi-Sense® system was used to perform surgical radiofrequency ablation of the LA posterior wall followed by endocardial ablation. Results: A total of 24 patients underwent convergent PsAF ablation, and 21 (84%) of them were male with a median age of 63. Twelve (50%) patients were obese. In total, 71% of patients had a severely dilated left atrium, and the majority (63%) had preserved left ventricular function. All were longstanding persistent. Eighteen (75%) patients had an AF duration of >2 years. There were no endocardial procedure complications. At 36 months, all patients were alive with no new stroke/transient ischaemic attack (TIA). Freedom from documented AF at 3, 6, 12, 18, 24, and 36 months was 83%, 78%, 74%, 74%, 74%, and 61%, respectively. There were no major surgical complications, with five minor complications recorded comprising minor wound infection, pericarditic pain, and hernia. Conclusions: Our data suggest that convergent AF ablation is effective with excellent immediate and long-term safety outcomes in a real-world cohort of patients with a significant duration of AF and evidence of established atrial remodelling. Convergent AF ablation appears to offer a safe and effective option for those who are unlikely to benefit from existing therapeutic strategies for maintaining sinus rhythm, and further evaluation of this exciting technique is warranted. Our cohort is unique within the published literature both in terms of length of follow-up and very low rate of adverse events.
The individual in our case was troubled with difficult to control arrhythmia in the context of RYR2-mutation positive catecholaminergic polymorphic ventricular tachycardia (CPVT) despite medication. Recurrent implantable cardioverter defibrillator (ICD) shocks occurred for ventricular tachycardia (VT) and ventricular fibrillation (VF) as well as inappropriate shocks as a result of rapidly conducted atrial fibrillation (AF). Catheter ablation was effective in controlling these episodes of AF. Despite left cardiac sympathetic denervation, episodes of ventricular arrhythmia and subsequent ICD shocks persisted. Contralateral sympathetic cardiac denervation was subsequently undertaken, with histology suggesting T-cell mediated ganglionitis. 18 months on, there have been no further episodes of ventricular arrhythmia.
Atrial Fibrillation , Defibrillators, Implantable , Tachycardia, Ventricular , Humans , Sympathectomy , T-Lymphocytes , Tachycardia, Ventricular/surgery , Treatment Outcome
There is increasing literature to suggest numerous subgroups of Brugada syndrome (BrS), including those with ST elevation in the lateral or inferior leads. We present a case of a patient presenting with recurrent collapse and inferior ST elevation degenerating to ventricular fibrillation and ultimately leading to a diagnosis of BrS.
Brugada Syndrome/diagnosis , Brugada Syndrome/therapy , Defibrillators, Implantable , ST Elevation Myocardial Infarction/complications , Ventricular Fibrillation/diagnosis , Ventricular Fibrillation/therapy , Aged , Coronary Angiography , Diagnosis, Differential , Disease Progression , Electrocardiography , Fever , Humans , Magnetic Resonance Imaging , Male , Recurrence
BACKGROUND: Atrial-ventricular differences in voltage-gated Na+ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na+ channel blocker ranolazine that has been shown to be safe and well tolerated in patients. OBJECTIVE: The present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na+ currents. METHODS: The fast and late components of whole-cell voltage-gated Na+ currents (respectively, I Na and I NaL) were recorded at room temperature (â¼22°C) from rat isolated atrial and ventricular myocytes. RESULTS: Atrial I Na activated at command potentials â¼5.5 mV more negative and inactivated at conditioning potentials â¼7 mV more negative than ventricular I Na. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I NaL activated by 3 nM ATX-II (IC50s â¼200 nM). Eleclazine (10 µM) inhibited I Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of I Na from inactivation in both cell types. CONCLUSIONS: Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I Na. The more negative voltage dependence of I Na activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.
The COVID-19 pandemic is an unprecedented challenge and will require novel therapeutic strategies. Affected patients are likely to be at risk of arrhythmia due to underlying comorbidities, polypharmacy and the disease process. Importantly, a number of the medications likely to receive significant use can themselves, particularly in combination, be pro-arrhythmic. Drug-induced prolongation of the QT interval is primarily caused by inhibition of the hERG potassium channel either directly and/or by impaired channel trafficking. Concurrent use of multiple hERG-blocking drugs may have a synergistic rather than additive effect which, in addition to any pre-existing polypharmacy, critical illness or electrolyte imbalance, may significantly increase the risk of arrhythmia and Torsades de Pointes. Knowledge of these risks will allow informed decisions regarding appropriate therapeutics and monitoring to keep our patients safe.
Hospital medicine in the UK is under unprecedented pressure, with increasing demand on physicians as well as challenges in recruiting new doctors into the physicianly specialties. We sought to assess the prevalence of the afternoon ward round and its effect on those undertaking them. We sampled each hospital within our postgraduate region, surveying junior doctors working on inpatient medical wards. We surveyed roughly two-thirds of eligible doctors, -finding that 30% of juniors had some commitment, of varying frequency, to ward rounds beginning after 1.00pm. Of the -doctors involved in afternoon ward rounds, the majority felt they contributed to late finishes, delayed discharge of -patients, reduced team efficiency and reduced job -satisfaction. Just under 80% felt they were less likely to consider a career in hospital medicine as a result The afternoon ward round lives on, and we should not -underestimate its effect. Low junior doctor morale coupled with high work intensity can lead to burnout as well as -impairing the effectiveness of the clinical service. Clinical -leaders should consider leaving this practice in the past so we can cope with the challenges of the future.
BACKGROUND: Direct current cardioversion (DCCV) is a safe and effective treatment for recent-onset atrial fibrillation (AF) or flutter and when performed in the emergency department (ED), it can provide an excellent treatment option for patients as well as reducing unnecessary hospital admissions and healthcare costs. However, appropriate periprocedural anticoagulation is absolutely essential to reduce the risk of adverse outcomes, chiefly thromboembolic stroke. Our intention was for 100% of patients undergoing DCCV in the ED to receive appropriate periprocedural anticoagulation. METHOD: We aimed to assess local practice with regards to periprocedural anticoagulation with a 1-year retrospective audit. We then undertook to deliver a multimodality educational programme in addition to producing new local protocols. Stakeholders were engaged within the cardiology, emergency medicine and governance departments as well as trust quality improvement team. This was undertaken across three PDSA cycles with prospective data collection on a rolling monthly basis with the use of real-time run charts, fed back to the ED. Teaching was delivered on a small group, electronic as well as departmental level, and a new protocol was created and delivered to guide clinicians in the management of patients with AF or flutter. RESULTS: While initial rates of periprocedural anticoagulation were suboptimal (with only 72% of eligible patients anticoagulated), following our programme of continuous monitoring and intervention, this steadily rose over the project timeline, achieving a high of 91% at the point of last data collection. CONCLUSION: We should champion the high number of these procedures carried out in the ED setting, a pressured environment with multiple competing challenges. However, local protocols should reflect best-practice guidance regarding decision-making around selecting rate versus rhythm control strategies, appropriate use of medication and eligibility for anticoagulation as per individualised thrombotic risk. This will allow us to deliver effective interventions in a safe, patient-centred approach.
Biosensors are enabling major advances in the field of analytics that are both facilitating and being facilitated by advances in synthetic biology. The ability of biosensors to rapidly and specifically detect a wide range of molecules makes them highly relevant to a range of industrial, medical, ecological, and scientific applications. Approaches to biosensor design are as diverse as their applications, with major biosensor classes including nucleic acids, proteins, and transcription factors. Each of these biosensor types has advantages and limitations based on the intended application, and the parameters that are required for optimal performance. Specifically, the choice of biosensor design must consider factors such as the ligand specificity, sensitivity, dynamic range, functional range, mode of output, time of activation, ease of use, and ease of engineering. This review discusses the rationale for designing the major classes of biosensor in the context of their limitations and assesses their suitability to different areas of biotechnological application.
BACKGROUND: Assembly of heterologous metabolic pathways is commonly required to generate microbial cell factories for industrial production of both commodity chemicals (including biofuels) and high-value chemicals. Promoter-mediated transcriptional regulation coordinates the expression of the individual components of these heterologous pathways. Expression patterns vary during culture as conditions change, and this can influence yeast physiology and productivity in both positive and negative ways. Well-characterized strategies are required for matching transcriptional regulation with desired output across changing culture conditions. RESULTS: Here, constitutive and inducible regulatory mechanisms were examined to optimize synthetic isoprenoid metabolic pathway modules for production of trans-nerolidol, an acyclic sesquiterpene alcohol, in yeast. The choice of regulatory system significantly affected physiological features (growth and productivity) over batch cultivation. Use of constitutive promoters resulted in poor growth during the exponential phase. Delaying expression of the assembled metabolic modules using the copper-inducible CUP1 promoter resulted in a 1.6-fold increase in the exponential-phase growth rate and a twofold increase in productivity in the post-exponential phase. However, repeated use of the CUP1 promoter in multiple expression cassettes resulted in genetic instability. A diauxie-inducible expression system, based on an engineered GAL regulatory circuit and a set of four different GAL promoters, was characterized and employed to assemble nerolidol synthetic metabolic modules. Nerolidol production was further improved by 60% to 392 mg L-1 using this approach. Various carbon source systems were investigated in batch/fed-batch cultivation to regulate induction through the GAL system; final nerolidol titres of 4-5.5 g L-1 were achieved, depending on the conditions. CONCLUSION: Direct comparison of different transcriptional regulatory mechanisms clearly demonstrated that coupling the output strength to the fermentation stage is important to optimize the growth fitness and overall productivities of engineered cells in industrially relevant processes. Applying different well-characterized promoters with the same induction behaviour mitigates against the risks of homologous sequence-mediated genetic instability. Using these approaches, we significantly improved sesquiterpene production in yeast.
The newest generation of smart-watches offer heart rate monitoring technology via photoplethysmography, a technology shown to demonstrate impressive ability in diagnosing arrhythmias including atrial fibrillation. Combining such technology with the portability, connectivity and other location and activity tracking features smart-watches could represent a powerful new tool in extended non-invasive arrhythmia detection. The technology itself, including potential uses and limitations, is discussed. There is a need for further software development but crucially, further work into clarifying the diagnostic accuracy of such technology.
Atrial Fibrillation/diagnosis , Electrocardiography, Ambulatory/instrumentation , Photoplethysmography/instrumentation , Equipment Design , Heart Rate , Humans , Software
Vagal atrial fibrillation (AF) remains an under-recognised entity, affecting younger patients often with structurally normal hearts. Although there remains no universal definition or diagnostic criteria, in this review we describe recognised triggers and associated features, including a well-established association with athletic training. We explore potential mechanisms, including the role of the autonomic nervous system and ganglionated plexi in initiating and maintaining arrhythmia. We discuss the limited evidence base addressing the question of progression to persistent AF, and debate the merits of anti-arrhythmic treatment, as well as uncertainty regarding the risk of stroke. Differences in suggested pharmacological therapy are highlighted and as is the emerging promise of radiofrequency catheter ablation as a therapeutic option. As we recognise the emerging burden of vagal AF, we hope to explore the important similarities and differences crucial to developing our understanding of the disorder, and highlight some significant questions which remain unanswered.
Atrial Fibrillation/diagnosis , Atrial Fibrillation/therapy , Catheter Ablation/methods , Vagus Nerve/physiopathology , Anti-Arrhythmia Agents/therapeutic use , Humans , Risk Factors , Treatment Outcome
BACKGROUND: There is growing interest in detecting paroxysmal atrial fibrillation (PAF) to identify patients at high risk of thromboembolic stroke. The implantable loop recorder (ILR) is emerging as a powerful new tool in the diagnosis of PAF. Widespread implantation has significant cost implications and their use must be targeted at those patients at most risk. METHODS: We retrospectively studied a population of 200 adult patients who underwent ILR implantation for the investigation of syncope or palpitations. Clinical data, baseline electrocardiogram (ECG) characteristics, and echocardiographic data were collected. All ECGs and electrograms (EGMs) were scrutinized by two blinded investigators. PAF incidence was defined as episodes lasting >30 seconds on EGMs recorded in ILR memory. RESULTS: Our ILR population consists of 200 patients, 111 (56%) male, with a mean age of 61.4 years (range 19-95). PAF was detected in 42 patients. The following factors were significant predictors of PAF by multivariate logistic regression analysis: cigarette smoking (odds ratio [OR] = 3.73, 95% confidence interval [CI] = 1.40-10.24, P = 0.009) and incomplete right bundle branch block (IRBBB; OR = 9.04, 95% CI = 2.51-34.64, P = 0.00088). Significant differences included incidence of IRBBB (P = 0.012), cigarette smoking (P = 0.026), hypercholesterolemia (P = 0.015), age (P = 0.002), estimated glomerular filtration rate (P = 0.031), left atrial volume (P = 0.019), and PR interval (P = 0.031). The PAF group had significantly higher CHA2 DS2 -VASc scores (P = 0.01). CONCLUSIONS: Our study reports predictive factors for PAF in an ILR population. We suggest that cigarette smoking and IRBBB are independently associated with paroxysmal AF in patients presenting with palpitations or syncope.
Atrial Fibrillation/diagnosis , Atrial Fibrillation/epidemiology , Bundle-Branch Block/epidemiology , Electrocardiography, Ambulatory/statistics & numerical data , Information Storage and Retrieval/statistics & numerical data , Smoking/epidemiology , Adult , Aged , Aged, 80 and over , Bundle-Branch Block/diagnosis , Comorbidity , Diagnosis, Computer-Assisted/methods , Diagnosis, Computer-Assisted/statistics & numerical data , Female , Humans , Incidence , Male , Middle Aged , Prognosis , Reproducibility of Results , Retrospective Studies , Risk Factors , Sensitivity and Specificity , United Kingdom/epidemiology
BACKGROUND: Implantable loop recorders (ILR) allow prolonged cardiac rhythm monitoring and improved diagnostic yield in syncope patients. Predictive factors for pacemaker (PM) implantation in the ILR population with unexplained syncope have not been adequately investigated. In this single center, retrospective, observational study we investigated factors that predict PM implantation in this population. METHODS: We retrospectively analyzed our ILR database of patients aged over 18 years who underwent ILR implantation for unexplained syncope between January 2009 and June 2013. Patient case notes were examined for demographics, history, electrocardiogram (ECG) abnormalities, investigations, and events during follow-up. The primary end-point was the detection of a symptomatic or asymptomatic bradycardia requiring PM implantation. RESULTS: During a period of 4.5 years, 200 patients were implanted with ILR for unexplained syncope, of who n = 33 (16.5%) had clinically significant bradycardia requiring PM implantation. After multivariable analysis, history of injury secondary to syncope was found to be the strongest independent predictor for PM implantation (odds ratio [OR]:9.1; P < 0.001; 95% confidence interval [CI]: (3.26-26.81). Other significant predictors included female sex, PR interval > 200msec, and age >75 years. In patients without conduction abnormalities on the ECG, history of injury secondary to syncope was found to be the strongest independent predictor for PM implantation (OR: 8.16; P = 0.00027; 95% [CI]: (2.67-26.27). CONCLUSIONS: A history of injury secondary to syncope and female sex were independent predictive factors for bradycardia necessitating PM implantation in patients receiving an ILR for syncope with or without ECG conduction abnormalities.
Arrhythmias, Cardiac/therapy , Pacemaker, Artificial , Syncope/therapy , Aged , Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/physiopathology , Electrocardiography , Female , Humans , Male , Middle Aged , Prognosis , Prosthesis Implantation , Retrospective Studies , Syncope/complications , Syncope/physiopathology
Recent NICE guidance has highlighted the importance of appropriate and safe intravenous fluid use. We aimed to improve the quality of out of hours fluid prescription in a Bristol hospital by ensuring that indications and cautions for fluid therapy were clearly documented at the time of initiation. Time-pressured on-call doctors need quick access to information regarding patients' care. A documented "fluid plan" allows doctors to undertake a more informed assessment of the patient's fluid balance, leading to safer prescriptions. Our ideal was for 100% of out of hours intravenous fluid prescriptions to be appropriate. Our process measures included the proportion of patients on intravenous fluids who had a documented fluid plan in the medical notes or on the prescription chart on Friday, prior to the weekend on call period. This was defined as mention of indications and/or cautions to fluid therapy. The introduction of a sticker to prompt fluid plan documentation did marginally improve use of fluid plans. It was notable that 96% of these were followed where plans were documented (n=23). Initiation of IV fluid with an accompanying plan is likely to make subsequent fluid prescriptions safer. Rapid turnover of staff and stationary proved significant barriers to consistent implementation of the sticker. Despite these challenges we demonstrated a "proof of concept", suggesting system modification to include fluid plans is safe and effective.
Both investigators had personally experienced situations when they were let down by emergency suctioning equipment on the wards: due to either lack of, or operator inability to use, equipment. Failings in emergency suction have been highlighted in a recent National Patient Safety Agency signal. We focused on improving the usability of cardiac arrest trolley suction: a complex process involving turning a small, hidden lever. We produced three clearly visible bright labels which provided simple prompts to the operator. Two wards and two sampling periods were used in a randomised controlled design. Medical, nursing and allied healthcare staff participated. A scenario of a vomiting patient was given and staff were asked to use emergency suction. This was timed. On the control ward, 5/10 staff members were able to successfully suction on day 1 and the mean time spent trying to activate suction was 43 seconds. On the second sampling day 6 were able to successfully suction and the mean time taken was 50 seconds. On the intervention ward, 7/10 staff members were able to suction with a mean time of 53 seconds spent. Post-intervention, all 10 staff members successfully suctioned with an average time of 30 seconds. The intervention gathered strongly positive feedback. These interventions are being incorporated into sustainable systems changes. Poor equipment design is a needless distraction during an emergency in a busy ward setting. Simple, innovative solutions provide assistance in a pressured situation. Ideally these would become uniform and lead to a culture shift towards simple, intuitive design.
This paper examines the history of the trope of psychoanalytic therapy in musical dramas, from Richard Wagner to Kurt Weill, concluding that psychoanalysis and the musical drama are, in some ways, companions and take cues from each other, beginning in the mid-19th century. In Wagner's music dramas, psychoanalytic themes and situations - specifically concerning the meaning and analysis of dreams - are presaged. In early modernist music dramas by Richard Strauss and Arnold Schoenberg (contemporaries of Freud), tacit representations of the drama of hysteria, its aetiology and "treatment" comprise key elements of the plot and resonate with dissonant musical soundscapes. By the middle of the 20th century, Kurt Weill places the relationship between analyst and patient in the foreground of his musical "Lady in the Dark," thereby making manifest what is latent in a century-spanning chain of musical works whose meaning centres, in part, around representations of psychoanalysis.
Dreams , Hysteria , Music , Physician-Patient Relations , Psychoanalytic Therapy , Symbolism , Authorship , Dreams/physiology , Dreams/psychology , Freudian Theory/history , History, 20th Century , Hysteria/ethnology , Hysteria/history , Hysteria/psychology , Language , Music/history , Music/psychology , Psychoanalysis/education , Psychoanalysis/history , Psychoanalytic Interpretation , Psychoanalytic Therapy/education
