Next generation sequencing analysis of patients with familial cervical artery dissection

Background: The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection

Renal dysfunction and outcome in left ventricular non-compaction

Background: While renal function has been observed to inversely correlate with clinical outcome in other cardiomyopathies, its prognostic significance in patients with left ventricular non-compaction cardiomyopathy (LVNC) has not been investigated. The aim of this study was to determine the prognostic value of renal function in LVNC patients. Methods: Patients with isolated LVNC as diagnosed by echocardiography and/or magnetic resonance imaging in 4 Swiss centers were retrospectively analyzed for this study. Values for creatinine, urea, and estimated glomerular filtration rate (eGFR) as assessed by the CKD-EPI 2009 formula were collected and analyzed by a Cox regression model for the occurrence of a composite endpoint (death or heart transplantation). Results: During the median observation period of 7.4 years 23 patients reached the endpoint. The age- and gender-corrected hazard ratios (HR) for death or heart transplantation were: 1.9 (95% confidence interval [CI] 1.4–2.6) for each increase over baseline creatinine level of 30 µmol/L (p < 0.001), 1.6 (95% CI 1.2–2.2) for each increase over baseline urea level of 5 mmol/L (p = 0.004), and 3.6 (95% CI 1.9–6.9) for each decrease below baseline eGFR level of 30 mL/min (p ≤ 0.001). The HR (log2) for every doubling of creatinine was 7.7 (95% CI 3–19.8; p < 0.001), for every doubling of urea 2.5 (95% CI 1.5–4.3; p < 0.001), and for every bisection of eGFR 5.3 (95% CI 2.4–11.6; p < 0.001). Conclusions: This study provides evidence that in patients with LVNC impairment in renal function is associated with an increased risk of death and heart transplantation suggesting that kidney function assessment should be standard in risk assessment of LVNC patients

The Fermi energy as common parameter to describe charge compensation mechanisms: A path to Fermi level engineering of oxide electroceramics

Chemical substitution, which can be iso- or heterovalent, is the primary strategy to tailor material properties. There are various ways how a material can react to substitution. Isovalent substitution changes the density of states while heterovalent substitution, i.e. doping, can induce electronic compensation, ionic compensation, valence changes of cations or anions, or result in the segregation or neutralization of the dopant. While all these can, in principle, occur simultaneously, it is often desirable to select a certain mechanism in order to determine material properties. Being able to predict and control the individual compensation mechanism should therefore be a key target of materials science. This contribution outlines the perspective that this could be achieved by taking the Fermi energy as a common descriptor for the different compensation mechanisms. This generalization becomes possible since the formation enthalpies of the defects involved in the various compensation mechanisms do all depend on the Fermi energy. In order to control material properties, it is then necessary to adjust the formation enthalpies and charge transition levels of the involved defects. Understanding how these depend on material composition will open up a new path for the design of materials by Fermi level engineering

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Etablierung eines Tiermodells zur perioperativen pharmakologischen Konditionierung von Ischämie- und Reperfusionsschäden des Rückenmarks nach Crossclamping der infrarenalen Aorta beim Kaninchen

Paraplegia is a relevant risk after aortic crossclamping procedures. In addition to operative strategies, pharmacological conditioning may contribute to decrease spinal cord vulnerability during hypoxic conditions. Previous studies showed that erythropoietin has neuroprotective effects and molecule modification (carbamylation) reduces hematologic side effects. In large animal models the neurological outcome could not be determined due to necessity of animal sacrifice. This study established an ischemia and reperfusion injury model with new Zealand white rabbits. Functional neurologic outcome could be assessed using a modified Tarlov score in addition to histological examination. Carbamylated and native erythropoietin were tested against a placebo group for pharmacologic conditioning. Conditioning with native erythropoietin resulted in a significantly improved clinical and histological outcome compared to the carbamylated erythropoietin and placebo group. This model allowed important clinical assessment after aortic crossclamping and results were highly reproducible

Arterial Aneurysm Localization Is Sex-Dependent

The aim of this study was to investigate sex-dependent aneurysm distributions. A total of 3107 patients with arterial aneurysms were diagnosed from 2006 to 2016. Patients with anything other than true aneurysms, hereditary connective tissue disorders or vasculitides (n = 918) were excluded. Affected arterial sites and age at first aneurysm diagnosis were compared between women and men by an unpaired two-tailed t-test and Fisher’s exact test. The study sample consisted of 2189 patients, of whom 1873 were men (85.6%) and 316 women (14.4%) (ratio m:w = 5.9:1). Men had considerably more aneurysms in the abdominal aorta (83.4% vs. 71.1%; p p p p p p p p < 0.001). Age at disease onset and further aneurysm distribution showed no considerable difference. The infrarenal segment might be considered a natural border for aneurysm formation in men and women suspected to have distinct genetic, pathophysiologic and ontogenetic factors. Screening modalities for women at risk might need further adjustment, particularly thoracic cross-sectional imaging complementation

Gene Expression Profiling in Abdominal Aortic Aneurysms

Gene expression profiling of abdominal aortic aneurysms (AAA) indicates that chronic inflammatory responses, active matrix metalloproteinases, and degradation of the extracellular matrix components are involved in disease development and progression. This study investigates intra- and interpersonal RNA genome-wide expression profiling differences (Illumina HumanHT-12, BeadCHIP expression) of 24 AAA biopsies from 12 patients using a single gene and pathway (GeneOntology, GO enrichment) analysis. Biopsies were collected during open surgical AAA repair and according to prior finite element analysis (FEA) from regions with the highest and lowest wall stress. Single gene analysis revealed a strong heterogeneity of RNA expression parameters within the same and different AAA biopsies. The pathway analysis of all samples showed significant enrichment of genes from three different signaling pathways (integrin signaling pathway: fold change FC 1.63, p = 0.001; cholecystokinin receptor pathway: FC 1.60, p = 0.011; inflammation mediated by chemokine signaling pathway: FC 1.45, p = 0.028). These results indicate heterogeneous gene expression patterns within the AAA vascular wall. Single biopsy investigations do not permit a comprehensive characterization of activated molecular processes in AAA disease