Fixed Point Approximation for Asymptotically Nonexpansive Type Mappings in Uniformly Convex Hyperbolic Spaces

We use a modified S-iterative process to prove some strong and Δ-convergence results for asymptotically nonexpansive type mappings in uniformly convex hyperbolic spaces, which includes Banach spaces and CAT(0) spaces. Thus, our results can be viewed as extension and generalization of several known results in Banach spaces and CAT(0) spaces (see, e.g., Abbas et al. (2012), Abbas et al. (2013), Bruck et al. (1993), and Xin and Cui (2011)) and improve many results in the literature

Understanding the functional impact of copy number alterations in breast cancer using a network modeling approach

Copy number alterations (CNAs) are thought to account for 85% of the variation in gene expression observed among breast tumours. The expression of cis-associated genes is impacted by CNAs occurring at proximal loci of these genes, whereas the expression of trans-associated genes is impacted by CNAs occurring at distal loci. While a majority of these CNA-driven genes responsible for breast tumourigenesis are cis-associated, trans-associated genes are thought to further abet the development of cancer and influence disease outcomes in patients. Here we present a network-based approach that integrates copy-number and expression profiles to identify putative cis- and trans-associated genes in breast cancer pathogenesis. We validate these cis- and trans-associated genes by employing them to subtype a large cohort of breast tumours obtained from the METABRIC consortium, and demonstrate that these genes accurately reconstruct the ten subtypes of breast cancer. We observe that individual breast cancer subtypes are driven by distinct sets of cis- and trans-associated genes. Among the cis-associated genes, we recover several known drivers of breast cancer (e.g. CCND1, ERRB2, MDM2 and ZNF703) and some novel putative drivers (e.g. BRF2 and SF3B3). siRNA-mediated knockdown of BRF2 across a panel of breast cancer cell lines showed significant reduction specifically in cell proliferation in HER2+ lines, thereby indicating that BRF2 could be a context-dependent oncogene and potentially targetable in these lines. Among the trans-associated genes, we identify modules of immune-response (CD2, CD19, CD38 and CD79B), mitotic/cell-cycle kinases (e.g. AURKB, MELK, PLK1 and TTK), and DNA-damage response genes (e.g. RFC4 and FEN1).Comment: 23 pages, 2 tables, 7 figure

Molecular signatures in breast cancer

The use of molecular signatures to add value to standard clinical and pathological parameters has impacted clinical practice in many cancer types, but perhaps most notably in the breast cancer field. This is, in part, due to the considerable complexity of the disease at the clinical, morphological and molecular levels. The adoption of molecular profiling of DNA, RNA and protein continues to reveal important differences in the intrinsic biology between molecular subtypes and has begun to impact the way patients are managed. Several bioinformatic tools have been developed using DNA or RNA-based signatures to stratify the disease into biologically and/or clinically meaningful subgroups. Here, we review the approaches that have been used to develop gene expression signatures into currently available diagnostic assays (e.g., OncotypeDX® and Mammaprint®), plus we describe the latest work on genome sequencing, the methodologies used in the discovery process of mutational signatures, and the potential of these signatures to impact the clinic

Foodborne Outbreak Investigation in a Festival at Panchkhal Municipality of Kavrepalanchok District in Central Nepal

Background: On September 2018, cluster of gastrointestinal cases following feast of Teej Festival was reported in Panchkhal Municipality of Kavrepalanchok, Nepal. The outbreak was investigated to identify the possible source of infection, causative agent and guide local control measures for prevention and control of the outbreak. Methods: Demographic and clinical details were collected from the cases, and the outbreak was described by time, place and person. Fourteen key informant interviews were conducted to assess the probable cause of infection, practice of food handling and preparation, source of drinking water. Semi-structured questionnaires were used to collect data from the cases. Blood examination, stool examination and culture and hepatitis serological test were done. Samples from wells and ponds were collected and microbiological tests were done in National Public Health Laboratory. Results: A total of 452 cases were identified with gastrointestinal illness and no reported deaths. All the affected population had taken food from the same place during the festival where children being more affected. Two stool samples detected Entamoeba Histolytica and some showed pus cells with no cyst or ova of organisms. Stool culture was negative. No definitive source of infection detected but was suspected to be due to improper food handling. Conclusion: This investigations confirmed the food borne outbreak in Panchkhal Municipality. The definitive causative agent of the foodborne outbreak was not identified. Proper and timely response to the outbreak is of utmost important, and can reduce the severity of the illness and halt further spread of the epidemics

Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer

The Homologous Recombination (HR) pathway is crucial for the repair of DNA double-strand breaks (DSBs) generated during DNA replication. Defects in HR repair have been linked to the initiation and development of a wide variety of human malignancies, and exploited in chemical, radiological and targeted therapies. In this study, we performed a personalised pathway analysis independently for four large sporadic breast cancer cohorts to investigate the status of HR pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics. Specifically, we first manually curated a list of HR genes according to our recent review on this pathway (Liu et al., 2014), and then applied a personalised pathway analysis method named Pathifier (Drier et al., 2013) on the expression levels of the curated genes to obtain an HR score quantifying HR pathway dysregulation in individual tumours. Based on the score, we observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes, and by using two published HR-defect signatures, we found HR pathway dysregulation reflects HR repair deficiency. Furthermore, we identified a novel association between HR pathway dysregulation and chromosomal instability (CIN) in sporadic breast cancer. Although GIN has long been considered as a hallmark of most solid tumours, with recent extensive studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in sporadic cancers remains poorly understood. Our results imply that HR pathway dysregulation might contribute to CIN in sporadic breast cancer. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved

Infants with esophageal atresia and right aortic arch: Characteristics and outcomes from the Midwest Pediatric Surgery Consortium

Purpose Right sided aortic arch (RAA) is a rare anatomic finding in infants with esophageal atresia with or without tracheoesophageal fistula (EA/TEF). In the presence of RAA, significant controversy exists regarding optimal side for thoracotomy in repair of the EA/TEF. The purpose of this study was to characterize the incidence, demographics, surgical approach, and outcomes of patients with RAA and EA/TEF. Methods A multi-institutional, IRB approved, retrospective cohort study of infants with EA/TEF treated at 11 children's hospitals in the United States over a 5-year period (2009 to 2014) was performed. All patients had a minimum of one-year follow-up. Results In a cohort of 396 infants with esophageal atresia, 20 (5%) had RAA, with 18 having EA with a distal TEF and 2 with pure EA. Compared to infants with left sided arch (LAA), RAA infants had a lower median birth weight, (1.96 kg (IQR 1.54–2.65) vs. 2.57 kg (2.00–3.03), p = 0.01), earlier gestational age (34.5 weeks (IQR 32–37) vs. 37 weeks (35–39), p = 0.01), and a higher incidence of congenital heart disease (90% vs. 32%, p  0.29). Conclusion RAA in infants with EA/TEF is rare with an incidence of 5%. Compared to infants with EA/TEF and LAA, infants with EA/TEF and RAA are more severely ill with lower birth weight and higher rates of prematurity and complex congenital heart disease. In neonates with RAA, surgical repair of the EA/TEF is technically feasible via thoracotomy from either chest. A higher incidence of anastomotic strictures may occur with a right-sided approach

Gastroesophageal Reflux and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) and Gastroesophageal reflux disease (GERD) commonly co-exist. Pathophysiological mechanisms causing IPF are still not well understood, and GERD has been implicated in both as a probable causative and disease-promoting entity. Although not conclusively proven, this relationship has been the subject of several studies, including therapeutic interventions aimed at treating GERD and its resultant effect on IPF and related outcomes. Our review aims to present the current concepts and understanding of these two disease processes, which are multifaceted. Their complex interaction includes epidemiology, pathophysiology, diagnosis, treatment, review of research studies conducted to date, and future directions for research

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity

Changing the Paradigm for Management of Pediatric Primary Spontaneous Pneumothorax: A Simple Aspiration Test Predicts Need for Operation

Purpose Chest tube (CT) management for pediatric primary spontaneous pneumothorax (PSP) is associated with long hospital stays and high recurrence rates. To streamline management, we explored simple aspiration as a test to predict need for surgery. Methods A multi-institution, prospective pilot study of patients with first presentation for PSP at 9 children’s hospitals was performed. Aspiration was performed through a pigtail catheter, followed by 6 h observation with CT clamped. If pneumothorax recurred during observation, the aspiration test failed and subsequent management was per surgeon discretion. Results Thirty-three patients were managed with simple aspiration. Aspiration was successful in 16 of 33 (48%), while 17 (52%) failed the aspiration test and required hospitalization. Twelve who failed aspiration underwent CT management, of which 10 (83%) failed CT management owing to either persistent air leak requiring VATS or subsequent PSP recurrence. Recurrence rate was significantly greater in the group that failed aspiration compared to the group that passed aspiration [10/12 (83%) vs 7/16 (44%), respectively, P = 0.028]. Conclusion Simple aspiration test upon presentation with PSP predicts chest tube failure with 83% positive predictive value. We recommend changing the PSP management algorithm to include an initial simple aspiration test, and if that fails, proceed directly to VATS

Trends in future health financing and coverage: future health spending and universal health coverage in 188 countries, 2016–40

Background: Achieving universal health coverage (UHC) requires health financing systems that provide prepaid pooled resources for key health services without placing undue financial stress on households. Understanding current and future trajectories of health financing is vital for progress towards UHC. We used historical health financing data for 188 countries from 1995 to 2015 to estimate future scenarios of health spending and pooled health spending through to 2040. Methods: We extracted historical data on gross domestic product (GDP) and health spending for 188 countries from 1995 to 2015, and projected annual GDP, development assistance for health, and government, out-of-pocket, and prepaid private health spending from 2015 through to 2040 as a reference scenario. These estimates were generated using an ensemble of models that varied key demographic and socioeconomic determinants. We generated better and worse alternative future scenarios based on the global distribution of historic health spending growth rates. Last, we used stochastic frontier analysis to investigate the association between pooled health resources and UHC index, a measure of a country's UHC service coverage. Finally, we estimated future UHC performance and the number of people covered under the three future scenarios. Findings: In the reference scenario, global health spending was projected to increase from US$10 trillion (95$20 trillion (18 trillion to 22 trillion) in 2040. Per capita health spending was projected to increase fastest in upper-middle-income countries, at 4·2% (3·4–5·1) per year, followed by lower-middle-income countries (4·0%, 3·6–4·5) and low-income countries (2·2%, 1·7–2·8). Despite global growth, per capita health spending was projected to range from only $40 (24–65) to$413 (263–668) in 2040 in low-income countries, and from $140 (90–200) to$1699 (711–3423) in lower-middle-income countries. Globally, the share of health spending covered by pooled resources would range widely, from 19·8% (10·3–38·6) in Nigeria to 97·9% (96·4–98·5) in Seychelles. Historical performance on the UHC index was significantly associated with pooled resources per capita. Across the alternative scenarios, we estimate UHC reaching between 5·1 billion (4·9 billion to 5·3 billion) and 5·6 billion (5·3 billion to 5·8 billion) lives in 2030. Interpretation: We chart future scenarios for health spending and its relationship with UHC. Ensuring that all countries have sustainable pooled health resources is crucial to the achievement of UHC. Funding: The Bill & Melinda Gates Foundation