The object binary interface: C++ objects for evolvable shared class libraries

Object-oriented design and object-oriented languages support the development of independent software components such as class libraries. When using such components, versioning becomes a key issue. While various ad-hoc techniques and coding idioms have been used to provide versioning, all of these techniques have deficiencies - ambiguity, the necessity of recompilation or re-coding, or the loss of binary compatibility of programs. Components from different software vendors are versioned at different times. Maintaining compatibility between versions must be consciously engineered. New technologies such as distributed objects further complicate libraries by requiring multiple implementations of a type simultaneously in a program. This paper describes a new C++ object model called the Shared Object Model for C++ users and a new implementation model called the Object Binary Interface for C++ implementors. These techniques provide a mechanism for allowing multiple implementations of an object in a program. Early analysis of this approach has shown it to have performance broadly comparable to conventional implementations

Protected Health Information filter (Philter): accurately and securely de-identifying free-text clinical notes.

There is a great and growing need to ascertain what exactly is the state of a patient, in terms of disease progression, actual care practices, pathology, adverse events, and much more, beyond the paucity of data available in structured medical record data. Ascertaining these harder-to-reach data elements is now critical for the accurate phenotyping of complex traits, detection of adverse outcomes, efficacy of off-label drug use, and longitudinal patient surveillance. Clinical notes often contain the most detailed and relevant digital information about individual patients, the nuances of their diseases, the treatment strategies selected by physicians, and the resulting outcomes. However, notes remain largely unused for research because they contain Protected Health Information (PHI), which is synonymous with individually identifying data. Previous clinical note de-identification approaches have been rigid and still too inaccurate to see any substantial real-world use, primarily because they have been trained with too small medical text corpora. To build a new de-identification tool, we created the largest manually annotated clinical note corpus for PHI and develop a customizable open-source de-identification software called Philter ("Protected Health Information filter"). Here we describe the design and evaluation of Philter, and show how it offers substantial real-world improvements over prior methods

PatientExploreR: an extensible application for dynamic visualization of patient clinical history from electronic health records in the OMOP common data model.

MotivationElectronic health records (EHRs) are quickly becoming omnipresent in healthcare, but interoperability issues and technical demands limit their use for biomedical and clinical research. Interactive and flexible software that interfaces directly with EHR data structured around a common data model (CDM) could accelerate more EHR-based research by making the data more accessible to researchers who lack computational expertise and/or domain knowledge.ResultsWe present PatientExploreR, an extensible application built on the R/Shiny framework that interfaces with a relational database of EHR data in the Observational Medical Outcomes Partnership CDM format. PatientExploreR produces patient-level interactive and dynamic reports and facilitates visualization of clinical data without any programming required. It allows researchers to easily construct and export patient cohorts from the EHR for analysis with other software. This application could enable easier exploration of patient-level data for physicians and researchers. PatientExploreR can incorporate EHR data from any institution that employs the CDM for users with approved access. The software code is free and open source under the MIT license, enabling institutions to install and users to expand and modify the application for their own purposes.Availability and implementationPatientExploreR can be freely obtained from GitHub: https://github.com/BenGlicksberg/PatientExploreR. We provide instructions for how researchers with approved access to their institutional EHR can use this package. We also release an open sandbox server of synthesized patient data for users without EHR access to explore: http://patientexplorer.ucsf.edu.Supplementary informationSupplementary data are available at Bioinformatics online

Paleogene deepwater mass composition of the tropical Pacific and implications for thermohaline circulation in a greenhouse world

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94621/1/ggge1162.pd

Assessment of microplastic-sorbed contaminant bioavailability through analysis of biomarker gene expression in larval zebrafish

publisher: Elsevier articletitle: Assessment of microplastic-sorbed contaminant bioavailability through analysis of biomarker gene expression in larval zebrafish journaltitle: Marine Pollution Bulletin articlelink: http://dx.doi.org/10.1016/j.marpolbul.2016.12.055 content_type: article copyright: © 2016 The Authors. Published by Elsevier Ltd

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Existence of a novel clathrin-independent endocytic pathway in yeast that depends on Rho1 and formin

Much like mammalian cells, yeast contain a Rho-dependent pathway for endocytosis in addition to canonical clathrin-dependent endocytosis

Carcinoma of an unknown primary: are EGF receptor, Her-2/neu, and c-Kit tyrosine kinases potential targets for therapy?

Carcinomas of an unknown primary site (CUP) are heterogeneous tumours with a median survival of only 8 months. Tyrosine kinase inhibitors are promising new drugs. The aim of this study was to determine the expression of EGF-receptor, Her-2/neu, and c-Kit tyrosine kinases in CUP. Paraffin-embedded specimens were obtained from 54 patients with a CUP who were included in the GEFCAPI 01 randomised phase II trial. Immunohistochemistry was performed using the Dako autostainer with antibodies directed against HER-2/neu protein, EGFR protein, and c-Kit protein (CD117). EGFR expression was found in 36 out of 54 samples (66%). In contrast, Her-2/neu overexpression and c-Kit positivity were only detected in 4 and 10% of patients, respectively. No significant association was found between the expression of the tyrosine kinase receptors and prognosis. EGFR expression was significantly associated with response to cisplatin-based chemotherapy: the response rates were 50 and 22% in patients with EGFR-positive tumours and EGFR-negative tumours, respectively (P<0.05). This study shows that EGFR is frequently expressed in CUP. This finding may prompt clinical trials investigating EGFR inhibitors in this setting. In contrast, c-Kit expression and Her-2/neu overexpression occur infrequently in CUP. EGFR expression was correlated to tumour chemosensitivity

SARS-CoV-2 evolution during treatment of chronic infection

SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE21, and is a major 54 antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising 55 antibodies in an immune suppressed individual treated with convalescent plasma, generating 56 whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was 57 observed in the overall viral population structure following two courses of remdesivir over the 58 first 57 days. However, following convalescent plasma therapy we observed large, dynamic 59 virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and 60 H69/V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred 61 serum antibodies diminished, viruses with the escape genotype diminished in frequency, before 62 returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape 63 double mutant bearing H69/V70 and D796H conferred modestly decreased sensitivity to 64 convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be 65 the main contributor to decreased susceptibility but incurred an infectivity defect. The 66 H69/V70 single mutant had two-fold higher infectivity compared to wild type, possibly 67 compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS68 CoV-2 during convalescent plasma therapy associated with emergence of viral variants with 69 evidence of reduced susceptibility to neutralising antibodies.COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute