Shaping the future US bioeconomy through safety, security, sustainability, and social responsibility.

Biomanufacturing practitioners and researchers describe the norms that should govern the growing, global field, to include safety, security, sustainability, and social responsibility. These '4S Principles' should be broadly adopted so that the future of the field may provide the greatest benefits to society.

Information Asymmetry in Hospitals: Evidence of the Lack of Cost Awareness in Clinicians.

BACKGROUND: Information asymmetries and the agency relationship are two defining features of the healthcare system. These market failures are often used as a rationale for government intervention. Many countries have government financing and provision of healthcare in order to correct for this, while health technology agencies also exist to improve efficiency. However, informational asymmetries and the resulting principal-agent problem still persist, and one example is the lack of cost awareness amongst clinicians. This study explores the cost awareness of clinicians across different settings. METHODS: We targeted four clinical cohorts: medical students, Senior House Officers/Interns, Mid-grade Senior Registrar/Residents, and Consultant/Attending Physicians, in six hospitals in the United Kingdom, the United States, Australia, New Zealand and Spain. The survey asked respondents to report the cost (as they recalled) of different types of scans, visits, medications and tests. Our analysis focused on the differential between the perceived/recalled cost and the actual cost. We explored variation across speciality, country and other potential confounders. Cost-awareness levels were estimated based on the cost estimates within 25% of the actual cost. RESULTS: We received 705 complete responses from six sites across five countries. Our analysis found that respondents often overestimated the cost of common tests while underestimating high-cost tests. The mean cost-awareness levels varied between 4 and 23% for different items. Respondents acknowledged that they did not feel they had received adequate training in cost awareness. DISCUSSION: The current financial climate means that cost awareness and the appropriate use of scarce healthcare resources is more paramount than perhaps ever before. Much of the focus of health economics research is on high-cost innovative technologies, yet there is considerable waste in the system with respect to overtreatment and overdiagnosis. Common reasons put forward for this include defensive medicine, poor education, clinical uncertainty and the institution of protocols. CONCLUSION: Given the role of clinicians in the healthcare system, as agents both for patients and for providers, more needs to be done to remove informational asymmetries and improve clinician cost awareness.

Getting to YES: The Evolution of the University of Pittsburgh Medical Center Hillman Cancer Center Youth Enjoy Science (YES) Academy.

The University of Pittsburgh Medical Center Hillman Cancer Center Academy (Hillman Academy) has the primary goal of reaching high school students from underrepresented and disadvantaged backgrounds and guiding them through a cutting-edge research and professional development experience that positions them for success in STEM. With this focus, the Hillman Academy has provided nearly 300 authentic mentored research internship opportunities to 239 students from diverse backgrounds over the past 13 years most of whom matriculated into STEM majors in higher education. These efforts have helped shape a more diverse generation of future scientists and clinicians, who will enrich these fields with their unique perspectives and lived experiences. In this paper, we describe our program and the strategies that led to its growth into a National Institutes of Health Youth Enjoy Science-funded program including our unique multi-site structure, tiered mentoring platform, multifaceted recruitment approach, professional and academic development activities, and a special highlight of a set of projects with Deaf and Hard of Hearing students. We also share student survey data from the past six years that indicate satisfaction with the program, self-perceived gains in key areas of scientific development, awareness of careers in STEM, and an increased desire to pursue advanced degrees in STEM.

A methodology for the modular structure planning of product-service systems.

Product-service system (PSS) is an important way of the transformation and upgrading of modern manufacturing industry, it is also one of core development trends of intelligent manufacturing. A PSS can be configured quickly and cheaply to meet the customer's personalized product and service requirements via a PPS design platform, and a modular master structure is the core of PSS design platform. When a PSS instance is configured, it needs to determine the module types and make decisions on the types of PSS firstly, so as to build a master structure for PSS. Therefore, the decision-making on module types and customization degree is a key step to establish the PSS modular master structure. This article proposes a five-step planning method for the modular structure planning of PSS. Firstly, the PSS module types are classified based on the Kano model. Then, bi-level decision-making on modules and its properties are finished by using conjoint analysis method, includes the customer's decision-making on modules and their properties, and the manufacturer's modules and their properties, which provides support for PSS modular optimization configuration design. Finally, the proposed methodology is validated through the case of power transformer. The proposed module planning method for the PSS modular structure helps to determine the module types for PSS services solution layer and generic part layer.

Influence of ward round order on critically ill patient outcomes.

PURPOSE: To examine the effect of order in which patients are seen on an Intensive Care Unit (ICU) ward round on ICU length of stay (LOS), mortality and duration of mechanical ventilation. MATERIALS AND METHODS: Retrospective observational study in a tertiary metropolitan ICU over a 12month period. All patients who occupied the first and last three bed spaces of the ICU ward round, without having moved bed spaces during admission, were included. Separate analyses were performed for the absolute first and last patients. RESULTS: 681 patients were included. There was no difference in the primary outcome, ICU LOS [median (IQR) 50 (23-102) hours for the first three patients seen vs. 51 (25-110) hours for the last three patients, p=0.594]. No differences were found in any secondary outcomes (hospital LOS, ICU mortality or duration of mechanical ventilation). CONCLUSIONS: The order in which patients were seen on an ICU ward did not affect ICU LOS nor related outcomes.

Empowering political participation through artificial intelligence.

Technologies based on artificial intelligence (AI) can radically change the existing political paradigm, empowering more diffused forms of political participation beyond elections-especially in the emergent worldwide context of unrestricted disclosure of governmental data online. The objective of this research is to investigate how civil society can use AI-based technologies to empower political participation. A sample of 721 publications was conducted through a combination of bibliometric analysis and systematic review, which revealed the characteristics and the nascent state of literature. This was followed by an exploratory Case Study, conducted through in-depth interviews and participant observation and supplemented by secondary materials. The content of the Case Study was extensively and systematically analysed through textual coding. We depicted a framework of how civil society can use AI-based technologies to nurture diffused political participation. This framework scrutinizes six focal areas and their respective dominant traits and descriptive features, aiming at contributing to guiding academic studies and political endeavours.

Modular design, application architecture, and usage of a self-service model for enterprise data delivery: the Duke Enterprise Data Unified Content Explorer (DEDUCE).

PURPOSE: Data generated in the care of patients are widely used to support clinical research and quality improvement, which has hastened the development of self-service query tools. User interface design for such tools, execution of query activity, and underlying application architecture have not been widely reported, and existing tools reflect a wide heterogeneity of methods and technical frameworks. We describe the design, application architecture, and use of a self-service model for enterprise data delivery within Duke Medicine. METHODS: Our query platform, the Duke Enterprise Data Unified Content Explorer (DEDUCE), supports enhanced data exploration, cohort identification, and data extraction from our enterprise data warehouse (EDW) using a series of modular environments that interact with a central keystone module, Cohort Manager (CM). A data-driven application architecture is implemented through three components: an application data dictionary, the concept of "smart dimensions", and dynamically-generated user interfaces. RESULTS: DEDUCE CM allows flexible hierarchies of EDW queries within a grid-like workspace. A cohort "join" functionality allows switching between filters based on criteria occurring within or across patient encounters. To date, 674 users have been trained and activated in DEDUCE, and logon activity shows a steady increase, with variability between months. A comparison of filter conditions and export criteria shows that these activities have different patterns of usage across subject areas. CONCLUSIONS: Organizations with sophisticated EDWs may find that users benefit from development of advanced query functionality, complimentary to the user interfaces and infrastructure used in other well-published models. Driven by its EDW context, the DEDUCE application architecture was also designed to be responsive to source data and to allow modification through alterations in metadata rather than programming, allowing an agile response to source system changes.

DEDUCE Clinical Text: An Ontology-based Module to Support Self-Service Clinical Notes Exploration and Cohort Development.

Large amounts of information, as well as opportunities for informing research, education, and operations, are contained within clinical text such as radiology reports and pathology reports. However, this content is less accessible and harder to leverage than structured, discrete data. We report on an extension to the Duke Enterprise Data Unified Content Explorer (DEDUCE), a self-service query tool developed to provide clinicians and researchers with access to data within the Duke Medicine Enterprise Data Warehouse (EDW). The DEDUCE Clinical Text module supports ontology-based text searching, enhanced filtering capabilities based on document attributes, and integration of clinical text with structured data and cohort development. The module is implemented with open-source tools extensible to other institutions, including a Java-based search engine (Apache Solr) with complementary full-text indexing library (Lucene) employed with a negation engine (NegEx) modified by clinical users to include to local domain-specific negation phrases.

Activation domains for controlling plant gene expression using designed transcription factors.

Targeted gene regulation via designed transcription factors has great potential for precise phenotypic modification and acceleration of novel crop trait development. To this end, designed transcriptional activators have been constructed by fusing transcriptional activation domains to DNA-binding proteins. In this study, a transcriptional activator from the herpes simplex virus, VP16, was used to identify plant regulatory proteins. Transcriptional activation domains were identified from each protein and fused with zinc finger DNA-binding proteins (ZFPs) to generate designed transcriptional activators. In addition, specific sequences within each transcriptional activation domain were modified to mimic the VP16 contact motif that interacts directly with RNA polymerase II core transcription factors. To evaluate these designed transcriptional activators, test systems were built in yeast and tobacco comprising reporter genes driven by promoters containing ZFP-binding sites upstream of the transcriptional start site. In yeast, transcriptional domains from the plant proteins ERF2 and PTI4 activated MEL1 reporter gene expression to levels similar to VP16 and the modified sequences displayed even greater levels of activation. Following stable transformation of the tobacco reporter system with transcriptional activators derived from ERF2, GUS reporter gene transcript accumulation was equal to or greater than those derived from VP16. Moreover, a modified ERF2 domain displayed significantly enhanced transcriptional activation compared with VP16 and with the unmodified ERF2 sequence. These results demonstrate that plant sequences capable of facilitating transcriptional activation can be found and, when fused to DNA-binding proteins, can enhance gene expression.

High readmission rates are associated with a significant economic burden and poor outcome in patients with grade III/IV acute GvHD.

Graft-versus-host disease (GvHD) is a common complication following haematopoietic stem cell transplant but little is published about the impact of this condition on hospital readmission rates. We report a retrospective analysis of readmission rates and associated costs in 187 consecutive allogeneic transplant patients to assess the impact of GvHD. The overall readmission rate was higher in patients with GvHD (86% (101/118) vs. 59% (41/69), p < 0.001). The readmission rate was higher both in the first 100 d from transplant (p = 0.02) and in the first year following transplant (p < 0.001). 151/455 (33%) of all readmission episodes occurred within 100 d of transplant. The mean number of inpatient days was significantly higher in patients with grade III/IV acute GvHD (101 d) compared with those with grade I/II GvHD (70 d; p = 0.003). The mean cost of readmission was higher in patients with GvHD (£28 860) than in non-GvHD patients (£13 405; p = 0.002) and in patients with grade III/IV GvHD (£40 012) compared with those patients with grade I/II GvHD (£24 560; p = 0.038). Survival was higher in those with grade I/II GvHD (55%) compared to grade III/IV GvHD (14%; p < 0.001). This study shows the high economic burden and poor overall survival associated with grade III/IV GvHD.

Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling.

BACKGROUND: Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodeling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR- and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodeling. METHODS: We investigated the effects of the kinase inhibitors on hemodynamics and remodeling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from days 21 to 35 with either vehicle, sunitinib (1mg/kg, 5mg/kg and 10mg/kg/day) or sorafenib (10mg/kg/day). PAB rats were treated with vehicle, sunitinib (10mg/kg/day) or sorafenib (10mg/kg/day) from days 7 to 21. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry. RESULTS: Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodeling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function. CONCLUSION: We demonstrated that sunitinib and sorafenib reversed RV remodeling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.

Functional profiling to select chemotherapy in untreated, advanced or metastatic non-small cell lung cancer.

BACKGROUND/AIM: To assess the impact of drug selection upon the treatment of advanced and metastatic non-small cell lung cancer (NSCLC), we applied a functional platform that measures drug-induced cell death in human tumor primary-culture micro-spheroids isolated from surgical specimens. PATIENTS AND METHODS: At diagnosis, microspheroids isolated by mechanical and enzymatic disaggregation were examined for drug-induced cell-death by morphology and staining characteristics. Drugs were administered using standard protocols. Thirty-one patients, who received at least one cycle of therapy, were evaluable. All patients signed informed consent. RESULTS: Twenty out of 31 patients responded (64.5%), 1 completely and 19 partially, providing a two-fold improvement over historical control of 30% (p=0.00015), a median time-to-progression of 8.5 months and a median overall survival of 21.3 months. CONCLUSION: This functional platform is feasible and provides a favorable objective response rate, time-to-progression and survival in advanced, metastatic, untreated NSCLC, and warrants further evaluation.

Uptake, efficacy, and systemic distribution of naked, inhaled short interfering RNA (siRNA) and locked nucleic acid (LNA) antisense.

Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) promise specific correction of disease-causing gene expression. Therapeutic implementation, however, has been forestalled by poor delivery to the appropriate tissue, cell type, and subcellular compartment. Topical administration is considered to circumvent these issues. The availability of inhalation devices and unmet medical need in lung disease has focused efforts in this tissue. We report the development of a novel cell sorting method for quantitative, cell type-specific analysis of siRNA, and locked nucleic acid (LNA) ASO uptake and efficacy after intratracheal (i.t.) administration in mice. Through fluorescent dye labeling, we compare the utility of this approach to whole animal and whole tissue analysis, and examine the extent of tissue distribution. We detail rapid systemic access and renal clearance for both therapeutic classes and lack of efficacy at the protein level in lung macrophages, epithelia, or other cell types. We nevertheless observe efficient redirection of i.t. administered phosphorothioate (PS) LNA ASO to the liver and kidney leading to targeted gene knockdown. These data suggest delivery remains a key obstacle to topically administered, naked oligonucleotide efficacy in the lung and introduce inhalation as a potentially viable alternative to injection for antisense administration to the liver and kidneys.

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway.

Misregulated ß-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of ß-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear ß-catenin. We show that these inhibitors efficiently block Wnt/ß-catenin-induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.

The DEDUCE Guided Query tool: providing simplified access to clinical data for research and quality improvement.

In many healthcare organizations, comparative effectiveness research and quality improvement (QI) investigations are hampered by a lack of access to data created as a byproduct of patient care. Data collection often hinges upon either manual chart review or ad hoc requests to technical experts who support legacy clinical systems. In order to facilitate this needed capacity for data exploration at our institution (Duke University Health System), we have designed and deployed a robust Web application for cohort identification and data extraction--the Duke Enterprise Data Unified Content Explorer (DEDUCE). DEDUCE is envisioned as a simple, web-based environment that allows investigators access to administrative, financial, and clinical information generated during patient care. By using business intelligence tools to create a view into Duke Medicine's enterprise data warehouse, DEDUCE provides a Guided Query functionality using a wizard-like interface that lets users filter through millions of clinical records, explore aggregate reports, and, export extracts. Researchers and QI specialists can obtain detailed patient- and observation-level extracts without needing to understand structured query language or the underlying database model. Developers designing such tools must devote sufficient training and develop application safeguards to ensure that patient-centered clinical researchers understand when observation-level extracts should be used. This may mitigate the risk of data being misunderstood and consequently used in an improper fashion.

Development of stable isotope and selenomethionine labeling methods for proteins expressed in Pseudomonas fluorescens.

Pseudomonas fluorescens is a robust protein expression system that is very well suited for high throughput protein expression for structural genomics studies. Since NMR spectroscopy and X-ray crystallography are both used by various investigators in structure elucidation studies, the availability of target proteins labeled with stable isotopes or selenomethionine is essential for the determination of protein structures. A completely defined medium for the expression and stable isotope labeling of proteins in P. fluorescens has been developed. The expression level of Bacillus thuringiensis Cry34 in the modified medium is comparable to that obtained in the original medium. In addition, more than 95% incorporation of 15N was obtained in Cry34 using 15N ammonium sulfate and the quality of the protein, as assessed by NMR analysis, is comparable to that made using commercial medium. High levels of selenomethionine (SeMet) incorporation in the Xenorhabdus nematophilus insecticidal protein XptA2 were also obtained in P. fluorescens using the defined medium, allowing development of a method for obtaining highly purified XptA2. The following observations were made when inhibitors of endogenous methionine biosynthesis were used in P. fluorescens culture when SeMet was substituted in XptA2: (I) there is little inhibition of cell growth or recombinant XptA2 expression in the presence of SeMet concentrations up to 300 mg/L in cell culture, (II) there was greater than 95% SeMet incorporation ratio in recombinant SeMet-labeled XptA2 (SeMet-XptA2) and the incorporation ratio is consistent and reproducible and (III) finally, purified SeMet-XptA2 possesses similar protein structure and insecticidal activity relative to the unlabeled counterpart XptA2 as shown by bioassay and differential scanning calorimetric analysis. The high SeMet incorporation should provide high accuracy and resolution in XptA2 phase determination by multiwavelength anomalous diffraction (MAD), indicating that P. fluorescens is an excellent expression host to produce SeMet-labeled proteins for structural study.

High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy.

The combination of high dose methylprednisolone and rituximab induces superior overall (93%) and complete (14%) response rates compared to high dose methylprednisolone alone (overall 43%, complete remission 0%) in heavily pre-treated chronic lymphocytic leukemia patients with advanced disease. Despite its efficacy the combination is not easily manageable because of the high rate of opportunistic infections.