Association between duration of gonadotrophin-releasing hormone agonist use and cardiovascular risks: A population-based competing-risk analysis

Background Although androgen deprivation therapy has known cardiovascular risks, it is unclear if its duration is related to cardiovascular risks. This study thus aimed to investigate the associations between gonadotrophin-releasing hormone (GnRH) agonist use duration and cardiovascular risks. Methods This retrospective cohort study included adult patients with prostate cancer receiving GnRH agonists in Hong Kong during 1999–2021. Patients who switched to GnRH antagonists, underwent bilateral orchidectomy, had <6 months of GnRH agonist, prior myocardial infarction (MI), or prior stroke was excluded. All patients were followed up until September 2021 for a composite endpoint of MI and stroke. Multivariable competing-risk regression using the Fine-Gray subdistribution model was used, with mortality from any cause as the competing event. Results In total, 4038 patients were analyzed (median age 74.9 years old, interquartile range (IQR) 68.7–80.8 years old). Over a median follow-up of 4.1 years (IQR 2.1–7.5 years), longer GnRH agonists use was associated with higher risk of the endpoint (sub-hazard ratio per year 1.04 [1.01–1.06], p = 0.001), with those using GnRH agonists for ≥2 years having an estimated 23% increase in the sub-hazard of the endpoint (sub-hazard ratio 1.23 [1.04–1.46], p = 0.017). Conclusion Longer GnRH agonist use may be associated with greater cardiovascular risks

Association between duration of gonadotrophin‐releasing hormone agonist use and cardiovascular risks: A population‐based competing‐risk analysis

Background Although androgen deprivation therapy has known cardiovascular risks, it is unclear if its duration is related to cardiovascular risks. This study thus aimed to investigate the associations between gonadotrophin-releasing hormone (GnRH) agonist use duration and cardiovascular risks. Methods This retrospective cohort study included adult patients with prostate cancer receiving GnRH agonists in Hong Kong during 1999–2021. Patients who switched to GnRH antagonists, underwent bilateral orchidectomy, had <6 months of GnRH agonist, prior myocardial infarction (MI), or prior stroke was excluded. All patients were followed up until September 2021 for a composite endpoint of MI and stroke. Multivariable competing-risk regression using the Fine-Gray subdistribution model was used, with mortality from any cause as the competing event. Results In total, 4038 patients were analyzed (median age 74.9 years old, interquartile range (IQR) 68.7–80.8 years old). Over a median follow-up of 4.1 years (IQR 2.1–7.5 years), longer GnRH agonists use was associated with higher risk of the endpoint (sub-hazard ratio per year 1.04 [1.01–1.06], p = 0.001), with those using GnRH agonists for ≥2 years having an estimated 23% increase in the sub-hazard of the endpoint (sub-hazard ratio 1.23 [1.04–1.46], p = 0.017). Conclusion Longer GnRH agonist use may be associated with greater cardiovascular risks

A Machine Learning Aided Systematic Review and Meta-Analysis of the Relative Risk of Atrial Fibrillation in Patients With Diabetes Mellitus

Background: Meta-analysis is a widely used tool in which weighted information from multiple similar studies is aggregated to increase statistical power. However, the exponential growth of publications in key areas of medical science has rendered manual identification of relevant studies increasingly time-consuming. The aim of this work was to develop a machine learning technique capable of robust automatic study selection for meta-analysis. We have validated this approach with an up-to-date meta-analysis to investigate the association between diabetes mellitus (DM) and new-onset atrial fibrillation (AF).Methods: The PubMed online database was searched from 1960 to September 2017 where 4,177 publications that mentioned both DM and AF were identified. Relevant studies were selected as follows. First, publications were clustered based on common text features using an unsupervised K-means algorithm. Clusters that best matched the selected set of potentially relevant studies (a “training” set of 139 articles) were then identified by using maximum entropy classification. The 139 articles selected automatically on this basis were screened manually to identify potentially relevant studies. To determine the validity of the automated process, a parallel set of studies was also assembled by manually screening all initially searched publications. Finally, detailed manual selection was performed on the full texts of the studies in both sets using standard criteria. Quality assessment, meta-regression random-effects models, sensitivity analysis and publication bias assessment were then conducted.Results: Machine learning-assisted screening identified the same 29 studies for meta-analysis as those identified by using manual screening alone. Machine learning enabled more robust and efficient study selection, reducing the number of studies needed for manual screening from 4,177 to 556 articles. A pooled analysis using the most conservative estimates indicated that patients with DM had ~49% greater risk of developing AF compared with individuals without DM. After adjusting for three additional risk factors i.e., hypertension, obesity and heart disease, the relative risk was 23%. Using multivariate adjusted models, the risk for developing AF in patients with DM was similar for all DM subtypes. Women with DM were 24% more likely to develop AF than men with DM. The risk for new-onset AF in patients with DM has also increased over the years.Conclusions: We have developed a novel machine learning method to identify publications suitable for inclusion in meta-analysis.This approach has the capacity to provide for a more efficient and more objective study selection process for future such studies. We have used it to demonstrate that DM is a strong, independent risk factor for AF, particularly for women

The Tpeak – Tend interval as an electrocardiographic risk marker of arrhythmic and mortality outcomes: a systematic review and meta-analysis

Background: The Tpeak – Tend interval, an electrocardiographic marker reflecting transmural dispersion of repolarization, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) in different clinical settings. Objective: This systematic review and meta-analysis evaluated the significance of Tpeak – Tend interval in predicting arrhythmic and/or mortality endpoints. Methods: PubMed, Embase, Cochrane Library and CINAHL Plus databases were searched through 30th November 2016.Results: Of the 854 studies identified initially, 33 observational studies involving 155856 patients were included in our meta-analysis. Tpeak – Tend interval prolongation (mean cut-off: 103.3 ± 17.4 ms) was a significant predictor of the arrhythmic or mortality outcomes (odds ratio (OR): 1.14, 95% CI: 1.11 to 1.17, p < 0.001). When different end-points were analyzed, the ORs are as follows: VT/VF (1.10, 95% CI: 1.06 to 1.13, p < 0.0001), SCD (1.27, 95% CI 1.17 to 1.39, p < 0.0001), cardiovascular death (1.40, 95% CI 1.19 to 1.64, p < 0.0001), and all-cause mortality (4.56, 95% CI 0.62 to 33.68, p < 0.0001). Subgroup analysis for each disease revealed that the risk of VT/VF or death was highest for Brugada syndrome (OR: 5.68, 95% CI: 1.57 to 20.53, p < 0.01), followed by hypertension (OR: 1.52, 95% CI: 1.26 to 1.85, p < .0001), heart failure (OR: 1.07, 95% CI: 1.04 to 1.11, p < .0001) and ischemic heart disease (OR: 1.06, 95% CI: 1.02 to 1.10, p = 0.001). In the general population, a prolonged Tpeak – Tend interval also predicted arrhythmic or mortality outcomes (OR: 1.59, 95% CI: 1.21 to 2.09, p < 0.001).Conclusion: The Tpeak – Tend interval is useful risk stratification tool in different diseases and in the general population

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

INTRODUCTION: A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. METHODS: We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case–control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). RESULTS: The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7–1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8–1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs. CONCLUSIONS: The MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer

The molecular basis of breast cancer pathological phenotypes

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or RPPA subtype. Marked nuclear pleomorphism, necrosis, inflammation and high mitotic count were associated with Basal-like subtype and have similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed using the METABRIC dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of epithelial tubule formation was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast

Percutaneous Coronary Intervention Versus Medical Therapy for Chronic Total Occlusion of Coronary Arteries:A Systematic Review and Meta-Analysis

PURPOSE OF REVIEW: Chronic total occlusion (CTO) of the coronary arteries is a significant clinical problem and has traditionally been treated by medical therapy or coronary artery bypass grafting. Recent studies have examined percutaneous coronary intervention (PCI) as an alternative option. RECENT FINDINGS: This systematic review and meta-analysis compared medical therapy to PCI for treating CTOs. PubMed and Embase were searched from their inception to March 2019 for studies that compared medical therapy and PCI for clinical outcomes in patients with CTOs. Quality of the included studies was assessed by Newcastle-Ottawa scale. The results were pooled by DerSimonian and Laird random- or fixed-effect models as appropriate. Heterogeneity between studies and publication bias was evaluated by I2 index and Egger's regression, respectively. Of the 703 entries screened, 17 studies were included in the final analysis. This comprised 11,493 participants. Compared to PCI, medical therapy including randomized and observational studies was significantly associated with higher risk of all-cause mortality (risk ratio (RR) 1.99, 95% CI 1.38-2.86), cardiac mortality (RR 2.36 (1.97-2.84)), and major adverse cardiac event (RR 1.25 (1.03-1.51)). However, no difference in the rate of myocardial infarction and repeat revascularization procedures was observed between the two groups. Univariate meta-regression demonstrated multiple covariates as independent moderating factors for myocardial infarction and repeat revascularization but not cardiac death and all-cause mortality. However, when only randomized studies were included, there was no difference in overall mortality or cardiac death. In CTO, when considering randomized and observational studies, medical therapy might be associated with a higher risk of mortality and myocardial infarction compared to PCI treatment

Disease Burden of Clostridium difficile Infections in Adults, Hong Kong, China, 2006-2014

Cross-sectional studies suggest an increasing trend in incidence and relatively low recurrence rates of Clostridium difficile infections in Asia than in Europe and North America. The temporal trend of C. difficile infection in Asia is not completely understood. We conducted a territory-wide population-based observational study to investigate the burden and clinical outcomes in Hong Kong, China, over a 9-year period. A total of 15,753 cases were identified, including 14,402 (91.4%) healthcare-associated cases and 817 (5.1%) community-associated cases. After adjustment for diagnostic test, we found that incidence increased from 15.41 cases/100,000 persons in 2006 to 36.31 cases/100,000 persons in 2014, an annual increase of 26%. This increase was associated with elderly patients, for whom incidence increased 3-fold over the period. Recurrence at 60 days increased from 5.7% in 2006 to 9.1% in 2014 (p<0.001). Our data suggest the need for further surveillance, especially in Asia, which contains ≈60% of the world’s population

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Nationwide Molecular Surveillance of Pandemic H1N1 Influenza A Virus Genomes: Canada, 2009

BACKGROUND: In April 2009, a novel triple-reassortant swine influenza A H1N1 virus ("A/H1N1pdm"; also known as SOIV) was detected and spread globally as the first influenza pandemic of the 21(st) century. Sequencing has since been conducted at an unprecedented rate globally in order to monitor the diversification of this emergent virus and to track mutations that may affect virus behavior. METHODOLOGY/PRINCIPAL FINDINGS: By Sanger sequencing, we determined consensus whole-genome sequences for A/H1N1pdm viruses sampled nationwide in Canada over 33 weeks during the 2009 first and second pandemic waves. A total of 235 virus genomes sampled from unique subjects were analyzed, providing insight into the temporal and spatial trajectory of A/H1N1pdm lineages within Canada. Three clades (2, 3, and 7) were identifiable within the first two weeks of A/H1N1pdm appearance, with clades 5 and 6 appearing thereafter; further diversification was not apparent. Only two viral sites displayed evidence of adaptive evolution, located in hemagglutinin (HA) corresponding to D222 in the HA receptor-binding site, and to E374 at HA2-subunit position 47. Among the Canadian sampled viruses, we observed notable genetic diversity (1.47 x 10⁻³ amino acid substitutions per site) in the gene encoding PB1, particularly within the viral genomic RNA (vRNA)-binding domain (residues 493-757). This genome data set supports the conclusion that A/H1N1pdm is evolving but not excessively relative to other H1N1 influenza A viruses. Entropy analysis was used to investigate whether any mutated A/H1N1pdm protein residues were associated with infection severity; however no virus genotypes were observed to trend with infection severity. One virus that harboured heterozygote coding mutations, including PB2 D567D/G, was attributed to a severe and potentially mixed infection; yet the functional significance of this PB2 mutation remains unknown. CONCLUSIONS/SIGNIFICANCE: These findings contribute to enhanced understanding of Influenza A/H1N1pdm viral dynamics