King's College

Background: Structural changes in the left atrium (LA) modestly predict outcomes in patients undergoing catheter ablation for atrial fibrillation (AF). Machine learning (ML) is a promising approach to personalize AF management strategies and improve predictive risk models after catheter ablation by integrating atrial geometry from cardiac computed tomography (CT) scans and patient-specific clinical data. We hypothesized that ML approaches based on a patient's specific data can identify responders to AF ablation. Methods: Consecutive patients undergoing AF ablation, who had preprocedural CT scans, demographics, and 1-year follow-up data, were included in the study for a retrospective analysis. The inputs of models were CT-derived morphological features from left atrial segmentation (including the shape, volume of the LA, LA appendage, and pulmonary vein ostia) along with deep features learned directly from raw CT images, and clinical data. These were merged intelligently in a framework to learn their individual importance and produce the optimal classification. Results: 321 patients (64.2 + 10.6 years, 69% male, 40% paroxysmal AF) were analyzed. Post 10-fold nested cross-validation, the model trained to intelligently merge and learn appropriate weights for clinical, morphological, and imaging data (AUC 0.821) outperformed those trained solely on clinical data (AUC 0.626), morphological (AUC 0.659) or imaging data (AUC 0.764). Conclusion: Our machine learning approach provides an end-to-end automated technique to predict AF ablation outcomes using deep learning from CT images, derived structural properties of LA, augmented by incorporation of clinical data in a merged ML framework. This can help develop personalized strategies for patient selection in invasive management of AF. This article is protected by copyright. All rights reserved.

Digital health was given impetus by the COVID-19 pandemic and demonstrated its potential for the delivery of safe care in the community. Remote monitoring and virtual wards are becoming mainstreamed across the UK. Artificial intelligence (AI) software has the potential to transform healthcare delivery but its trustworthiness is a key challenge. Positive staff attitudes towards digital health and new ways of working require staff education and engagement. Continued attention is required to meet the needs of those without access to digital technology and its use.

Background and Aims Little is known about the extent of mitochondrial respiratory chain (MRC) activity dysfunction in patients with alcoholic hepatitis (AH). We aimed to assess the hepatic MRC activity in AH patients and its potential impact on the severity and prognosis of this life‐threatening liver disease. Methods MRC complexes were measured in liver biopsies of 98 AH patients (non‐severe, 17; severe, 81) and in 12 histologically normal livers (NL). Severity was assessed according to Maddrey's Index and MELD score. Corticosteroid response rate and cumulative mortality were also evaluated. Results The activity of the five MRC complexes was markedly decreased in the liver of AH patients compared with that of NL subjects, being significantly lower in patients with severe AH than in those with non‐severe AH. There was a negative correlation between the activity of all MRC complexes and the severity of AH. Interestingly, only complex I and III activities showed a significant positive correlation with the corticosteroid response rate and a significant negative correlation with the mortality rate at all‐time points studied. In a multivariate regression analysis, besides the MELD score and the corticosteroid response rate, complex I activity was significantly associated with 3‐month mortality (OR = 6.03; p = 0.034) and complex III activity with 6‐month mortality (OR = 4.70; p = 0.041) in AH patients. Conclusion Our results indicate that MRC activity is markedly decreased in the liver of AH patients, and, particularly, the impairment of MRC complexes I and III activity appears to have a significant impact on the clinical outcomes of patients with AH.

The essays presented in Wennberg and Sandström's Questioning the Entrepreneurial State tackle the idea of the state not merely supporting innovation and entrepreneurship through creating a favorable environment, but instead making decisions about what entrepreneurial ventures to pursue. It provides a much-needed holistic critique of the entrepreneurial state that is likely to appeal to a big-tent audience within the Austrian community, and it provides a primer on a wealth of academic foundations upon which to build for researchers interested in studying the idea of the entrepreneurial state.

Camus famously expresses despair about life's meaninglessness and the radical, existential impotence of human reason. Each human soul, cast into a body, wakes into conscious life presuming the world fundamentally makes sense—and that she's up to the task of discerning its order, meaning, and profound value. As the lucid discern, the world lets us all down. More, even in a universe chock-a-block with purpose, our reasoning faculties—exercised with utmost intelligence—would come up fatally short. Reason: the butter knife drawn at a gun fight. Gal Yehezkel doesn’t share Camus’ despair about reason. In fact, the previous sentence is a serious contender for philosophical understatement of the year. The Conceptual Foundation of Morality (CFM) is Yehezkel's attempt to ‘establish’ that human reason is fit to discern the order, meaning, and profound value we confront, in the run of life, as rational agents (p. 1). Yehezkel's fundamental hope is nothing less than to purge humanity of any need for faith. Most crucially, the most basic demands of morality will be proven rationally binding upon any agent, ‘human or not’ (p. 1). No butter knife. Ratio victor.

LINKED CONTENT This article is linked to Artru et al papers. To view these articles, visit https://doi.org/10.1111/apt.16080 and https://doi.org/10.1111/apt.17343

Introduction: Conduction system pacing (CSP), in the form of His bundle pacing (HBP) or left bundle branch pacing (LBBP), is emerging as valuable cardiac resynchronization therapy (CRT) delivery methods. However, patient selection and therapy personalization for CSP delivery remain poorly characterized. We aim to compare pacing-induced electrical synchrony during CRT, HBP, LBBP, HBP with left ventricular (LV) epicardial lead (HOT-CRT), and LBBP with LV epicardial lead (LOT-CRT) in patients with different conduction disease presentations using computational modeling. Methods: We simulated ventricular activation on twenty-four four-chamber heart geometries including His-Purkinje systems with proximal left bundle branch block (LBBB). We simulated septal scar, LV lateral wall scar, and mild and severe myocardium and LV His-Purkinje system conduction disease by decreasing the conduction velocity (CV) down to 70% and 35% of healthy CV. Electrical synchrony was measured by the shortest interval to activate 90% of the ventricles (BIVAT-90). Results: Severe LV His-Purkinje conduction disease favored CRT (BIVAT-90: HBP 101.5±7.8ms vs CRT 93.0±8.9ms, P<0.05), with additional electrical synchrony induced by HOT-CRT (87.6±6.7ms, P<0.05) and LOT-CRT (73.9±7.6ms, P<0.05). Patients with slow myocardium CV benefit more from CSP compared to CRT (BIVAT-90: CRT 134.5±24.1ms; HBP 97.1±9.9ms, P<0.01; LBBP: 101.5±10.7ms, P<0.01). Septal but not lateral wall scar made CSP ineffective, while CRT was able to resynchronize the ventricles in the presence of septal scar (BIVAT-90: baseline 119.1±10.8ms vs CRT 85.1±14.9ms, P<0.01). Conclusion: Severe LV His-Purkinje conduction disease attenuates benefits of CSP, with additional improvements achieved with HOT-CRT and LOT-CRT. Septal but not lateral wall scar make CSP ineffective. This article is protected by copyright. All rights reserved.

To assess the success of apical surgery procedures performed using TotalFill® Root Repair Material putty (Schöttlander, Letchworth, UK) as a root end filling material. This case series consisting of 29 teeth in 22 patients highlights the use of TotalFill RRM putty as a root end filling material treated at the Edinburgh Dental Institute by Registrars and Consultants, from 1st January 2017 and 13th March 2019. Outcome was assessed clinically and radiographically over 30 months following completion of treatment. Apical surgery is an option to manage cases of failed endodontic treatment and survival rates in the region of 90% have been reported for teeth following the procedure. Root end filling following retrograde preparation forms an integral part of the procedure. Mineral Trioxide Aggregate (MTA) has been considered the gold standard material for this purpose for a number of years but has some associated handling and placement difficulties. Newer bioceramic materials in putty form have been designed to overcome these difficulties, while retaining advantageous biological properties. The overall survival rate of teeth in the series was 93%, with a success rate of 86%. Due to its improved handling properties and similar clinical performance, this material may prove a useful tool in the apical surgery armamentarium.

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+ spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+ handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies.

Objective: Low rates of inclusion of real-world evidence (RWE) during regulation may arise from lack of clarity and consensus on its definition. A conceptually mature definition of RWE may have pragmatic utility, increasing its inclusion during regulation. The aim was to develop a definition of RWE to promote inclusion in regulatory submissions and assess its conceptual maturity. Methods: Thirteen medical affairs pharmaceutical physicians completed two qualitative online surveys to generate items needed in a definition of RWE. Items that reached a consensus index of > 50% (CI > = 0.51) were retained in the final definition. The maturity of the definition was assessed using concept analysis. Results: After attrition, 11 participants completed the study and generated 18 items to be included in a definition of RWE. All items reached the consensus threshold and were included. The definition was conceptually mature on three of the four dimensions: the potential for a consensual definition across stakeholders, a description of its characteristics and clear preconditions and outcomes. Further research is needed to delineate the boundaries of RWE. Conclusions: A definition of RWE was generated that may increase its inclusion during medicines regulation, especially with further refinement from regulators and other stakeholders.

Objective: To determine the relative burdens of maternal and perinatal complications, for preterm and term pre-eclampsia. Design: Prospective observational cohort study. Setting: Two English maternity units. Population: Unselected women with singleton pregnancies who developed pre-eclampsia (International Society for the Study of Hypertension in Pregnancy definition). Methods: Outcomes were ascertained by health record review and compared between pregnancies with preterm (vs. term) pre-eclampsia. Main outcome measures: Severe maternal hypertension, maternal mortality or major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal unit (NNU) admission ≥48 hours, and birthweight <3rd percentile. Results: Among 40,241 singleton pregnancies, 298 (0.7% [95% confidence interval 0.66-0.83]) and 1194 (3.0% [2.8-3.1]) developed preterm and term pre-eclampsia, respectively. Women with preterm (vs term) pre-eclampsia more commonly experienced adverse maternal or perinatal events (severe hypertension: 18.5% [14.5-23.3] vs 13.6% [11.7-15.6]; maternal mortality/major morbidity: 7.4% [4.9-10.9] vs 2.2% [1.5-3.2]; perinatal mortality/major neonatal morbidity: 29.5% [24.6-34.9] vs 2.2% [1.5-3.2]; and birthweight <3rd percentile: 54.4% [48.7-59.9] vs 14.2% [12.4-16.3]). However, in absolute terms, most maternal complications occurred in women with term pre-eclampsia, as did a large proportion of perinatal complications: severe hypertension (74.7% [68.5-80.0]); maternal mortality/major morbidity (54.2% [40.3-67.4]), perinatal mortality/major neonatal morbidity (22.8% [16.1-31.3]); NNU admission ≥48 hours (38.1% [32.4-44.1]); and birthweight <3rd percentile (51.2% [45.8-56.5]). Conclusions: While adverse event risks are greater with preterm (vs term) pre-eclampsia, term disease is associated with at least equivalent total numbers of maternal, and a significant proportion of perinatal, adverse events. Increased efforts should be made to decrease the incidence of term pre-eclampsia.

Objective: The aim of this study was to assess whether there has been a change in presentations of Biliary Atresia (BA) in England and Wales during the first and second COVID-19 lockdowns (January - June 2020 and 2021). Design: This population study assessed all confirmed cases of BA, from January 2020 to December 2021 across the 3 UK paediatric liver centers originating from England and Wales. Data was then compared to the incidence of confirmed BA cases from January - December 2017, 2018, and 2019. Results: During January - June 2020 and 2021, there were only 8 and 12 presenting cases of BA in England and Wales, compared to 16, 13 and 18 for the same time periods in 2017, 2018 and 2019 respectively. This difference was significant in a two-sided t-test for 2020 (p = 0.035) but not for 2021 (p = 0.385). There was no difference in the mean days to Kasai procedure in January - June 2020 and 2021 compared to 2017-2019, however average time to Kasai after the lockdown periods was significantly higher. Conclusions: There was a significant reduction in the presenting cases of BA during the first COVID-19 lockdown, with an increased time for BA referrals after the pandemic lockdowns were lifted in England and Wales.

Introduction The Trauma Audit and Research Network report “Major Trauma in Older People” highlighted the need to recognise falls in older patients as a mechanism leading to potentially life-threatening injuries. Reasons behind falls can be equally serious and must be addressed concurrently. A Frail Trauma Pathway was introduced in the Emergency Department (ED) of a Major Trauma Centre (MTC) and subsequent audit revealed it was underutilised. We relaunched the Frail Trauma Pathway incorporating a checklist with the aim of improving patient care. Method Retrospective data was collected over one week, including patients over 65 years with a Clinical Frailty Score ≥5, a low velocity trauma and multiple injuries or isolated head injury. We then updated the Frail Trauma Pathway incorporating a checklist, re-distributed it throughout the ED, sent staff email reminders and held teaching sessions. An educational “Advent Calendar” was circulated daily in December. Following this we repeated data collection. Results 20 patients pre and 18 post-intervention fitted inclusion criteria. There was a reduction in admission rates, improvement in ED senior doctor review for primary survey, increase in timely administration of Parkinson’s disease medication and venous thromboembolism assessment. However, there was a decline in other parameters measured. Due to the small patient cohort, it is difficult to assess if changes in results post-intervention are statistically significant. Conclusion Several aspects of the frailty pathway showed improvement, notably admission reduction. This QIP demonstrates the difficulties of instigating change in an MTC, where numerous pathways result in ‘information overload’ and staff numbers are large and constantly changing. By focusing on the frail trauma checklist and incorporating it into our electronic records system we hope to improve compliance with the pathway. Further research on a national level is required to determine how to best care for this expanding cohort of patients.

It is widely assumed that our actions shape our brains and that the resulting connections determine who we are. To test this idea in a reductionist setting, in which genes and environment are controlled, we investigated differences in neuroanatomy and structural covariance by ex vivo structural magnetic resonance imaging (MRI) in mice whose behavioral activity was continuously tracked for 3 months in a large, enriched environment. We confirmed that environmental enrichment increases mouse hippocampal volumes. Stratifying the enriched group according to individual longitudinal behavioral trajectories, however, revealed striking differences in mouse brain structural covariance in continuously highly active mice compared to those whose trajectories showed signs of habituating activity. Network-based statistics identified distinct sub-networks of murine structural covariance underlying these differences in behavioral activity. Together, these results reveal that differentiated behavioral trajectories of mice in an enriched environment are associated with differences in brain connectivity.

Aortic stenosis (AS) is a serious and complex condition, for which optimal management continues to evolve rapidly. An understanding of current clinical practice guidelines is critical to effective patient care and shared decision-making. This state of the art review of the 2021 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines and 2020 American College of Cardiology/American Heart Association Guidelines compares their recommendations for AS based on the evidence to date. The European and American guidelines were generally congruent with the exception of three key distinctions. First, the European guidelines recommend intervening at a left ventricular ejection fraction of 55%, compared with 60% over serial imaging by the American guidelines for asymptomatic patients. Second, the European guidelines recommend a threshold of ≥65 years for surgical bioprosthesis, whereas the American guidelines employ multiple age categories, providing latitude for patient factors and preferences. Third, the guidelines endorse different age cut-offs for transcatheter vs. surgical aortic valve replacement, despite limited evidence. This review also discusses trends indicating a decreasing proportion of mechanical valve replacements. Finally, the review identifies gaps in the literature for areas including transcatheter aortic valve implantation in asymptomatic patients, the appropriateness of Ross procedures, concomitant coronary revascularization with aortic valve replacement, and bicuspid AS. To summarize, this state of the art review compares the latest European and American guidelines on the management of AS to highlight three areas of divergence: timing of intervention, valve selection, and surgical vs. transcatheter aortic valve replacement criteria.

Few studies have examined brief transdiagnostic groups. The Take Control Course (TCC) was developed for patients with mild to moderate common mental health problems. We examined whether TCC is non-inferior to individual low-intensity cognitive behaviour therapy (CBT) in a single-blind individually randomised parallel non-inferiority trial. The primary outcomes were depression (PHQ9) and anxiety (GAD7) at 6-month follow-up (primary outcome point) and 12-month follow-up. The non-inferiority margin that we set, based on previous trials, corresponds to approximately 3 points on the PHQ9 and approximately 2.5 points on the GAD7. Intention-to-treat (ITT) and per-protocol (PP) analyses of 6-month data of 156 randomised patients indicated that TCC was non-inferior to individual low-intensity CBT on anxiety (ITT Coefficient = 0.24; 95% CI: -1.45 to 1.92; d = 0.04; p = .79), and depression (ITT Coefficient = 0.82; 95% CI: -1.06 to 2.69; d = 0.14; p = .39) outcomes, and functioning (ITT Coefficient = 0.69; 95% CI: -2.56 to 3.94; d = 0.08; p = .68). The findings at 12 months were inconclusive and require further testing. This randomised trial provides preliminary support that TCC is not less effective than short-term individual CBT within Improving Access to Psychological Therapies (IAPT) services.

Background Regulating the marketing of commercial formula products is a long-term commitment required to protect breastfeeding. Marketing strategies of formula manufacturers, retailers and distributors evolve at a rapid rate. Objective The aim of this research was to describe exposure of pregnant women and mothers of young children in South Africa to marketing of commercial formula products, compared to international recommendations and national legislation. Methods Using mobile phone marketing diaries twenty participants in Cape Town and Johannesburg documented the formula marketing they were exposed to for one week. Ten mothers were interviewed to explore their perceptions towards marketing exposure in more depth. Results Women reported limited infant formula advertising, but an abundance of strategies used to market growing-up formula and powdered drinks for children over 36 months. Strategies included product packaging, in-store displays, online distribution channels and educational material about product ranges. Online strategies were reported, namely social media marketing (sponsored adverts and support groups), websites and mobile phone applications providing infant and young child feeding information and price discounts, print and TV advertisements, and competitions. Products for children over 36 months are cross-promoted with products prohibited to be advertised by national legislation. Conclusions South African women are being exposed to covert marketing of infant, follow-up, and growing-up formula. Explicit marketing of products for children over 36 months of age allows formula companies to provide messages about branding and use of commercial formula products to mothers. National legislation should be updated and effectively implemented to address changing marketing strategies.