Notes

Aimed towards TAM in order to Control Pancreatic Cancers.
COVID-19, like all pandemics, has territorial specificities that needs to be considered the impact of the COVID-19 crisis strongly differs not only across countries, but also across regions, districts and municipalities within countries. There are several factors that, potentially, can contribute to the differentiated impact of COVID-19, and explain the disparities seen among areas. This study aims to contribute to this debate by analysing the role of health system and social trust in lessening the impact of the Covid-19 pandemic in French départements.

The data used in this study have been provided by the INSEE and the French Ministry of Health. Database is made up of the 96 départements of metropolitan France. We use spatial analysis techniques to identify the groups of areas that are particularly affected, and to test the influence of local socioeconomic factors on the spread of the epidemic.

Our exploratory spatial analysis reveals the heterogeneity and spatial autocorrelation of the disease. The use of spatial econometric models, then, allows us to highlight the impact of emergency services, and social capital in reducing the exposition to Covid-19. Our results also report on the role of spillover effects between neighbouring areas.

This research shows that, although individual characteristics are important factors in explaining the probability of contracting Covid-19 desease, health care services and social trust factors also play a significant role in curbing the epidemic's outbreak. These findings should have an interest for policy makers in the prevention of future waves of Covid-19 pandemic.
This research shows that, although individual characteristics are important factors in explaining the probability of contracting Covid-19 desease, health care services and social trust factors also play a significant role in curbing the epidemic's outbreak. These findings should have an interest for policy makers in the prevention of future waves of Covid-19 pandemic.The two cell-type C4 photosynthetic pathway requires both anatomical and biochemical specialisation to achieve a functional CO2 concentrating mechanism. While a great deal of research has been done on Kranz anatomy and cell specific expression and activity of enzymes in the C4 pathway, less attention has been paid to partitioning of carbohydrate synthesis between the cell types of C4 leaves. As early as the 1970s it became apparent that, in the small number of species examined at the time, sucrose was predominantly synthesised in the mesophyll cells and starch in the bundle sheath cells. Here we discuss how this partitioning is achieved in C4 plants and explore whether this is a consequence of C4 metabolism or indeed a requirement for its evolution and efficient operation.Embryonic formation and patterning of the vertebrate spinal column requires coordination of many molecular cues. After birth, the integrity of the spine is impacted by developmental abnormalities of the skeletal, muscular and nervous systems, which may result in deformities, such as kyphosis and scoliosis. We sought to identify novel genetic mouse models of severe spine deformity by implementing in vivo skeletal radiography as part of a high-throughput saturation mutagenesis screen. We report selected examples of genetic mouse models following radiographic screening of 54,497 mice from 1275 pedigrees. An estimated 30.44% of autosomal genes harbored predicted damaging alleles examined twice or more in the homozygous state. Of the 1275 pedigrees screened, 7.4% presented with severe spine deformity developing in multiple mice, and of these, meiotic mapping implicated N-ethyl-N-nitrosourea alleles in 21% of pedigrees. Our study provides proof of concept that saturation mutagenesis is capable of discovering novel mouse models of human disease, including conditions with skeletal, neural and neuromuscular pathologies. Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3. By integrating results with a human clinical exome database, we identified a patient with undiagnosed skeletal disease who harbored recessive mutations in SCUBE3, and we demonstrated that disease-associated mutations are associated with reduced transactivation of Smad signaling in vitro. All radiographic results and mouse models are made publicly available through the Mutagenetix online database with the goal of advancing understanding of spine development and discovering novel mouse models of human disease.
Digital ulcers (DUs) related to digital occlusive arterial disease (DOAD) are frequent in patients with systemic sclerosis (SSc). Finger systolic blood pressure (FSBP) and digital-brachial pressure index (DBI) using laser Doppler flowmetry constitute a non-invasive means of detecting DOAD in SSc, although thresholds have yet to be established for defining DOAD. The purpose of this study was to ascertain FSBP and DBI thresholds to detect DOAD in SSc patients. The intra/interday reproducibility of curve reading by 4 vascular physicians in relation to finger pressure measurement was also investigated.

SSc patients were followed in this single-center study (Rennes University Hospital, France) between November 2017 and October 2019.Theses patients underwent tests before and after heating at two visits spaced 10 days apart. DOAD was diagnosed on the basis of post-warming skin blood flow of ≤ 206 arbitrary units measured by LDF, contingent on previous results validated by arteriography as a gold standard. An interday kappa coefficient with a 95% confidence interval was used to assess reproducibility.

16 (10 females; mean age 63 ± 9 years) SSc patients were included. Mean time interval between visits was 9 ± 5 days. The best FSBP threshold for DOAD diagnosis was 76 mmHg and DBI was 0.74 after warming. FSBP and DBI sensitivity/specificity were 59.1%[49.6%; 68.5%]/92.5% [85.3%; 99.6%] and 73.3%[64.9%; 81.8%]/83.0% [72.9%; 93.1%] respectively. Intra/interday reproducibility ranged from fair to good.

The conclusions drawn from this study suggest that FSBP ≤ 76 mmHg and DBI ≤ 0.74 thresholds are potentially reliable indicators of DOAD and demonstrate fair to good intra and interday reproducibility.
The conclusions drawn from this study suggest that FSBP ≤ 76 mmHg and DBI ≤ 0.74 thresholds are potentially reliable indicators of DOAD and demonstrate fair to good intra and interday reproducibility.
Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.

We employed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs - leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducibliated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome.This article provides a brief overview of drug resistance to antiviral therapy as well as known and emergent variability in key SARS-CoV-2 viral sequences. The purpose is to stimulate deliberation about the need to consider drug resistance prior to widespread roll-out of antivirals for SARS-CoV-2. Many existing candidate agents have mechanisms of action involving drug targets likely to be critical for future drug development. Resistance emerged quickly with monotherapies deployed for other pulmonary viruses such as influenza virus, and in HIV mutations in key drug targets compromised efficacy of multiple drugs within a class. The potential for drug resistance in SARS-CoV-2 has not yet been rigorously debated or assessed, and we call for more academic and industry research on this potentially important future threat prior to widespread roll-out of monotherapies for COVID-19 treatment and prevention.
Ventricular tachycardia (VT) substrate-based ablation has an increasing role in patients with structural heart disease-related VT. VT is linked to re-entry in relation to myocardial scarring with areas of conduction block (core scar) and areas of slow conduction [border zone (BZ)]. VT substrate can be analysed by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Our study aims to analyse the role of LGE-CMR in identifying predictors of VT recurrence after ablation.

We analysed 110 consecutive patients who underwent VT ablation from 2013 to 2018. All patients underwent a preprocedural LGE-CMR, and in 94 patients (85.5%), the CMR was used to aid the ablation. All LGE-CMR images were semi-automatically processed using dedicated software to detect scarring and conducting channels. After a median follow-up of 2.7 ± 1.6 years, the overall VT recurrence was 41.8% with an implantable cardioverter-defibrillator shock reduction from 43.6% to 28.2% before and after ablation, respectively. The amount s a helpful and feasible technique to identify patients with high risk of VT recurrence after ablation. LV mass, septal LGE distribution, and transmural channels were predictive factors of post-ablation VT recurrence.
The current study evaluates survival rates among Systemic Sclerosis-associated Pulmonary Arterial Hypertension (SSc-PAH) patients on intravenous (IV) prostanoids, and short-term impact of IV prostanoids on clinical and haemodynamic parameters.

Baseline demographics, invasive and non-invasive data, ESC (European Society of Cardiology) score and REVEAL score of 81 SSc-PAH patients (median age 61 years, interquartile range 54-67 years, 84% females) were prospectively recorded, from November 2006 till November 2020, before initiation of IV prostanoids, and at first formal reassessment. Survival data were retrieved from National Health Service Spine and hospital databases.

Significant improvements in clinical and haemodynamic parameters in response to IV prostanoid therapy were documented. Functional class (FC) (16.6% improved by 1FC, p = 0.041), mean pulmonary arterial pressure (-6.5mmHg, p = 0.036), pulmonary vascular resistance (PVR) (-2.6 WU, p = 0.012), cardiac index (CI) (+0.7l/min/m2, p = 0.003) and mixed venous oxygen saturation (SvO2) (+3%, p = 0.036), improved. Estimated survival for CTD-PAH patients on IV prostanoids was 64%, 31%, and 18%, at 1-year, 3-years, and 5-years, respectively. Independent baseline predictors of mortality were older age (HR1.043, 95% CI 1.011-1.075, p = 0.007), higher N-terminal pro-brain natriuretic peptide levels (HR2.191, 95% CI 1.131-4.243, p = 0.020), and lower SvO2 levels (HR0.962, 95% CI0.926-0.998, p = 0.039). High ESC risk or high and very high REVEAL score was associated with significantly worse survival compared to patients with lower risk scores, both at baseline and when reassessed after a median of 6.5 months.

Survival among SSc-PAH patients on IV prostanoids remains poor, risk scoring at baseline and after 6.5-months therapy improves prognostication.
Survival among SSc-PAH patients on IV prostanoids remains poor, risk scoring at baseline and after 6.5-months therapy improves prognostication.
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