A new and automated risk prediction of coronary artery disease using clinical endpoints and medical imaging-derived patient-specific insights: protocol for the retrospective GeoCAD cohort study

INTRODUCTION: Coronary artery disease (CAD) is the leading cause of death worldwide. More than a quarter of cardiovascular events are unexplained by current absolute cardiovascular disease risk calculators, and individuals without clinical risk factors have been shown to have worse outcomes. The 'anatomy of risk' hypothesis recognises that adverse anatomical features of coronary arteries enhance atherogenic haemodynamics, which in turn mediate the localisation and progression of plaques. We propose a new risk prediction method predicated on CT coronary angiography (CTCA) data and state-of-the-art machine learning methods based on a better understanding of anatomical risk for CAD. This may open new pathways in the early implementation of personalised preventive therapies in susceptible individuals as a potential key in addressing the growing burden of CAD. METHODS AND ANALYSIS: GeoCAD is a retrospective cohort study in 1000 adult patients who have undergone CTCA for investigation of suspected CAD. It is a proof-of-concept study to test the hypothesis that advanced image-derived patient-specific data can accurately predict long-term cardiovascular events. The objectives are to (1) profile CTCA images with respect to variations in anatomical shape and associated haemodynamic risk expressing, at least in part, an individual's CAD risk, (2) develop a machine-learning algorithm for the rapid assessment of anatomical risk directly from unprocessed CTCA images and (3) to build a novel CAD risk model combining traditional risk factors with these novel anatomical biomarkers to provide a higher accuracy CAD risk prediction tool. ETHICS AND DISSEMINATION: The study protocol has been approved by the St Vincent's Hospital Human Research Ethics Committee, Sydney-2020/ETH02127 and the NSW Population and Health Service Research Ethics Committee-2021/ETH00990. The project outcomes will be published in peer-reviewed and biomedical journals, scientific conferences and as a higher degree research thesis

NUCLEOTIDE SEQUENCE VARIATION IN LEPTIN GENE OF MURRAH BUFFALO (BUBALUS BUBALIS)

Leptin is a 16 kD protein, synthesized by adipose tissue and is involved in regulation of feed intake, energy balance, fertility and immune functions. Present study was undertaken with the objectives of sequence characterization and studying the nucleotide variation in leptin gene in Murrah buffalo. The leptin gene consists of three exons and two introns which spans about 18.9kb, of which the first exon is not transcribed into protein. In buffaloes, the leptin gene is located on chromosome eight and maps to BBU 8q32. The leptin gene was amplified by PCR using oligonucleotide primers to obtain 289 bp fragment comprising of exon 2 and 405 bp fragment containing exon 3 of leptin gene. The amplicons were sequenced to identify variation at nucleotide level. Sequence comparison of buffalo with cattle reveals variation at five nucleotide sequences at positions 983, 1083, 1147, 1152, 1221 and all the SNPs are synonymous resulting no in change in amino acids. Three of these eight nucleotide variations have been reported for the first time in buffalo. The results indicate conservation of DNA sequence between cattle and buffalo. Nucleotide sequence variations observed at leptin gene between Bubalus bubalis and Bos taurus species revealed 97% nucleotide identity

The first documentation of the immune response to cutaneous leishmaniasis caused by Leishmania donovani in Sri Lanka.

Introduction and Objectives: The predominant form of leishmaniasis seen in Sri Lanka is cutaneous leishmaniasis (CL) caused by Leishmania donovani, a species commonly causing visceral disease. The objective of this study was to explore the human host immune response to CL in Sri Lanka. Methods: A descriptive comparative study was carried out on nine CL patients referred to the Department of Parasitology, Faculty of Medicine, University of Peradeniya, Sri Lanka, during 2011-2013. mRNA was extracted from the skin biopsy samples and reverse transcribed to cDNA and tested for Th1 and Th2 cytokines by using specific primers for IFN-γ, IL-2 (Th1 cytokines) and IL-4, IL-10 (Th2 cytokines). The results were compared with different characteristics of the lesion (number, duration, size and type of lesion). Results: This study revealed that the majority of CL patients (5/9) elicited a Th1 response whereas a Th2 response was not detected in any of the patients. Of the Th1 cytokine positive patients, majority had single lesions, with a shorter duration and smaller sized lesions which were of the plaque type. Of those which exhibited a negative Th1 response, the majority were larger lesions with a longer duration and were of the papular-nodular type. Conclusions: The study suggests that the predominant immune response to CL caused by L. donovani in Sri Lanka, is a Th1 type of response which may explain the localization of L. donovani which is usually a viscerotropic species, to skin tissue. Limitations of study: This study was done only in nine patients due to resource limitations. A continuation of this study is indicated to validate these results.</p

Genomic Surveillance of Recent Dengue Outbreaks in Colombo, Sri Lanka

All four serotypes of the dengue virus (DENV1–4) cause a phenotypically similar illness, but serial infections from different serotypes increase the risk of severe disease. Thus, genomic surveillance of circulating viruses is important to detect serotype switches that precede community outbreaks of disproportionate magnitude. A phylogenetic analysis was conducted on near full length DENV genomes sequenced from serum collected from a prospective cohort study from the Colombo district, Sri Lanka during a 28-month period using Oxford nanopore technology, and the consensus sequences were analyzed using maximum likelihood and Bayesian evolutionary analysis. From 523 patients, 328 DENV sequences were successfully generated (DENV1: 43, DENV2: 219, DENV3:66). Most circulating sequences originated from a common ancestor that was estimated to have existed from around 2010 for DENV2 and around 2015/2016 for DENV1 and DENV3. Four distinct outbreaks coinciding with monsoon rain seasons were identified during the observation period mostly driven by DENV2 cosmopolitan genotype, except for a large outbreak in 2019 contributed by DENV3 genotype I. This serotype switch did not result in a more clinically severe illness. Phylogeographic analyses showed that all outbreaks started within Colombo city and then spread to the rest of the district. In 2019, DENV3 genotype I, previously, rarely reported in Sri Lanka, is likely to have contributed to a disease outbreak. However, this did not result in more severe disease in those infected, probably due to pre-existing DENV3 immunity in the community. Targeted vector control within Colombo city before anticipated seasonal outbreaks may help to limit the geographic spread of outbreaks

Automated segmentation of normal and diseased coronary arteries – The ASOCA challenge

Cardiovascular disease is a major cause of death worldwide. Computed Tomography Coronary Angiography (CTCA) is a non-invasive method used to evaluate coronary artery disease, as well as evaluating and reconstructing heart and coronary vessel structures. Reconstructed models have a wide array of for educational, training and research applications such as the study of diseased and non-diseased coronary anatomy, machine learning based disease risk prediction and in-silico and in-vitro testing of medical devices. However, coronary arteries are difficult to image due to their small size, location, and movement, causing poor resolution and artefacts. Segmentation of coronary arteries has traditionally focused on semi-automatic methods where a human expert guides the algorithm and corrects errors, which severely limits large-scale applications and integration within clinical systems. International challenges aiming to overcome this barrier have focussed on specific tasks such as centreline extraction, stenosis quantification, and segmentation of specific artery segments only. Here we present the results of the first challenge to develop fully automatic segmentation methods of full coronary artery trees and establish the first large standardized dataset of normal and diseased arteries. This forms a new automated segmentation benchmark allowing the automated processing of CTCAs directly relevant for large-scale and personalized clinical applications

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P =.01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery

Breaking ‘128-bit Secure’ Supersingular Binary Curves

In late 2012 and early 2013 the discrete logarithm problem (DLP) in finite fields of small characteristic underwent a dramatic series of breakthroughs, culminating in a heuristic quasi-polynomial time algorithm, due to Barbulescu, Gaudry, Joux and Thomé. Using these developments, Adj, Menezes, Oliveira and Rodríguez-Henríquez analysed the concrete security of the DLP, as it arises from pairings on (the Jacobians of) various genus one and two supersingular curves in the literature, which were originally thought to be 128-bit secure. In particular, they suggested that the new algorithms have no impact on the security of a genus one curve over F21223 , and reduce the security of a genus two curve over F2367 to 94.6 bits. In this paper we propose a new field representation and efficient general descent principles which together make the new techniques far more practical. Indeed, at the ‘128-bit security level’ our analysis shows that the aforementioned genus one curve has approximately 59 bits of security, and we report a total break of the genus two curv

Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history

The distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we generated a de novo genome assembly of the black rat, 67 ancient black rat mitogenomes and 36 ancient nuclear genomes from sites spanning the 1st-17th centuries CE in Europe and North Africa. Analyses of mitochondrial DNA confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6th and 10th centuries CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.Competing Interest StatementThe authors have declared no competing interest.- Results and Discussion -- The demographic history of Rattus rattus and its closely related species -- A global phylogeography of the black rat based on mitochondrial DNA -- Ancient genomes reveal the relationships of European black rats over space and time - Discussion - Method