Prolonged persistence of mutagenic DNA lesions in somatic cells.

DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment1-3. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours3,4, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium5-12. Persistent DNA lesions occurred at increased rates, with distinctive mutational signatures, in donors exposed to tobacco or chemotherapy, suggesting that they can arise from exogenous mutagens. In haematopoietic stem cells, persistent DNA lesions, probably from endogenous sources, generated the characteristic mutational signature SBS1913; occurred steadily throughout life, including in utero; and endured for 2.2 years on average, with 15-25% of lesions lasting at least 3 years. We estimate that on average, a haematopoietic stem cell has approximately eight such lesions at any moment in time, half of which will generate a mutation with each cell cycle. Overall, 16% of mutations in blood cells are attributable to SBS19, and similar proportions of driver mutations in blood cancers exhibit this signature. These data indicate the existence of a family of DNA lesions that arise from endogenous and exogenous mutagens, are present in low numbers per genome, persist for months to years, and can generate a substantial fraction of the mutation burden of somatic cells

The role of cardiovascular multimodality imaging in the evaluation of Anderson-Fabry disease: from early diagnosis to therapy monitoring A clinical consensus statement of the ESC Working Group on Myocardial & Pericardial Diseases and the European Association of Cardiovascular Imaging of the ESC.

Anderson-Fabry disease (AFD) is a rare genetic disease with X-linked transmission characterized by a defect in the enzyme alpha-galactosidase A (alpha-GAL), which impairs glycosphingolipid metabolism and leads to an excessive storage of globotriaosylceramide (Gb3) within lysosomes. AFD involves renal, cardiac, vascular, and nervous systems and is mainly observed in male patients with onset in childhood, although cardiac manifestation is often shown in adults. AFD cardiomyopathy is caused by the accumulation of Gb3 within myocytes first showed by left ventricular (LV) hypertrophy and diastolic dysfunction, leading to restrictive cardiomyopathy and systolic heart failure with biventricular involvement. The diagnosis of AFD cardiomyopathy may be insidious in the first stages and requires accurate differential diagnosis with other cardiomyopathies with hypertrophic phenotype. However, it is fundamental to promptly initiate specific therapies that have shown promising results, particularly for early treatment. A careful integration between clinical evaluation, genetic tests, and cardiac imaging is required to diagnose AFD with cardiac involvement. Basic and advanced echocardiography, cardiac magnetic resonance, and nuclear imaging may offer pivotal information for early diagnosis (Central illustration) and the management of these patients is often limited to centres with high expertise in the field. This clinical consensus statement, developed by experts from the European Society of Cardiology (ESC) Working Group on Myocardial & Pericardial Diseases and the European Association of Cardiovascular Imaging of the ESC, aims to provide practical advice for all clinicians regarding the use of multimodality imaging to simplify the diagnostic evaluation, prognostic stratification, and management of cardiac involvement in AFD

Essays in Macroeconomics: Consumption, Fiscal Multipliers, and Oil Prices

This thesis, titled Essays in Macroeconomics: Consumption, Fiscal Multipliers, and Oil Prices, contains three papers in the broad macroeconomics field three chapters. Three abstracts of the papers have been presented here. Chapter 1 aims to investigate the response of consumption to transitory shocks in a heterogeneous agent model with two assets and default risk. In order to analyse this response, the paper studies the application of discrete choice techniques (Extreme Value Shocks Method/Taste Shocks Method) in several versions of the model. The method appears to be reliable in capturing the effect of endogeneity of the borrowing constraint due to default in both the one-asset and two-asset models. The baseline results show that the presence of default raises the aggregate marginal propensity to consume as the pricing of risk creates further credit frictions for many households. Furthermore, the findings also suggest that households' responses vary more widely across heterogeneous households if there are endogenous borrowing constraints and spreads. Keywords: Heterogeneous agent model, MPC, Tasteshock, Liquid/illiquid asset, Default. Chapter 2 examines the effects of social spending on GDP growth in the UK economy. The Structural Vector Autoregressive (SVAR) method with sign restriction has been applied to quarterly data for 27 years in order to assess the impact of social expenditure shocks on economic growth. The study suggests that a positive shock in social spending increases GDP growth in the short term. In addition, results are robust to different countries and under different monetary policies. Furthermore, the analysis found that negative tax shock also has a positive impact on GDP. Keywords: Social spending, GDP growth, Structural Vector Autoregressive (SVAR), Sign restriction. Chapter 3 investigates the influence of the pandemic and trade policy uncertainty on the dynamics of oil price returns over the last two decades, using a Mixed-Frequency Vector Autoregressive (MF-VAR) model. The study found that pandemic uncertainty and, more importantly, trade policy uncertainty significantly explain EU Brent and WTI oil price returns. Additionally, pandemic and trade policy uncertainty shocks are linked with lower (higher) oil price returns in the short-term (medium-term). Furthermore, while the mixed-frequency approach captures the persistent response of oil price returns to the uncertainty shocks, the single common-frequency (i.e., quarterly) framework only uncovers a muted reaction. Keywords: Oil price fluctuations, Pandemic uncertainty, Trade policy uncertainty, World uncertainty, Mixed-frequency VAR model, Mixed-frequency Granger-causality test

A dynamical view of Tijdeman's solution of the chairman assignment problem

In 1980, R. Tijdeman provided an online algorithm that generates sequences over a finite alphabet with minimal discrepancy, that is, such that the occurrence of each letter optimally tracks its frequency. We define discrete dynamical systems generating these sequences. The dynamical systems are defined as exchanges of polytopal pieces, yielding cut and project schemes, and they code tilings of the line whose sets of vertices form model sets. We prove that these sequences of low discrepancy are natural codings of toral translations with respect to polytopal atoms, and that they generate a minimal and uniquely ergodic subshift with purely discrete spectrum. Finally, we show that the factor complexity of these sequences is of polynomial growth order n d − 1 , where d is the cardinality of the alphabet

Hypertrophic cardiomyopathy management: a systematic review of the clinical practice guidelines and recommendations.

AIMS: In light of recent advances in imaging techniques, molecular understanding and therapeutic options in hypertrophic cardiomyopathy (HCM), we performed a systematic review of current guidelines for the diagnosis and management of HCM in order to identify consensus and discrepant areas in the clinical practice guidelines. METHODS AND RESULTS: We systematically reviewed the English language guidelines and recommendations for the management of HCM in adults. MEDLINE and EMBASE databases were searched for guidelines published in the last 10 years. Following a systematic search, three guidelines on the diagnosis and management of HCM were identified, all of which were robustly developed (AGREE rigour of development score ≥50%). These guidelines were authored by the major European (ESC; 2023), American (AHA/ACC/AMSSM/HRS/PACES/SCMR; 2024) and Japanese (JCS/JHFS; 2018) cardiovascular societies. There was broad consensus on echocardiographic recommendations, the medical and invasive management of HCM, the application of genetic testing and family screening, and exercise and reproductive recommendations in HCM. There were areas of variability in the definition and diagnostic criteria for HCM, cardiovascular magnetic resonance (CMR) imaging recommendations and assessment of sudden cardiac death (SCD) risk and prevention strategies. Due to the JCS/JHFS guideline being older, there are no recommendations on the use of cardiac myosin ATPase inhibitors. CONCLUSION: Contemporary guidelines for HCM achieve consensus across a broad range of criteria and recommendations concerning diagnosis and management. However, variations in the approach towards risk assessment for SCD exist between the guidelines. There are also more subtle differences concerning diagnostic criteria and the utility of late gadolinium enhancement for risk stratification, which will likely evolve as the evidence-base broadens

Self-directed violence and unclear intent presentation within a major trauma system. A multisite analysis.

BACKGROUND: Determining trauma as an act of Self-directed violence (SDV) or from high risk or unclear behaviours is challenging for trauma clinicians and may be affected by patient sex and mechanism of injury. The aim of this study was to examine the differences in characteristics and outcomes between those who have intentionally directed violence towards themselves with those of unclear intent, within a regional trauma system. METHODS: Data was collected between January 2018 and December 2021 in patients who had been identified as a result of either self-directed violence (SDV) defined as any intentional act that can cause injury to one's self, including death or participated in high-risk behaviours, where the intent was unclear (UI). Differences between female and male patients presenting with SDV and unclear intent were explored. RESULTS: Overall, 2760 patients were identified, with a median age of 39 years (IQR 28-54) and just over a quarter of females (28 %). Falls from height were the most common mechanism of injury in all groups. SDV was recorded in 45 % of patients, and previous mental health diagnoses were almost three times as prevalent in this group compared to those of unclear intent (SDV: 42 % vs UI: 13 %). In the sex-based analysis females were more likely than males to have a history of depression (49 % vs 31 %, p < 0.0001). There were few sex differences in the SDV group but women of unclear intent were older, with a quarter being aged 65 years or over (Females: 26 % vs. Males: 11 %, p < 0.0001). Females of unclear intent were also more likely to have sustained a high level fall (Females: 29 % vs. Males:11 %, p < 0.001). CONCLUSION: Previous mental health co-morbidity was associated with self-directed violence in our cohort. Yet the determinants of intent for over half of the patients were unclear. Trauma clinicians should actively enquire regarding intent of injury and escalate to clinical psychology or psychiatry teams as indicated. Those with mental health comorbidities, previous depression and older women may all have an increased risk where intent is unclear and warrants further investigation. Understanding the predictors and characteristics of unclear intent and high-risk behaviours are key to implementation of public health strategies around prevention of self-directed violence and suicide

Enhancing the performance of catalysts in turbulent premixed fuel-lean hydrogen/air combustion

Catalytic-aided combustion is a proven technique for burning highly lean and ultra-lean mixtures of hydrogen and air. However, the noble catalyst required for combustion is naturally scarce and therefore expensive. In this study, we focus on a numerical investigation to determine the best way of coating a platinum catalyst inside a catalytic hydrogen reactor. We study various planar and non-planar reactors and find that the reactor with a combination of half and full cylinders is the most effective in H2 conversion. Compared to an equivalent catalytic planar reactor, the non-planar configuration increases the H2 conversion by 30.7 %. The results show that enhancing mass and heat convection can significantly increase the H2 conversion. Furthermore, in a non-planar reactor, surfaces with an enhanced mass and heat transfer can achieve up to 50 % catalyst savings when coated with a catalyst, while still maintaining a conversion rate of 2 kg/s per unit of catalytically-coated surface area