Increased burden of cardiovascular disease in people with liver disease: unequal geographical variations, risk factors and excess years of life lost

BACKGROUND: People with liver disease are at increased risk of developing cardiovascular disease (CVD), however, there has yet been an investigation of incidence burden, risk, and premature mortality across a wide range of liver conditions and cardiovascular outcomes. METHODS: We employed population-wide electronic health records (EHRs; from 1998 to 2020) consisting of almost 4 million adults to assess regional variations in disease burden of five liver conditions, alcoholic liver disease (ALD), autoimmune liver disease, chronic hepatitis B infection (HBV), chronic hepatitis C infection (HCV) and NAFLD, in England. We analysed regional differences in incidence rates for 17 manifestations of CVD in people with or without liver disease. The associations between biomarkers and comorbidities and risk of CVD in patients with liver disease were estimated using Cox models. For each liver condition, we estimated excess years of life lost (YLL) attributable to CVD (i.e., difference in YLL between people with or without CVD). RESULTS: The age-standardised incidence rate for any liver disease was 114.5 per 100,000 person years. The highest incidence was observed in NAFLD (85.5), followed by ALD (24.7), HCV (6.0), HBV (4.1) and autoimmune liver disease (3.7). Regionally, the North West and North East regions consistently exhibited high incidence burden. Age-specific incidence rate analyses revealed that the peak incidence for liver disease of non-viral aetiology is reached in individuals aged 50–59 years. Patients with liver disease had a two-fold higher incidence burden of CVD (2634.6 per 100,000 persons) compared to individuals without liver disease (1339.7 per 100,000 persons). When comparing across liver diseases, atrial fibrillation was the most common initial CVD presentation while hypertrophic cardiomyopathy was the least common. We noted strong positive associations between body mass index and current smoking and risk of CVD. Patients who also had diabetes, hypertension, proteinuric kidney disease, chronic kidney disease, diverticular disease and gastro-oesophageal reflex disorders had a higher risk of CVD, as do patients with low albumin, raised C-reactive protein and raised International Normalized Ratio levels. All types of CVD were associated with shorter life expectancies. When evaluating excess YLLs by age of CVD onset and by liver disease type, differences in YLLs, when comparing across CVD types, were more pronounced at younger ages. CONCLUSIONS: We developed a public online app (https://lailab.shinyapps.io/cvd_in_liver_disease/) to showcase results interactively. We provide a blueprint that revealed previously underappreciated clinical factors related to the risk of CVD, which differed in the magnitude of effects across liver diseases. We found significant geographical variations in the burden of liver disease and CVD, highlighting the need to devise local solutions. Targeted policies and regional initiatives addressing underserved communities might help improve equity of access to CVD screening and treatment

Erlotinib in patients with previously irradiated, recurrent brain metastases from non-small cell lung cancer: Two case reports

Background: With the current improvements in primary lung care, the long-term control of brain metastases becomes a clinical challenge. No established therapeutic approaches exist for cranial relapse after response to previous radiotherapy and systemic therapy. Tyrosine kinase inhibitors like erlotinib with its proven activity in non-small cell lung cancer may provide clinical benefits in such patients. Patients and Methods: Two case reports are presented illustrating the efficacy of erlotinib in patients with recurrent brain metastases and parallel thoracic progression. Results: Both patients showed lasting partial remissions in the brain and lung, and clinical symptom improvement. Conclusion: The observed survival times of above 18 and 15 months, respectively, since occurrence of cranial disease manifestation in line with the achieved progression-free survival times of 9 and 6 months by the erlotinib third-line therapy are remarkable. The use of targeted therapies after whole-brain irradiation should be investigated more systematically in prospective clinical trials

Aharonov-Bohm interference in topological insulator nanoribbons

Topological insulators represent novel phases of quantum matter with an insulating bulk gap and gapless edges or surface states. The two-dimensional topological insulator phase was predicted in HgTe quantum wells and confirmed by transport measurements. Recently, Bi2Se3 and related materials have been proposed as three-dimensional topological insulators with a single Dirac cone on the surface and verified by angle-resolved photoemission spectroscopy experiments. Here, we show unambiguous transport evidence of topological surface states through periodic quantum interference effects in layered single-crystalline Bi2Se3 nanoribbons. Pronounced Aharonov-Bohm oscillations in the magnetoresistance clearly demonstrate the coverage of two-dimensional electrons on the entire surface, as expected from the topological nature of the surface states. The dominance of the primary h/e oscillation and its temperature dependence demonstrate the robustness of these electronic states. Our results suggest that topological insulator nanoribbons afford novel promising materials for future spintronic devices at room temperature.Comment: 5 pages, 4 figures, RevTex forma

Virtual Recovery of Content from X-Ray Micro-Tomography Scans of Damaged Historic Scrolls

Part of this work was carried out with funding from the EPSRC (project EP/G010110/1, High defnition X-ray microtomography and advanced visualisation techniques for information recovery from unopenable historical documents), the China Postdoctoral Innovation Program (No. 230210342) and the China Scholarship Council (File No. 201406020068

Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound.

PURPOSE: Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study. EXPERIMENTAL DESIGN: Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®Liquid to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx. RESULTS: 81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor. CONCLUSIONS: We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses

Improving the sensitivity of Higgs boson searches in the golden channel

Leptonic decays of the Higgs boson in the ZZ* channel yield what is known as the golden channel due to its clean signature and good total invariant mass resolution. In addition, the full kinematic distribution of the decay products can be reconstructed, which, nonetheless, is not taken into account in traditional search strategy relying only on measurements of the total invariant mass. In this work we implement a type of multivariate analysis known as the matrix element method, which exploits differences in the full production and decay matrix elements between the Higgs boson and the dominant irreducible background from q bar{q} -> ZZ*. Analytic expressions of the differential distributions for both the signal and the background are also presented. We perform a study for the Large Hadron Collider at sqrt{s}=7 TeV for Higgs masses between 175 and 350 GeV. We find that, with an integrated luminosity of 2.5 fb^-1 or higher, improvements in the order of 10 - 20 % could be obtained for both discovery significance and exclusion limits in the high mass region, where the differences in the angular correlations between signal and background are most pronounced.Comment: 31 pages, 8 figures. v2: Minus signs in definitions of angles corrected. Typos fixed. Reference added. Cosmetic changes to Figure 4. Additional sentence added for clarificatio

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems

Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

Estimation of Parent Specific DNA Copy Number in Tumors using High-Density Genotyping Arrays

Chromosomal gains and losses comprise an important type of genetic change in tumors, and can now be assayed using microarray hybridization-based experiments. Most current statistical models for DNA copy number estimate total copy number, which do not distinguish between the underlying quantities of the two inherited chromosomes. This latter information, sometimes called parent specific copy number, is important for identifying allele-specific amplifications and deletions, for quantifying normal cell contamination, and for giving a more complete molecular portrait of the tumor. We propose a stochastic segmentation model for parent-specific DNA copy number in tumor samples, and give an estimation procedure that is computationally efficient and can be applied to data from the current high density genotyping platforms. The proposed method does not require matched normal samples, and can estimate the unknown genotypes simultaneously with the parent specific copy number. The new method is used to analyze 223 glioblastoma samples from the Cancer Genome Atlas (TCGA) project, giving a more comprehensive summary of the copy number events in these samples. Detailed case studies on these samples reveal the additional insights that can be gained from an allele-specific copy number analysis, such as the quantification of fractional gains and losses, the identification of copy neutral loss of heterozygosity, and the characterization of regions of simultaneous changes of both inherited chromosomes

Exploring novel correlations in trilepton channels at the LHC for the minimal supersymmetric inverse seesaw model

We investigate signatures of the minimal supersymmetric inverse seesaw model at the large hadron collider (LHC) with three isolated leptons and large missing energy (3\ell + \mET or 2\ell + 1\tau + \mET, with \ell=e,\mu) in the final state. This signal has its origin in the decay of chargino-neutralino (\chpm1\ntrl2) pair, produced in pp collisions. The two body decays of the lighter chargino into a charged lepton and a singlet sneutrino has a characteristic decay pattern which is correlated with the observed large atmospheric neutrino mixing angle. This correlation is potentially observable at the LHC by looking at the ratios of cross sections of the trilepton + \mET channels in certain flavour specific modes. We show that even after considering possible leading standard model backgrounds these final states can lead to reasonable discovery significance at the LHC with both 7 TeV and 14 TeV center-of-mass energy.Comment: 28 pages, 9 .eps figures. 3 new figures and discussions on LHC observables added, minor modifications in text and in the abstract, 23 new references added, matches with the published version in JHE