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Background Pneumonia is the leading infection-related cause of death. The use of simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials. Research Question What are the clinical criteria and contemporary epidemiology trends that are helpful in the identification of patients at high risk of nosocomial pneumonia? Study Design and Methods Within the ICUs of 28 US hospitals, we conducted a prospective cohort study among adults who had been hospitalized >48 hours and were considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients who experienced the development of nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures that are associated with increased risk of pneumonia development during the ICU admission. Results Between February 6, 2016, and October 7, 2016, 4,613 high-risk patients were enrolled. Among 1,464 high-risk patients (32%) who were treated for possible nosocomial pneumonia, 537 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures that are associated with increased risk of nosocomial pneumonia development (c-statistic, 0.709; 95% CI, 0.686-0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days. Interpretation Treatment for nosocomial pneumonia is common among patients in the ICU who are receiving high levels of respiratory support, yet more than one-half of patients who are treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk.

Compared with classroom learning, online learning requires students to self-regulate their learning processes and to maintain their motivation to achieve their learning goals. This study investigated whether the interventions based on the Attention, Relevance, Confidence, and Satisfaction model and the modified Introducing the new concepts, Metacognitive questioning, Practicing, Reviewing and reducing difficulties, Obtaining mastery, Verification, and Enrichment method can promote students’ motivation and use of self-regulated learning (SRL) strategies in a web-based mathematics learning environment. Two-hundred thirty-six Chinese high school students were randomly divided into four groups: motivational design group, SRL intervention group, motivational design and SRL intervention group, and the control group. Questionnaires and tests were administered to measure the changes in motivation, use of SRL strategies, and academic gains before and after the respective interventions. Findings of this study suggest that the knowledge gain of students learning mathematics online can be maximized when they receive instructional assistance in both motivation and use of SRL strategies.

A strong synergy can result from China-US antimicrobial resistance (AMR) collaborations given similarities and differences between their respective healthcare systems and research infrastructures. The Antibacterial Resistance Leadership Group has employed a model of realistic growth, starting with a feasible, relatively low-resource observational study in a critical priority pathogen. This and other observational studies will provide vital scientific information required for the rational design of future interventional trials. In addition, it provides a mutual, low-risk opportunity for determining the strengths and opportunities of the research collaboration. Issues identified during the observational studies can be addressed prior to the initiation of high-resource interventional studies. Collaborative clinical AMR studies between China and the United States have tremendous potential to decrease AMR rates, improve responsible antibiotic use, and ultimately improve the lives of patients in both countries.

Background Prospectively identifying patients at highest risk for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) by implementing a risk assessment scoring tool may help focus prevention efforts, optimize the screening process to improve clinical trial feasibility, and enhance development of new antibacterial agents. Methods Within the intensive care units (ICU) of 28 US hospitals, between February 6, 2016 and October 7, 2016, patients hospitalized >48 hours and receiving high levels of respiratory support were prospectively followed for meeting the definition of HABP/VABP recommended in US FDA draft guidance. Patient demographics, medical comorbidities, and treatment exposures were recorded. The association between candidate risk factors and odds of developing HABP/VABP was evaluated with a multivariable logistic regression model. Risk factors were selected using backward selection with α = 0.1 for model inclusion. A web-based scoring system was developed to estimate the risk of HABP/VABP from the risk factors identified. Results A total of 5,101 patients were enrolled, of whom 1,005 (20%) developed HABP/VABp. 4,613 patients were included in the model, excluding 488 (10%) with HABP/VABP at or before enrollment. There are 15 variables included in the model. APACHE II admission score >20 (P < 0.001, OR 2.14, 95% CI 2.00–2.29), admission diagnosis of trauma (P < 0.001, OR 3.31, 95% CI 1.90–5.74), frequent oral or lower respiratory tract suctioning (P < 0.001, OR 2.33, 95% CI 1.81–2.99), and receipt of enteral nutrition (P < 0.001, OR 2.31, 95% CI 1.69–3.16) were the key drivers of increased pneumonia risk. The model demonstrated excellent discrimination (bias-corrected C-statistic 0.861, 95% CI 0.843–0.880). The web-based scoring system can be accessed via this link: https://ctti-habpvabp.shinyapps.io/web_based_tool/. Conclusion Using a web-based scoring system, ICU patients at highest risk for developing HABP/VABP can be accurately identified. Prospective implementation of this tool may assist in focusing additional prevention efforts on the highest risk patients and enhance new drug development for HABP/VABP. Disclosures S. P. Bergin, CTTI: Investigator and Scientific Advisor, Research support and Travel to study related meetings. A. Coles, CTTI: Investigator and Scientific Advisor, Salary. S. B. Calvert, CTTI: Employee, Salary. M. J. Zervos, CTTI: Investigator, Research support. A. C. Bardossy, CTTI: Investigator, Research support. M. Kollef, CTTI: Investigator, Research support. M. J. Durkin, CTTI: Investigator, Research support. M. Sims, CTTI: Investigator, Research support. C. Greenshields, CTTI: Investigator, Research support. B. A. Kabchi, CTTI: Investigator, Research support. H. K. Donnelly, CTTI: Collaborator and Scientific Advisor, Research support and Salary. P. Tenaerts, CTTI: Employee, Salary. P. Gu, CTTI: Collaborator, Research support and Salary. V. G. Fowler Jr., CTTI: Investigator and Scientific Advisor, Research support and Salary. Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee, Grant recipient and Research support. Cerexa/Actavis/Allegan: Grant Investigator, Grant recipient. Pfizer: Consultant and Grant Investigator, Consulting fee and Grant recipient. Advanced Liquid Logics: Grant Investigator, Grant recipient. NIH: Investigator, Grant recipient, Research support and Salary. MedImmune: Consultant and Grant Investigator, Consulting fee and Grant recipient. Basilea: Consultant and Grant Investigator, Consulting fee and Grant recipient. Karius: Grant Investigator, Grant recipient. Contrafect: Consultant and Grant Investigator, Consulting fee and Grant recipient. Regeneron: Grant Investigator, Grant recipient. Genentech: Consultant and Grant Investigator, Consulting fee and Grant recipient. Achaogen: Consultant, Consulting fee. Astellas: Consultant, Consulting fee. Arsanis: Consultant, Consulting fee. Affinergy: Consultant, Consulting fee. Bayer: Consultant, Consulting fee. Cerexa: Consultant, Consulting fee. Cubist: Consultant, Consulting fee. Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. Grifols: Consultant, Consulting fee. Medicines Co.: Consultant, Consulting fee. Novartis: Consultant, Consulting fee. Novadigm: Consultant, Consulting fee. Theravance: Consultant, Consulting fee and Speaker honorarium. xBiotech: Consultant, Consulting fee. Green Cross: Consultant, Speaker honorarium. T. L. Holland, CTTI: Investigator and Scientific Advisor, Research support and Salary.

One of the mechanisms by which tumor cells evade the immune system is the lack of proper antigen-presenting cells. Improvement in host immunity against tumor cells can be achieved by promoting the differentiation of dendritic cells (DCs) from immature myeloid cells (Gr-1+Ly-6C+F4/80+) that accumulate in the bone marrow and lymphoid organs of mice with large tumor burdens. The enriched immature myeloid cells inhibit T-cell proliferation and tumor-specific T-cell response, which can be reversed by the differentiation of immature myeloid cells or depletion of F4/80+ cells. Sorted Gr-1+/F4/80+ immature myeloid cells differentiated into CD11c+ cells that express CD80 and I-A/I-E (MHC class II) in the presence of recombinant murine granulocyte macrophage colony-stimulating factor (GM-CSF). Furthermore, intratumoral gene delivery of GM-CSF not only promoted the differentiation of carboxyfluoroscein succinimidyl ester-labeled immature myeloid cells into CD11c+ cells with the characteristics of mature DCs (CD80+, I-A/I-E+) but also enhanced innate natural killer and adaptive cytolytic T-cell activities in mice treated with interleukin (IL)-12 and anti-4–1BB combination therapy. More importantly, intratumoral delivery of GM-CSF and IL-12 genes in combination with 4–1BB costimulation greatly improved the long-term survival rate of mice bearing large tumors and eradicated the untreated existing hepatic tumor. The results suggest that inducing the maturation of immature myeloid cells, thus preventing their inhibitory activity and enhancing their antigen-presenting capability, by GM-CSF gene therapy is a critically important step in the development of effective antitumor responses in hosts with advanced tumors.

The interactions between NK cells and dendritic cells (DCs) have been previously demonstrated in vitro. In this report, the in vivo cross-regulation between NK cells and DCs was studied in tumor-bearing mice treated with adenoviral vector expressing IL-12 and agonistic anti-4-1BB Abs. NK cells are essential for both tumor rejection and CTL development in the combination therapy (IL-12 plus anti-4-1BB). The numbers and functional activities of both NK cells and DCs in tumor-infiltrating leukocytes were synergistically increased in the IL-12 plus anti-4-1BB-treated mice compared with treatment with either reagent alone. NK depletion in vivo resulted in a significant decrease in the number of DCs in tumor-infiltrating leukocytes, strongly suggesting that NK cells are involved in the activation and expansion of DCs. The mechanism by which IL-12-activated NK cells regulate DC functions is, in part, mediated through the secretion of IFN-γ that leads to the up-regulation of 4-1BB by DCs. Furthermore, 4-1BB activation in conjunction with IL-12 gene delivery increased tumor infiltration of green fluorescence protein-labeled DCs and enhanced their MHC class II expression. The activation of DCs by NK cells and the subsequent development of antitumoral CTL responses facilitated by 4-1BB-activated DCs may account for the synergistic effects observed in the combination therapy in comparison to adenoviral vector expressing IL-12 or anti-4-1BB treatment alone.

In previous reports, systemic administration of a stimulatory monoclonal antibody directed against the 4-1BB receptor had no effect on survival or tumor burden in mice inoculated with the poorly immunogenic B16-F10 melanoma. We combined IL-12 gene transfer with 4-1BB costimulation to explore a previously noted cooperative anti-tumor effect against this model tumor. We hypothesize that the innate immune response mediated by IL-12-activated natural killer (NK) cells initiates the activation of the immune system, leading to the priming of T cells, whereas 4-1BB costimulation enhances the function of primed tumor-specific T cells. The effect of the combination therapy on the growth of subcutaneous (s.c.) tumors and pulmonary metastasis was examined. The combination therapy significantly retarded the growth of subcutaneously-inoculated tumors, and 50% of tumor-bearing mice survived with complete tumor regression. In contrast, neither IL-12 gene transfer nor anti-4-1BB antibody administration alone was as effective. Enhanced CTL activity against both B16-F10 tumor cells and TRP-2-pulsed EL4 syngeneic tumor cells was observed in tumor-bearing animals treated with the combination therapy 2 weeks after treatment and, in long-term survivors from this combination therapy, at >120 days. In a pulmonary metastatic model, only the combination therapy generated significant protection against metastasis. In vivo depletion of NK or CD8(+) but not CD4(+) subsets eliminated the protective immunity. Furthermore, NK cell depletion significantly reduced both tumor-specific CTL activity and the number of tumor-specific IFN-gamma-producing cells, suggesting that this synergistic effect requires the participation of both NK and CD8(+) T cells.