bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome
Authors: Nieto-Marín Paloma , Tinaquero David , Utrilla Raquel G , Cebrián Jorge , González-Guerra Andrés , Crespo-García Teresa , Cámara-Checa Anabel , Rubio-Alarcón Marcos , Dago María , Alfayate Silvia , Filgueiras-Rama David , Peinado Rafael , López-Sendón José Luis , Jalife José , Tamargo Juan , Bernal Juan Antonio , Caballero Ricardo , Delpón Eva ,   the ITACA Consortium Investigators, Arribas F , Pérez-Villacastín J , Alonso-Martín J J , Atienza F , López-Sendón J L , Toquero J , Hernández-Madrid A , Delpón E 
Published: February 2021

Abstract

Aims
The transcription factor Tbx5 controls cardiogenesis and drives Scn5a expression in mice. We have identified two variants in TBX5 encoding p. D111Y and p. F206L Tbx5, respectively, in two unrelated patients with structurally normal hearts diagnosed with long QT (LQTS) and Brugada (BrS) syndrome. Here, we characterized the consequences of each variant to unravel the underlying disease mechanisms.

Methods and results
We combined clinical analysis with in vivo and in vitro electrophysiological and molecular techniques in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), HL-1 cells, and cardiomyocytes from mice trans-expressing human wild-type (WT) or mutant proteins. Tbx5 increased transcription of SCN5A encoding cardiac Nav1.5 channels, while repressing CAMK2D and SPTBN4 genes encoding Ca/calmodulin kinase IIδ (CaMKIIδ) and βIV-spectrin, respectively. These effects significantly increased Na current (INa) in hiPSC-CMs and in cardiomyocytes from mice trans-expressing Tbx5. Consequently, action potential (AP) amplitudes increased and QRS interval narrowed in the mouse electrocardiogram. p. F206L Tbx5 bound to the SCN5A promoter failed to transactivate it, thus precluding the pro-transcriptional effect of WT Tbx5. Therefore, p. F206L markedly decreased INa in hiPSC-CM, HL-1 cells and mouse cardiomyocytes. The INa decrease in p. F206L trans-expressing mice translated into QRS widening and increased flecainide sensitivity. p. D111Y Tbx5 increased SCN5A expression but failed to repress CAMK2D and SPTBN4. The increased CaMKIIδ and βIV-spectrin significantly augmented the late component of INa (INaL) which, in turn, significantly prolonged AP duration in both hiPSC-CMs and mouse cardiomyocytes. Ranolazine, a selective INaL inhibitor, eliminated the QT and QTc intervals prolongation seen in p. D111Y trans-expressing mice.

Conclusions
In addition to peak INa, Tbx5 critically regulates INaL and the duration of repolarization in human cardiomyocytes. Our original results suggest that TBX5 variants associate with and modulate the intensity of the electrical phenotype in LQTS and BrS patients.
Effect of a dedicated mitral heart team compared to a general heart team on survival: a retrospective, comparative, non-randomized interventional cohort study based on prospectively registered data
Authors: Sardari Nia Peyman , Olsthoorn Jules R , Heuts Samuel , van Kuijk Sander M J , Vainer Jindrich , Streukens Sebastian , Schalla Simon , Segers Patrique , Barenbrug Paul , Crijns Harry J G M , Maessen Jos G 
Published: February 2021

Abstract

OBJECTIVES
Although in both the US and European guidelines the ‘heart team approach’ is a class I recommendation, supporting evidence is still lacking. Therefore, we sought to provide comparative survival data of patients with mitral valve disease referred to the general and the dedicated heart team.

METHODS
In this retrospective cohort, patients evaluated for mitral valve disease by a general heart team (2009–2014) and a dedicated mitral valve heart team (2014–2018) were included. Decision-making was recorded prospectively in heart team electronic forms. The end point was overall survival from decision of the heart team.

RESULTS
In total, 1145 patients were included of whom 641 (56%) were discussed by dedicated heart team and 504 (44%) by general heart team. At 5 years, survival probability was 0.74 [95% confidence interval (CI) 0.68–0.79] for the dedicated heart team group compared to 0.70 (95% CI 0.66–0.74, P = 0.040) for the general heart team. Relative risk of mortality adjusted for EuroSCORE II, treatment groups (surgical, transcatheter and non-intervention), mitral valve pathology (degenerative, functional, rheumatic and others) and 13 other baseline characteristics for patients in the dedicated heart team was 29% lower [hazard ratio (HR) 0.71, 95% CI 0.54–0.95; P = 0.019] than for the general heart team. The adjusted relative risk of mortality was 61% lower for patients following the advice of the heart team (HR 0.39, 95% CI 0.25–0.62; P &lt; 0.001) and 43% lower for patients following the advice of the general heart team (HR 0.57, 95% CI 0.37–0.87; P = 0.010) compared to those who did not follow the advice of the heart team.

CONCLUSIONS
In this retrospective cohort, patients treated for mitral valve disease based on a dedicated heart team decision have significantly higher survival independent of the allocated treatment, mitral valve pathology and baseline characteristics.
A call to action for new global approaches to cardiovascular disease drug solutions
Authors: Figtree Gemma A , Broadfoot Keith , Casadei Barbara , Califf Robert , Crea Filippo , Drummond Grant R , Freedman Jane E , Guzik Tomasz J , Harrison David , Hausenloy Derek J , Hill Joseph A , Januzzi James L , Kingwell Bronwyn A , Lam Carolyn S P , MacRae Calum A , Misselwitz Frank , Miura Tetsuji , Ritchie Rebecca H , Tomaszewski Maciej , Wu Joseph C , Xiao Junjie , Zannad Faiez 
Published: February 2021

Abstract
Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic ‘buckets’. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased ‘omic’ approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
Risk stratification of patients undergoing transvenous lead extraction with the ELECTRa Registry Outcome Score (EROS): an ESC EHRA EORP European lead extraction ConTRolled ELECTRa registry analysis
Authors: Sidhu Baldeep S , Ayis Salma , Gould Justin , Elliott Mark K , Mehta Vishal , Kennergren Charles , Butter Christian , Deharo Jean-Claude , Kutarski Andrzej , Maggioni Aldo P , Auricchio Angelo , Kuck Karl-Heinz , Blomström-Lundqvist Carina , Bongiorni Maria Grazia , Rinaldi Christopher A ,   the ELECTRa Investigators Group
Published: February 2021

Abstract

Aims
Transvenous lead extraction is associated with a significant risk of complications and identifying patients at highest risk pre-procedurally will enable interventions to be planned accordingly. We developed the ELECTRa Registry Outcome Score (EROS) and applied it to the ELECTRa registry to determine if it could appropriately risk-stratify patients.

Methods and results
EROS was devised to risk-stratify patients into low risk (EROS 1), intermediate risk (EROS 2), and high risk (EROS 3). This was applied to the ESC EORP European Lead Extraction ConTRolled ELECTRa registry; 57.5% EROS 1, 31.8% EROS 2, and 10.7% EROS 3. Patients with EROS 3 or 2 were significantly more likely to require powered sheaths and a femoral approach to complete procedures. Patients with EROS 3 were more likely to suffer procedure-related major complications including deaths (5.1 vs. 1.3%; P &lt; 0.0001), both intra-procedural (3.5 vs. 0.8%; P = 0.0001) and post-procedural (1.6 vs. 0.5%; P = 0.0192). They were more likely to suffer post-procedural deaths (0.8 vs. 0.2%; P 0.0449), cardiac avulsion or tear (3.8 vs. 0.5%; P &lt; 0.0001), and cardiovascular lesions requiring pericardiocentesis, chest tube, or surgical repair (4.6 vs. 1.0%; P &lt; 0.0001). EROS 3 was associated with procedure-related major complications including deaths [odds ratio (OR) 3.333, 95% confidence interval (CI) 1.879–5.914; P &lt; 0.0001] and all-cause in-hospital major complications including deaths (OR 2.339, 95% CI 1.439–3.803; P = 0.0006).

Conclusion
EROS successfully identified patients who were at increased risk of significant procedural complications that require urgent surgical intervention.
Self-reported symptoms in French primary care SARS-CoV-2 patients: association with gender and age group
Authors: Sebo Paul , Maisonneuve Hubert , Lourdaux Julie , Cuzin Clara , Floquet Martin , Tudrej Benoit , Haller Dagmar M 
Published: February 2021

Abstract

Introduction
The early identification of COVID-19 patients is of outmost importance in the current pandemic. As with other pathogens, presenting symptoms of SARS-CoV-2 may vary, depending on sociodemographic factors. We aimed to describe the clinical characteristics of COVID-19 patients by age/gender and to assess whether the diagnostic performance of these symptoms varied according to these variables.

Methods
We analysed data from a cross-sectional study involving primary care patients undergoing RT-PCR testing in Lyon, France. Among patients who tested positive, we examined whether there was an association between age/gender and various symptoms. In addition, we calculated the diagnostic performance of the most specific symptoms (smell/taste disorder).

Results
Among 1543 consecutive patients, 253 tested positive (16%). There were significant age/gender-related differences in symptoms. In middle-aged women, the diagnostic performance of smell/taste disorders were AUC = 0.65 [95%CI 0.59–0.71] and PPV = 72% [95%CI 53–87%], that is higher than in the entire sample (smell/taste disorders: AUC = 0.59 [95%CI 0.57–0.62] and PPV = 57% [95%CI 47–67%]. In contrast, the negative predictive values of smell/taste disorders were similar in both groups (85% [95%CI 81–89%] for middle-age women and 86% [95%CI 85–88%] for the entire sample).

Conclusion
We found significant age/gender-related differences in the clinical characteristics of COVID-19 patients. Screening strategies based on smell/taste disorders performed better in middle-aged women, but could not ensure a diagnosis of COVID-19 in any subgroup of patients. Future diagnostic strategies should use age/gender differentiated approaches.
Soil depth matters: shift in composition and inter-kingdom co-occurrence patterns of microorganisms in forest soils
Authors: Mundra Sunil , Kjønaas O Janne , Morgado Luis N , Krabberød Anders Kristian , Ransedokken Yngvild , Kauserud Håvard 
Published: February 2021

ABSTRACT
Soil depth represents a strong physiochemical gradient that greatly affects soil-dwelling microorganisms. Fungal communities are typically structured by soil depth, but how other microorganisms are structured is less known. Here, we tested whether depth-dependent variation in soil chemistry affects the distribution and co-occurrence patterns of soil microbial communities. This was investigated by DNA metabarcoding in conjunction with network analyses of bacteria, fungi, as well as other micro-eukaryotes, sampled in four different soil depths in Norwegian birch forests. Strong compositional turnover in microbial assemblages with soil depth was detected for all organismal groups. Significantly greater microbial diversity and fungal biomass appeared in the nutrient-rich organic layer, with sharp decrease towards the less nutrient-rich mineral zones. The proportions of copiotrophic bacteria, Arthropoda and Apicomplexa were markedly higher in the organic layer, while patterns were opposite for oligotrophic bacteria, Cercozoa, Ascomycota and ectomycorrhizal fungi. Network analyses indicated more intensive inter-kingdom co-occurrence patterns in the upper mineral layer (0–5 cm) compared to the above organic and the lower mineral soil, signifying substantial influence of soil depth on biotic interactions. This study supports the view that different microbial groups are adapted to different forest soil strata, with varying level of interactions along the depth gradient.
Genome stability is guarded by yeast Rtt105 through multiple mechanisms
Authors: Corda Yves , Maestroni Laetitia , Luciano Pierre , Najem Maria Y , Géli Vincent 
Published: February 2021

AbstractTy1 mobile DNA element is the most abundant and mutagenic retrotransposon present in the genome of the budding yeast Saccharomyces cerevisiae. Protein regulator of Ty1 transposition 105 (Rtt105) associates with large subunit of RPA and facilitates its loading onto a single-stranded DNA at replication forks. Here, we dissect the role of RTT105 in the maintenance of genome stability under normal conditions and upon various replication stresses through multiple genetic analyses. RTT105 is essential for viability in cells experiencing replication problems and in cells lacking functional S-phase checkpoints and DNA repair pathways involving homologous recombination. Our genetic analyses also indicate that RTT105 is crucial when cohesion is affected and is required for the establishment of normal heterochromatic structures. Moreover, RTT105 plays a role in telomere maintenance as its function is important for the telomere elongation phenotype resulting from the Est1 tethering to telomeres. Genetic analyses indicate that rtt105Δ affects the growth of several rfa1 mutants but does not aggravate their telomere length defects. Analysis of the phenotypes of rtt105Δ cells expressing NLS-Rfa1 fusion protein reveals that RTT105 safeguards genome stability through its role in RPA nuclear import but also by directly affecting RPA function in genome stability maintenance during replication.
Racial/Ethnic Differences in Women’s Life Event Exposure Across Midlife
Authors: Koffer R E , Thurston R C , Bromberger J T , Matthews K A 
Published: February 2021

Abstract

Objective
Stressful life events are associated with poorer physical, cognitive, and mental health. Examining life events trends across midlife illustrates normative experiences of stress in a critical life period for intervention and disease prevention. Further, there is a critical need for research with racially/ethnically diverse samples to identify differences in life event exposure, as they may relate to later health disparities.

Method
Annual life event reports were analyzed from 3,066 White, Black, Hispanic, Chinese, and Japanese women in the Study of Women’s Health Across the Nation. Across ages 43–65, longitudinal trajectories were fit to annual number of life events and 9 subcategories of life events (i.e., work problems, economic problems, partner unemployment, illness/accident of loved one, caregiving, bereavement, relationship problems, family legal/police problems, and violent events that happened to the self or family). Racial/ethnic differences were examined, controlling for education.

Results
Number of annual life events declined with age and plateaued in later midlife. This pattern was largely consistent across types of life events, though family health and bereavement-related life events increased in later midlife. Compared to White women, Black women experienced more life events, while Chinese, Hispanic, and Japanese women experienced fewer life events. Racial/ethnic differences were amplified in specific subtypes of life events.

Discussion
Racial/ethnic differences in exposure to life events across midlife may contribute to racial/ethnic health disparities in later life.
Dementia-Friendly Neighborhood and the Built Environment: A Scoping Review
Authors: Gan Daniel R Y , Chaudhury Habib , Mann Jim , Wister Andrew V 
Published: February 2021

Abstract

Background and Objectives
There has been a proliferation of research on dementia-friendly communities in recent years, particularly on interpersonal and social aspects. Nonetheless, the neighborhood built environment remains a co-constituent of the lived experience of people living with dementia (PLWD) that is amenable to interventions for health and well-being in the community. This scoping review presents a narrative synthesis of empirical research on dementia-friendly neighborhoods, with a focus on the built environment and its associated sociobehavioral aspects. Planning and design principles are distilled to identify research and policy implications.

Research Design and Methods
We reviewed 29 articles identified through a systematic search of AgeLine, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Global Health, Medical Literature Analysis and Retrieval System Online, and Scopus. Peer-reviewed articles that employed quantitative and/or qualitative methods in community settings were included.

Results
An equal number of studies focused on behavioral/psychosocial aspects of the built environment and assessment of specific environmental features. The former often used qualitative methods, whereas statistical methods were common in studies on discrete features of the neighborhood built environment. Few studies focused on rural contexts. Emerging research areas include interactions between dementia risk factors and neighborhood environments to support primary and secondary prevention.

Discussion and Implications
The body of literature needs expansion into planning and design fields to foster community participation of PLWD by optimizing environmental stimuli, minimizing environmental barriers, and engaging PLWD in dementia-friendly community initiatives. While evidence has accumulated on landmarks and social participation at the individual level, research at the community and policy levels is limited. This requires advanced mixed methods.
The interplay of fast waves and slow convection in geodynamo simulations nearing Earth’s core conditions
Authors: Aubert Julien , Gillet Nicolas 
Published: February 2021

SUMMARY
Ground observatory and satellite-based determinations of temporal variations in the geomagnetic field probe a decadal to annual timescale range where Earth’s core slow, inertialess convective motions and rapidly propagating, inertia-bearing hydromagnetic waves are in interplay. Here we numerically model and jointly investigate these two important features with the help of a geodynamo simulation that (to date) is the closest to the dynamical regime of Earth’s core. This model also considerably enlarges the scope of a previous asymptotic scaling analysis, which in turn strengthens the relevance of the approach to describe Earth’s core dynamics. Three classes of hydrodynamic and hydromagnetic waves are identified in the model output, all with propagation velocity largely exceeding that of convective advection: axisymmetric, geostrophic Alfvén torsional waves, and non-axisymmetric, quasi-geostrophic Alfvén and Rossby waves. The contribution of these waves to the geomagnetic acceleration amounts to an enrichment and flattening of its energy density spectral profile at decadal timescales, thereby providing a constraint on the extent of the $f^{-4}$ range observed in the geomagnetic frequency power spectrum. As the model approaches Earth’s core conditions, this spectral broadening arises because the decreasing inertia allows for waves at increasing frequencies. Through non-linear energy transfers with convection underlain by Lorentz stresses, these waves also extract an increasing amount of energy from the underlying convection as their key timescale decreases towards a realistic value. The flow and magnetic acceleration energies carried by waves both linearly increase with the ratio of the magnetic diffusion timescale to the Alfvén timescale, highlighting the dominance of Alfvén waves in the signal and the stabilizing control of magnetic dissipation at non-axisymmetric scales. Extrapolation of the results to Earth’s core conditions supports the detectability of Alfvén waves in geomagnetic observations, either as axisymmetric torsional oscillations or through the geomagnetic jerks caused by non-axisymmetric waves. In contrast, Rossby waves appear to be too fast and carry too little magnetic energy to be detectable in geomagnetic acceleration signals of limited spatio-temporal resolution.
ADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in Huntington’s disease
Authors: Cozzolino Flora , Vezzoli Elena , Cheroni Cristina , Besusso Dario , Conforti Paola , Valenza Marta , Iacobucci Ilaria , Monaco Vittoria , Birolini Giulia , Bombaci Mauro , Falqui Andrea , Saftig Paul , Rossi Riccardo L , Monti Maria , Cattaneo Elena , Zuccato Chiara 
Published: February 2021

Abstract
Synaptic dysfunction and cognitive decline in Huntington’s disease (HD) involve hyperactive A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). To identify the molecular mechanisms through which ADAM10 is associated with synaptic dysfunction in HD, we performed an immunoaffinity purification–mass spectrometry (IP–MS) study of endogenous ADAM10 in the brains of wild-type and HD mice. We found that proteins implicated in synapse organization, synaptic plasticity, and vesicle and organelles trafficking interact with ADAM10, suggesting that it may act as hub protein at the excitatory synapse. Importantly, the ADAM10 interactome is enriched in presynaptic proteins and ADAM10 co-immunoprecipitates with piccolo (PCLO), a key player in the recycling and maintenance of synaptic vesicles. In contrast, reduced ADAM10/PCLO immunoprecipitation occurs in the HD brain, with decreased density of synaptic vesicles in the reserve and docked pools at the HD presynaptic terminal. Conditional heterozygous deletion of ADAM10 in the forebrain of HD mice reduces active ADAM10 to wild-type level and normalizes ADAM10/PCLO complex formation and synaptic vesicle density and distribution. The results indicate that presynaptic ADAM10 and PCLO are a relevant component of HD pathogenesis.
Regulating Infrastructure: Human Rights and the Sustainable Development Goals in Myanmar
Authors: Palmer Emma 
Published: February 2021

Abstract
Infrastructure projects, including roads, railways, power, telecommunications and water facilities, are considered necessary to promote many different human rights and the Sustainable Development Goals (SDGs). Infrastructure development has been a central feature of the Myanmar government’s policies, including the Myanmar Sustainable Development Plan 2018–2030, to sustain economic growth and achieve the SDGs. As in many countries, public–private partnerships are promoted to help implement these policies. Yet, infrastructure projects have been associated with serious human rights violations, including in Myanmar. This article explores the links between infrastructure, international human rights law and the SDGs. It analyses how this relationship is governed by international, domestic, ‘soft’ law and self-regulatory mechanisms. It then assesses Myanmar’s legal and policy framework for promoting infrastructure investment and implementing the SDGs. It concludes that there is scope to further clarify responsibilities and accountability mechanisms for the human rights impacts of infrastructure investment.