Advanced Clinical Decision Support for Vaccine Adverse Event Detection and Reporting.

BACKGROUND: Reporting of adverse events (AEs) following vaccination can help identify rare or unexpected complications of immunizations and aid in characterizing potential vaccine safety signals. We developed an open-source, generalizable clinical decision support system called Electronic Support for Public Health-Vaccine Adverse Event Reporting System (ESP-VAERS) to assist clinicians with AE detection and reporting. METHODS: ESP-VAERS monitors patients' electronic health records for new diagnoses, changes in laboratory values, and new allergies following vaccinations. When suggestive events are found, ESP-VAERS sends the patient's clinician a secure electronic message with an invitation to affirm or refute the message, add comments, and submit an automated, prepopulated electronic report to VAERS. High-probability AEs are reported automatically if the clinician does not respond. We implemented ESP-VAERS in December 2012 throughout the MetroHealth System, an integrated healthcare system in Ohio. We queried the VAERS database to determine MetroHealth's baseline reporting rates from January 2009 to March 2012 and then assessed changes in reporting rates with ESP-VAERS. RESULTS: In the 8 months following implementation, 91 622 vaccinations were given. ESP-VAERS sent 1385 messages to responsible clinicians describing potential AEs. Clinicians opened 1304 (94.2%) messages, responded to 209 (15.1%), and confirmed 16 for transmission to VAERS. An additional 16 high-probability AEs were sent automatically. Reported events included seizure, pleural effusion, and lymphocytopenia. The odds of a VAERS report submission during the implementation period were 30.2 (95% confidence interval, 9.52-95.5) times greater than the odds during the comparable preimplementation period. CONCLUSIONS: An open-source, electronic health record-based clinical decision support system can increase AE detection and reporting rates in VAERS.

Emergence of segregation in evolving social networks.

In many social networks, there is a high correlation between the similarity of actors and the existence of relationships between them. This paper introduces a model of network evolution where actors are assumed to have a small aversion from being connected to others who are dissimilar to themselves, and yet no actor strictly prefers a segregated network. This model is motivated by Schelling's [Schelling TC (1969) Models of segregation. Am Econ Rev 59:488-493] classic model of residential segregation, and we show that Schelling's results also apply to the structure of networks; namely, segregated networks always emerge regardless of the level of aversion. In addition, we prove analytically that attribute similarity among connected network actors always reaches a stationary distribution, and this distribution is independent of network topology and the level of aversion bias. This research provides a basis for more complex models of social interaction that are driven in part by the underlying attributes of network actors and helps advance our understanding of why dysfunctional social network structures may emerge.

"Through the digits, through the fingers": Variations on the string figure as imaginary digital medium.

This article considers artistic engagements with string figure performance and collection as 'imaginary' articulations of digital media. As an object of anthropological inquiry, the string figure emerges in 1888 with a short paper by Franz Boas. Encouraged by more mainstream publications by Caroline Furness Jansen (2008) and Kathleen Haddon (1930), over the course of the 20th century the string figure would become a model through which largely western writers and artists have explored both the anxieties and dreams of ideal, embodied and networked communication technologies. The present article explores, specifically, the collecting projects and films of Harry Smith in the 1960s and 1970s; the video-performance piece of 1974, titled String Games: Improvisations for Inter-City Video, by the interdisciplinary artist Vera Frenkel; and the string figure exhibit at David Wilson's Museum of Jurassic Technology in Culver City, California. Through a media-archeological lens, the history of string figure fascination takes shape as a repository of dreams about (digital) communication, which, it is additionally suggested in a final section, might yet allow for the expansion and enlargement of conceptions of both digitality and media.

Leveraging collaborative research networks against antimicrobial resistance in Asia.

Background: Antimicrobial resistance (AMR) is a global health security threat requiring research collaboration globally and regionally. Despite repeated calls for international research collaboration in Asia, literature analyzing the nature of collaborative AMR research in Asia has been sparse. This study aims to describe the characteristics of the AMR research network in Asia and investigate the factors influencing collaborative tie formation between organizations. Methods: We carried out a mixed-methods study by combining social network analysis (SNA) and in-depth interviews. SNA was first conducted on primary data to describe the characteristics of the AMR research network in Asia. Exponential random graph models (ERGMs) were then used to examine the influence of factors such as organization type, country affluence levels, regional proximity and One Health research on collaborative tie formation among organizations. In-depth interviews were conducted with network participants to provide contextual insights to the quantitative data. Results: The results reveal that the research network exhibits a core-periphery structure, where a minority of organizations have a significantly higher number of collaborations with others. The most influential organizations in the network are academic institutions from high-income countries within and outside Asia. The ERGM results demonstrate that organizations prefer to collaborate with others of similar organization types, country-based affluence levels and One Health domains of focus, but also with others across different World Health Organization regions. The qualitative analysis identified three main themes: the challenges that impede collaboration, the central role of academic institutions, and the nature of collaborations across One Health domains, giving rise to important empirical milestones in understanding AMR research in Asia. Conclusion: We thus recommend leveraging academic institutions as "integrators" to bridge differences, increasing funds channelled towards research capacity building to alleviate structural barriers to collaboration, streamlining collaborative mechanisms to overcome cumbersome administrative hurdles, and increasing efforts to establish trust between all organizations.

Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation.

Indoleamine 2,3 dioxygenase (IDO) has emerged as an important mediator of immune tolerance via inhibition of Th1 responses. However, the role of IDO in antigen-induced tolerance or allergic inflammation in the airways that is regulated by Th2 responses has not been elucidated. By using IDO(-/-) mice, we found no impairment of airway tolerance, but, surprisingly, absence of IDO provided significant relief from establishment of allergic airways disease, as evident from attenuated Th2 cytokine production, airway inflammation, mucus secretion, airway hyperresponsiveness, and serum ovalbumin-specific IgE. Myeloid dendritic cells isolated from lung-draining lymph nodes of mice immunized for either Th1 or Th2 response revealed fewer mature dendritic cells in the lymph nodes of IDO(-/-) mice. However, the net functional impact of IDO deficiency on antigen-induced responses was more remarkable in the Th2 model than in the Th1 model. Collectively, these data suggest that IDO is not required for the induction of immune tolerance in the airways but plays a role in promoting Th2-mediated allergic airway inflammation via unique effects on lung dendritic cells.

Integration of a patient-centred MUO/CUP service within a new acute oncology service: challenges and rewards.

BACKGROUND: Holistic approach to the clinical management pathway for malignancy of undefined primary origin (MUO)/carcinoma of unknown primary (CUP) patients remains an unmet clinical need. To address this, an MUO/CUP service was implemented during conception of a new acute oncology service (AOS). METHODOLOGY: Over a comparable 17 months' duration, patient outcomes pre-MUO/CUP service implementation was retrospectively analysed and compared prospectively with post-service implementation database. Performance measures of MUO/CUP service were compared against national recommendations. RESULTS: In the retrospective cohort (n=32), median age was 71.5 years and median length of hospital stay (LOS) was 11.25 days. In the prospective cohort (n=42), median age was 75.5 years, median LOS was 7.75 days (p=0.037). Post-service implementation, 100% patients were discussed in MUO/CUP multidisciplinary team meeting; 96% of inpatient referrals were reviewed by oncology within 24-48 hours. In the prospective group, median overall survival (OS) was 73 days vs 35 days in the retrospective group (p=0.045; hazard ratio (HR) 1.61). Out of 20 patients suitable for anti-cancer treatment in the prospective group, 85% were treated within 31 days from the decision-to-treat; 90% were treated within 62 days of referral. Within the prospective group, median OS was 214 days in the treated sub-group, compared with 44 days in patients receiving best supportive care only (p<0.0001; HR 3.19). CONCLUSION: Timely specialised input from AOS with a dedicated MUO/CUP team can achieve enhanced patient-centred and healthcare-centred outcomes, both in terms of survival and hospital stay. However, heterogeneity in both retrospective and prospective study groups, as well as discrepancies in coding, makes direct comparison between both groups challenging.

Pituitary metastasis: a clinical overview.

The pituitary gland is an unusual site for metastatic spread and has been associated with a poor prognosis. Clinical presentation is variable but can include visual field defects, cranial nerve palsies, anterior pituitary dysfunction and/ or diabetes insipidus. Management options include surgery or radiotherapy, chemotherapy/immunotherapy or a conservative approach. The pituitary should not be overlooked as a site for metastasis in patients with known cancer and can be the first presentation of neoplastic disease in some patients. Given that patients are now living longer with cancer, clinicians should be alert to the varied presentation of pituitary metastasis. We provide a clinical overview of pituitary metastasis with the aid of illustrative clinical cases.

TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice.

Steroid-resistant asthma comprises an important source of morbidity in patient populations. T(H)17 cells represent a distinct population of CD4(+) Th cells that mediate neutrophilic inflammation and are characterized by the production of IL-17, IL-22, and IL-6. To investigate the function of T(H)17 cells in the context of Ag-induced airway inflammation, we polarized naive CD4(+) T cells from DO11.10 OVA-specific TCR-transgenic mice to a T(H)2 or T(H)17 phenotype by culturing in conditioned medium. In addition, we also tested the steroid responsiveness of T(H)2 and T(H)17 cells. In vitro, T(H)17 cytokine responses were not sensitive to dexamethasone (DEX) treatment despite immunocytochemistry confirming glucocorticoid receptor translocation to the nucleus following treatment. Transfer of T(H)2 cells to mice challenged with OVA protein resulted in lymphocyte and eosinophil emigration into the lung that was markedly reduced by DEX treatment, whereas T(H)17 transfer resulted in increased CXC chemokine secretion and neutrophil influx that was not attenuated by DEX. Transfer of T(H)17 or T(H)2 cells was sufficient to induce airway hyperresponsiveness (AHR) to methacholine. Interestingly, AHR was not attenuated by DEX in the T(H)17 group. These data demonstrate that polarized Ag-specific T cells result in specific lung pathologies. Both T(H)2 and T(H)17 cells are able to induce AHR, whereas T(H)17 cell-mediated airway inflammation and AHR are steroid resistant, indicating a potential role for T(H)17 cells in steroid-resistant asthma.

Occurrence of ciprofloxacin-, trimethoprim-sulfamethoxazole-, and vancomycin-resistant bacteria in a municipal wastewater treatment plant.

The occurrence of antibiotic-resistant bacteria was evaluated in aqueous samples obtained from a municipal wastewater treatment plant. Samples collected from the influent, clarifier effluent, and disinfected effluent were assayed for fecal coliforms, E. coli, and enterococci exhibiting resistance to ciprofloxacin, trimethoprim-sulfamethoxazole, and vancomycin. Membrane filtration of samples was followed by plating on growth media containing various concentrations of antibiotic. Bacterial colonies on plates with antibiotic exposures greater than the clinical minimum inhibitory concentrations were counted and considered resistant. The numbers of drug-resistant organisms in influent ranged from nondetectable to 7 x 10(5) colony-forming units (CFU)/100 mL for fecal coliforms, nondetectable to 5 x 10(4) CFU/100 mL for E. coli, and nondetectable to 6 x 10(5) CFU/100 mL for enterococci. Fecal coliforms, E. coli, and enterococci with reduced susceptibility to antibiotics were also detected in influent and clarifier effluent; however, the disinfected effluent did not contain resistant bacteria. Species-level identification of enterococci revealed that resistant enterococci were predominantly E. faecalis.

WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer.

WWOX (WW domain containing oxidoreductase), a putative tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3-24.1, is altered in breast, esophageal, and ovarian cancer. Because the FRA3B/FHIT locus at 3p14.2 is a preferential target for genetic changes caused by tobacco smoke, we intended to evaluate the status of the FRA16D/WWOX gene in non-small cell lung cancer; we have analyzed 27 paired normal and tumor lung tissues and 8 lung cancer cell lines for WWOX alterations by reverse transcriptase-PCR, loss of heterozygosity, and mutation analysis. Transcripts missing WWOX exons were detected in 7 primary tumors (7 of 27; 25.9%) and 5 of 8 cell lines. In addition, loss of heterozygosity at the WWOX locus was observed in 10 primary tumors (10 of 27; 37.0%). We conclude that WWOX alterations occur in a significant fraction of lung cancers and may contribute to the pathogenesis of non-small cell lung cancer.

Use of cyclooxygenase-2 inhibition to enhance the efficacy of immunotherapy.

Antitumor effects of cyclooxygenase-2 (COX-2) inhibition have been reported in a wide variety of tumor models and in human cancers, both as chemoprevention and therapy. Human mesothelioma tumors have been shown to overexpress COX-2 and high levels of COX-2 protein have been demonstrated to be a prognostic factor, indicating poor outcome in this tumor. In this study, we determined that inhibition of COX-2 by oral administration of Rofecoxib significantly slowed but did not cure the growth of small tumors in mesothelioma-bearing mice. Large tumors were unaffected. This effect was dependent on the presence of CD8+ T cells and was associated with increased tumor-infiltrating lymphocytes. Because these activities are consistent with a mechanism that results in a decrease in the immunosuppressive environment of the tumor, we additionally examined the effect of COX-2 blockade combined with Ad.IFN-beta therapy, a treatment that we have previously demonstrated results in expansion of antitumor CD8+ CTLs and cures a high percentage of small mesothelioma tumors in mice. Ad.IFN-beta therapy combined with COX-2 inhibition was associated with an increased number of T cells within tumors and resulted in cures of small tumors, significant inhibition of the growth of large established tumors, and inhibition of the growth of metastatic tumor foci after surgical debulking. The additive effects of these modes of treatment suggests that it would be rational to combine COX-2 inhibition with immuno- and immunogene therapy approaches (perhaps in conjunction with surgical debulking) in human clinical trials of treatment of mesothelioma and other tumors.

Empirical Models of Social Learning in a Large, Evolving Network.

This paper advances theories of social learning through an empirical examination of how social networks change over time. Social networks are important for learning because they constrain individuals' access to information about the behaviors and cognitions of other people. Using data on a large social network of mobile device users over a one-month time period, we test three hypotheses: 1) attraction homophily causes individuals to form ties on the basis of attribute similarity, 2) aversion homophily causes individuals to delete existing ties on the basis of attribute dissimilarity, and 3) social influence causes individuals to adopt the attributes of others they share direct ties with. Statistical models offer varied degrees of support for all three hypotheses and show that these mechanisms are more complex than assumed in prior work. Although homophily is normally thought of as a process of attraction, people also avoid relationships with others who are different. These mechanisms have distinct effects on network structure. While social influence does help explain behavior, people tend to follow global trends more than they follow their friends.

Regulatory T cells and cytokines in malignant pleural effusions secondary to mesothelioma and carcinoma.

Immunotherapy against a variety of malignancies, including pleural-based malignancies, has shown promise in animal models and early human clinical trials, but successful efforts will need to address immunosuppressive factors of the tumor and host, particularly certain cytokines and CD4(+) CD25(+) regulatory T cells (Treg). Here, we evaluated the cellular and cytokine components of malignant pleural effusions from 44 patients with previously diagnosed mesothelioma, non-small cell lung cancer (NSCLC), or breast cancer and found significant differences in the immune profile of pleural effusions secondary to mesothelioma vs. carcinoma. Although a high prevalence of functionally suppressive CD4(+) CD25(+) T cells was found in carcinomatous pleural effusions, mesothelioma pleural effusions contained significantly fewer CD4(+) CD25(+) T cells. Activated CD8(+) T cells in pleural fluid were significantly more prevalent in mesothelioma than carcinoma. However, there is clear patient-to-patient variability and occasional mesothelioma patients with high percentages of CD4(+) CD25(+) pleural effusion T cells and low percentages of CD8(+) CD25(+) pleural effusion T cells can be identified. Mesothelioma pleural effusions contained the highest concentrations of the immunosuppressive cytokine transforming growth factor (TGF)-beta. Thus, the contribution of cellular and cytokine components of immunosuppression associated with malignant pleural effusions varies by tumor histology and by the individual patient. These results have implications for the development of immunotherapy directed to the malignant pleural space, and suggest the need to tailor immunotherapy to overcome immunosuppressive mechanisms in tumor environments.

Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown etiology that results in significant morbidity and mortality. The pathogenesis of IPF is not completely understood. Because recent studies have implicated insulin-like growth factor-I (IGF-I) in the pathogenesis of fibrosis, we examined the expression and function of insulin-like growth factor binding proteins (IGFBP)-3 and -5 in IPF. IGFBP-3 and -5 levels were increased in vivo in IPF lung tissues and in vitro in fibroblasts cultured from IPF lung. The IGFBPs secreted by IPF fibroblasts are functionally active and can bind IGF-I, and IGFBPs secreted by primary fibroblasts bind extracellular matrix components. Our results also suggest that IGFBPs may be involved in the initiation and/or perpetuation of fibrosis by virtue of their ability to induce the production of extracellular matrix components such as collagen type I and fibronectin in normal primary adult lung fibroblasts. Although transforming growth factor-beta increased IGFBP-3 production by primary fibroblasts in a time-dependent manner, IGFBP-5 levels were not increased by transforming growth factor-beta. Taken together, our results suggest that IGFBPs play an important role in the development of fibrosis in IPF.

Treatment of lung cancer using clinically relevant oral doses of the cyclooxygenase-2 inhibitor rofecoxib: potential value as adjuvant therapy after surgery.

OBJECTIVE: To investigate the uses and limitations of cyclooxygenase- (COX) 2 inhibition using clinically relevant doses of oral rofecoxib in the treatment of murine models of non-small-cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: Overexpression of COX-2 has been reported in lung cancer. Several studies have demonstrated that high doses of COX-2 inhibitors could inhibit the growth of rodent and human lung cancer cell lines. The potential uses and limitations of COX-2 inhibition at doses equivalent to those currently approved for use in humans have not been well studied. METHODS: Three murine NSCLC cell lines were injected into the flanks of mice to establish tumor xenografts. Mice were treated orally with low doses of a COX-2 inhibitor (rofecoxib chow, 0.0075%). Mechanisms were evaluated by analysis of tumor-infiltrating lymphocytes. To study rofecoxib as adjuvant therapy, large established tumors (14-18 days after tumor inoculation) were surgically debulked and animals were treated with rofecoxib starting 3 days before surgery. Recurrence of the tumor after debulking was monitored. RESULTS: Rofecoxib significantly slowed the growth of small (0-120 mm) tumors (P < 0.01-0.05) in all 3 cell lines, with higher efficacy in the more immunogenic tumors. Minimal responses were noted in larger tumors. Rofecoxib appeared to augment CD8 T cell infiltration in immunogenic tumors. Rofecoxib significantly reduced the recurrence rate after debulking (P < 0.01). CONCLUSIONS: Clinically relevant doses of the COX-2 inhibitor rofecoxib given orally were effective in inhibiting the growth of small (but not large) tumors in 3 murine NSCLC cell lines tested and in preventing recurrences after surgical debulking. Depending on the immunogenicity of human tumors, COX-2 inhibition might be useful as adjuvant therapy for surgically resectable NSCLC.

Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis.

IL-17R signaling is critical for pulmonary neutrophil recruitment and host defense against Gram-negative bacteria through the coordinated release of G-CSF and CXC chemokine elaboration. In this study, we show that IL-17R is localized to basal airway cells in human lung tissue, and functional IL-17R signaling occurs on the basolateral surface of human bronchial epithelial (HBE) cells. IL-17A and IL-17F were potent inducers of growth-related oncogene-alpha and G-CSF in HBE cells, and significant synergism was observed with TNF-alpha largely due to signaling via TNFRI. The activities of both IL-17A and IL-17F were blocked by a specific anti-IL-17R Ab, but only IL-17A was blocked with a soluble IL-17R, suggesting that cell membrane IL-17R is required for signaling by both IL-17A and IL-17F. Because IL-17A and IL-17F both regulate lung neutrophil recruitment, we measured these molecules as well as the proximal regulator IL-23p19 in the sputum of patients with cystic fibrosis (CF) undergoing pulmonary exacerbation. We found significantly elevated levels of these molecules in the sputum of patients with CF who were colonized with Pseudomonas aeruginosa at the time of pulmonary exacerbation, and the levels declined with therapy directed against P. aeruginosa. IL-23 and the downstream cytokines IL-17A and IL-17F are critical molecules for proinflammatory gene expression in HBE cells and are likely involved in the proinflammatory cytokine network involved with CF pathogenesis.

Interleukin-2 is one of the targets of 1,25-dihydroxyvitamin D3 in the immune system.

Interleukin (IL)-2 knockout (KO) mice, which spontaneously develop symptoms of inflammatory bowel disease similar to ulcerative colitis in humans, were made vitamin D deficient (D-) or vitamin D sufficient (D+) or were supplemented with 1,25-dihydroxyvitamin D(3) (1,25D3). 1,25-Dihydroxyvitamin D3 supplementation, but not vitamin D supplementation, reduced the early mortality of IL-2 KO mice. However, colitis severity was not different in D-, D+, or 1,25D3 IL-2 KO mice. Cells from D- IL-2 KO mice produced more interferon (IFN)-gamma than cells from all other mice. Con A-induced proliferation was upregulated in IL-2 KO mice and downregulated in wildtype (WT) mice fed 1,25D3. All other measured immune responses in cells from IL-2 KO mice were unchanged by vitamin D status. In vitro addition of 1,25-dihydroxyvitamin D3 significantly reduced the production of IL-10 and IFN-gamma in cells from D- and D+ WT mice. Conversely, IFN-gamma and IL-10 production in cells from IL-2 KO mice were refractory to in vitro 1,25-dihydroxyvitamin D3 treatments. In the absence of IL-2, vitamin D was ineffective for suppressing colitis and ineffective for the in vitro downregulation of IL-10 or IFN-gamma production. One target of 1,25-dihydroxyvitamin D3 in the immune system is the IL-2 gene.