An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA.

Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro

Impact of irreversibility and uncertainty on the timing of infrastructure projects

This paper argues that because of the irreversibility and uncertainty associated with Build - Operate - Transfer (BOT) infrastructure projects, their financial evaluation should also routinely include the determination of the value of the option to defer the construction start-up. This ensures that project viability is comprehensively assessed before any revenue or loan guarantees are considered by project sponsors to support the project. This paper shows that the framework can be used even in the context of the intuitive binomial lattice model. This requires estimating volatility directly from the evolution of the net operating income while accounting for the correlation between the revenue and costs functions. This approach ensures that the uncertainties usually associated with toll revenues, in particular, are thoroughly investigated and their impact on project viability is thoroughly assessed. This paper illustrates the usefulness of the framework with data from an actual (BOT) toll road project. The results show that by postponing the project for a couple of years the project turns out to be viable, whereas it was not without the deferral. The evaluation approach proposed therefore provides a better framework for determining when and the extent of government financial support, if any, that may be needed to support a BOT project on the basis of project economics. The analysis may also be applicable to private sector investment projects, which are characterized by irreversibility and a high rate of uncertainty

Declining use of combination infliximab and immunomodulator for inflammatory bowel disease in the community setting.

To describe trends of combination therapy (CT) of infliximab (IFX) and immunomodulator (IMM) for inflammatory bowel disease (IBD) in the community setting.A retrospective study was conducted of all IBD patients referred for IFX infusion to our community infusion center between 04/01/01 and 12/31/14. CT was defined as use of IFX with either azathioprine, 6-mercaptopurine, or methotrexate. We analyzed trends of CT usage overall, for Crohn\u27s disease (CD) and ulcerative colitis (UC), and for the subgroups of induction patients. We also analyzed the trends of CT use in these groups over the study period, and compared the rates of CT use prior to and after publication of the landmark SONIC trial.Of 258 IBD patients identified during the 12 year study period, 60 (23.3%) received CT, including 35 of 133 (26.3%) induction patients. Based on the Cochran-Armitage trend test, we observed decreasing CT use for IBD patients overall (P \u3c 0.0001) and IBD induction patients, (P = 0.0024). Of 154 CD patients, 37 (24.68%) had CT, including 20 of 77 (26%) induction patients. The Cochran Armitage test showed a trend towards decreasing CT use for CD overall (P \u3c 0.0001) and CD induction, (P = 0.0024). Overall, 43.8% of CD patients received CT pre-SONIC vs 7.4% post-SONIC (P \u3c 0.0001). For CD induction, 40.0% received CT pre-SONIC vs 10.8% post-SONIC (P = 0.0035). Among the 93 patients with UC, 19 (20.4%) received CT. Of 50 induction patients, 14 (28.0%) received CT. The trend test of the 49 patients with a known year of induction again failed to demonstrate any significant trends in the use of CT (P = 0.6).We observed a trend away from CT use in IBD. A disconnect appears to exist between expert opinion and evidence favoring CT with IFX and IMM, and evolving community practice

Antimicrobial resistance: a biopsychosocial problem requiring innovative interdisciplinary and imaginative interventions

To date, antimicrobials have been understood through largely biomedical perspectives. There has been a tendency to focus upon the effectiveness of pharmaceuticals within individual bodies. However, the growing threat of antimicrobial resistance demands we reconsider how we think about antimicrobials and their effects. Rather than understanding them primarily within bodies, it is increasingly important to consider their effects between bodies, between species and across environments. We need to reduce the drivers of antimicrobial resistance (AMR) at a global level, focusing on the connections between prescribing in one country and resistance mechanisms in another. We need to engage with the ways antimicrobials within the food chain will impact upon human healthcare. Moreover, we need to realise what happens within the ward will impact upon the environment (through waste water). In the future, imaginative interventions will be required that must make the most of biomedicine but draw equally across a wider range of disciplines (e.g. engineering, ecologists) and include an ever-increasing set of professionals (e.g. nurses, veterinarians and farmers). Such collective action demands a shift to working in new interdisciplinary, inter-professional ways. Mutual respect and understanding is required to enable each perspective to be combined to yield synergistic effects

The identification of salient beliefs concerning university students’ decision to participate in sport

The aim of this study was to identify salient beliefs toward university-provided recreational sport in first-year undergraduate students. A purposive sample of 76 students (36 males, 40 females; mean age: 19.2 ± 1.7 years) undertaking various degree subjects at a higher education institution in the North of England, United Kingdom, was used in the study. The instrument was a theory-based open-ended questionnaire informed by the Theory of Planned Behavior, addressing behavioral, normative, and control beliefs. Thematic content analysis and coding was conducted on 30 randomly selected questionnaires followed by a frequency count to identify the modal salient beliefs. The modal set revealed 17 beliefs from a possible 53: six behavioral, five normative, and six control. These beliefs were related to health benefits, enjoyment, friendships, time constraints, study workloads, awareness, and the perception of family, friends, and academics. The results highlight the factors that should be targeted for intervention and provide data to be utilized for a second main quantitative study which will identify more specific belief targets. Due to equivocal intervention success, this formative research can serve to help increase the number of students participating in university recreational spor

Comparative analysis between condom use clusters and risk behaviours among portuguese university students

The research on condom use has been focused on high-risk individuals, paying less attention to those who have moderate risk or safe sexual conducts. In order to design accurate interventions, potential differences among the condom use behavior groups must be considered. The goal was to assess possible differences in individuals presenting different types of risk behavior. 140 heterosexual university students answered a self-reported questionnaire about their sexual history, condom use habits, sexual self-esteem, sexual satisfaction, sexual control, attitudes towards condoms, self-efficacy to condom use, and emotions and feelings during sexual intercourse. A cluster analysis was conducted using the results about condom use and risk behaviors. Three groups with different risk levels emerged, presenting differences over sexual self-efficacy, attitudes towards condoms, socio-demographic variables, and sexual history. The results suggest the condom use inconsistency is highly associated with other risk behaviors but the contrary does not necessarily happens. Condom use consistent users also presented risk behaviors as smoking and drinking. The group differences suggest the risks were more affected by the combination of lack of skills with a negative attitude toward condoms than by contextual or personal variables. These differences sustain the need of an intervention adjusted to the individual's risk levels, since they differ on skills and beliefs that may hinder or promote the adoption of health behaviors.Foundation for Science and Technology/Fundacao para a Ciencia e Tecnologia (Portugal)info:eu-repo/semantics/publishedVersio

A paradigm for restenosis after angioplasty: clues for the development of new preventive therapies

Restenosis after intravascular intervention is one of the most important unsolved clinical and economic problems in the management of cardiovascular disease. Although neither its pathogenesis nor its prevention are yet defined, the early and late histologic appearance of the angioplasty state are known. Immediately after angioplasty, the atheroma has fissures, and the normal segment of the vessel circumference is stretched. There is substantial evidence of intimal injury. When restenosis develops at 1-4 months the histologic appearance of the restenotic lesion is intimal hyperplasia. Given this endpoint, we may theorize that the proximate cause of this response is denuding and stretching vascular injury. Since the healing response to tissue injury has been studied extensively, we can hypothesize the major milestones in the temporal sequence of restenosis are platelet aggregation, inflammatory cell infiltration, release of growth factors, medial smooth muscle cell modulation and proliferation, proteoglycan synthesis and extracellular matrix remodeling. At each of these steps, there are potential inhibitors. The resolution of the problem of restenosis may require both removal of atheroma mass and appropriate timing and effective delivery of inhibitors of intimal hyperplasia to the injury site in adequate concentration.Biomedical Reviews 1992; 1: 13-24

The role of brand loyalty and social media in e-commerce interfaces: survey results and implications for user interfaces

This paper explores the role of brand loyalty and social media in e-commerce interfaces. A survey consisting of 118 respondents was contacted to address the questions relating to online shopping and brand loyalty. Link between the frequency of access and time spent on an e-commerce user interface, and brand loyalty, gender and age profile differences, and the role of social media to branding and on-line shopping was analyzed. It was found that online loyalty differs from offline loyalty and loyalty also differed across genders, showing men were more loyal than women when shopping online. Information shared about products on social media by friends and family played an important role in purchase decision making. Website interface and ease of navigation were also key aspects for online shopping. The research concluded with recommendations to create multimodal websites which are more interactive and targeted so customer experience is enhanced and loyalty is achieved through the use of interactivity and social media

Pretreatment nutritional status and response to checkpoint inhibitors in lung cancer.

Background:Checkpoint inhibitors are integral to non-small-cell lung cancer treatment. Existing data suggests that nutritional status may play a role in antitumor immunity. Materials & methods:This retrospective study of 106 non-small-cell lung cancer patients who started checkpoint inhibitors between 2014 and 2017 at our institution assessed relationship of nutritional parameters to overall survival (OS) and progression-free survival. Results:Mean age was 68.7 ± 9.2 years and 59.4% patients were male. On multivariate analysis for OS, hypoalbuminemia and significant weight loss were prognostic at p-values of 0.0005 and 0.0052, respectively. We noted a parabolic association between age and OS (p = 0.026, 0.0025). Conclusion:In our study, some malnutrition parameters were associated with decreased OS. U-shape relationship between age and OS noted here warrants further evaluation