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The AXL receptor and its activating ligand, growth arrest–specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression in aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Moreover, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.

Designers and developers are increasingly writing manifestos to express frustration and uncertainty as they struggle to negotiate between the possibilities that IoT technologies offer, and the ethical concerns they engender. Manifestos are defining of a 'moment of crisis' and their recent proliferation indicates a desire for change. We analyze the messages manifesto authors have for their readers. Emerging from a sense of uncertainty, these manifestos create publics for debate, demand attention and call for change. While manifestos provide potential roadmaps for a better future, they also express a deep concern and even fear of the state of the world and the role of technology in it. We highlight how practitioners are responding to unstable and rapidly changing times and detail what solutions they envision, and what conflicts these might bring about. Our analysis suggests new ways HCI might theorize and design for responsibility while attending to the perils of responsibilisation.

Background Although medical school programs oriented toward postgraduate specialty training have the potential to reduce the duration and cost of medical school for US medical students, success depends on the ability of students to predict their postgraduate specialties. It is clear that first-year choices are poorly predictive, but it is not known when predictions become sufficiently reliable to support specialty-oriented learning programs. We therefore examined the predictive value of specialty preferences expressed at the ends of the first, second and third years of medical school and asked whether concurrent expressions of confidence in choices improved predictive ability. We also investigated the possibility that discrepancies between predicted and actual postgraduate specialty training were related to scores on an examination of knowledge in basic biomedical sciences required for US medical school graduation (the United States Medical Licensing Examination (USLME) Step 1 examination). Method We calculated positive and negative predictive values (PPV and NPV, respectively) for specialty choices and the sensitivity and specificity of asking for choices for 634 University of Colorado School of Medicine students who trained in 23 accredited residencies from 2011 through 2015. We examined the effect of confidence in first choices in 609 students, and in 334 students, sought an association between USMLE Step 1 scores and switching from postgraduate training specialties predicted at the end of year 2. Results The PPV of first choices improved from years 1 through 3. NPV was high throughout. PPVs of year 3 first choices ranged from 79% in Anesthesiology to 95% in Psychiatry. Expressions of confidence in first choices did not improve PPV. Sensitivity of asking for first choices increased with time; specificity was consistently high. USLME Step 1 scores were higher for students who ultimately trained in specialties more competitive than first-choice specialties at the end of year 2. Conclusions Specialty-oriented learning programs during medical school must accommodate students who change career plans. The PPV of specialty first choices improves each year, but even year 3 predictions can be inaccurate with potential loss of students from specialty-specific programs. USMLE Step 1 scores appeared to affect career plans expressed at the end of year 2. Electronic supplementary material The online version of this article (10.1186/s12909-018-1138-x) contains supplementary material, which is available to authorized users.

Background. Adeno-/tonsillectomy is a commonly performed procedure with internationally standardised and recognised indications. Despite this, there exists considerable international (190 - 850/100 000 people ≤19 years of age) and regional variation in adeno-/tonsillectomy rates. This variation has been ascribed to differences in clinical practice and referral patterns, as well as social and family factors, rather than differences in clinical need or regional morbidity. Objectives. To describe the adeno-/tonsillectomy rate in the South African private healthcare sector, and regional variations thereof. To compare local rates with international rates and to assess current trends in adeno-/tonsillectomy clinical practice. Methods. Analysis of adeno-/tonsillectomy data from January 2012 to December 2013, provided by the largest South African private healthcare funder, accounting for 31% of the medical scheme market. Rates are expressed per 100 000 people ≤19 years of age. Results. The tonsillectomy rate in the South African private healthcare sector was 1888/100 000 people ≤19 years of age in 2012. In 2013, the rate dropped significantly (p-value

Table S1. Population characteristics. Table S2. Time-related trends for Positive and Negative Predictive Value (PPV and NPV, respectively) and Sensitivity and Specificity within specialties. Table S3a. End of Year 1 – P values for differences in Positive Predictive value (PPV), Negative Predictive Value (NPV), Sensitivity (Sens) and Specificity (Spec) of 1st choice among specialties. Table S3b. End of Year 2 – P values for differences in Positive Predictive value (PPV), Negative Predictive Value (NPV), Sensitivity (Sens) and Specificity (Spec) of 1st choice among specialties. Table S3c. End of Year 3 – P values for differences in Positive Predictive value (PPV), Negative Predictive Value (NPV), Sensitivity (Sens) and Specificity (Spec) of 1st choice among specialties. Table S4. Step 1 scores by match specialty for 2014-15 First Year Residents who graduated from U.S. and Canadian medical schools and for University of Colorado School of Medicine (CUSOM) students who matched during 2011-2015. Table S5. Year 2 predictions (by 1st choice) of postgraduate training specialty categorized by actual postgraduate specialty. Figure S1. Study population flow diagram. (DOCX 102 kb)

Evidence is mounting that the temporal dynamics of the climate system are changing at the same time as the average global temperature is increasing due to multiple climate forcings. A large number of extreme weather events such as prolonged cold spells, heatwaves, droughts and floods have been recorded around the world in the past 10 years. Such changes in the temporal scaling behaviour of climate time-series data can be difficult to detect. While there are easy and direct ways of analysing climate data by calculating the means and variances for different levels of temporal aggregation, these methods can miss more subtle changes in their dynamics. This paper describes multi-scale entropy (MSE) analysis as a tool to study climate time-series data and to identify temporal scales of variability and their change over time in climate time-series. MSE estimates the sample entropy of the time-series after coarse-graining at different temporal scales. An application of MSE to Central European, variance-adjusted, mean monthly air temperature anomalies (CRUTEM4v) is provided. The results show that the temporal scales of the current climate (1960–2014) are different from the long-term average (1850–1960). For temporal scale factors longer than 12 months, the sample entropy increased markedly compared to the long-term record. Such an increase can be explained by systems theory with greater complexity in the regional temperature data. From 1961 the patterns of monthly air temperatures are less regular at time-scales greater than 12 months than in the earlier time period. This finding suggests that, at these inter-annual time scales, the temperature variability has become less predictable than in the past. It is possible that climate system feedbacks are expressed in altered temporal scales of the European temperature time-series data. A comparison with the variance and Shannon entropy shows that MSE analysis can provide additional information on the statistical properties of climate time-series data that can go undetected using traditional methods. © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).

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This article examines the work that goes in to ‘making room’ for ethics, literally and figuratively. It follows the activities of a capacity building Asia-Pacific NGO in training and recognising ethics review committees, using multi-sited field materials collected over 12 months between 2009 and 2010. Two queries drive this article: First, how are spaces made for ethical review –politically, infrastructurally, materially – as committee members campaign for attention to ethics and access to resources in which to conduct their meetings? Second, how are the limits of ‘local circumstance’ negotiated during a review of the committee’s work: what does the implementation of standards in the area of ethics look like? I then discuss what standards of ethics practice mean for more fraught questions of the universal in bioethics. Rather than regarding ethics systems as backgrounds to global health projects, this article’s STS and ethnographic approach reveals ethical review as a site of contested standardisation.

Capacity building in biomedical research ethics review has been a European priority since the early 2000s. Prompted by the increase in data originating in internationally sponsored trials in emerging economies, a range of capacity building initiatives were put in place in the field of ethical review to ensure the protection of human subjects participating in research. Drawing on fieldwork with the Forum for Ethical Review Committees in the Asian and Western Pacific Region, I explore two distinct forms taken by capacity building within that organization to support and train members of ethics review committees. The first, with an emphasis on standards and measurability, takes as its priority international accountability for clinical trial research. e second explores how the organization goes about persuading trainees to see and do ‘ethics’ differently. is distinction between forms of capacity allows me to explore what will count as ‘success’ in research ethics capacity building.

* Abbreviations: ABP — : American Board of Pediatrics ABMS — : American Board of Medical Specialties ACGME — : Accreditation Council for Graduate Medical Education CBME — : competency-based medical education EPA — : entrustable professional activity FOPO — : Federation of Pediatric Organizations MOC — : Maintenance of Certification SCTC — : Subspecialty Clinical Training and Certification The American Board of Pediatrics (ABP) certifies general pediatricians and pediatric subspecialists based on standards of excellence that lead to high-quality health care during infancy, childhood, adolescence, and the transition into adulthood. Thus, central to the ABP’s mission is assurance to the public that a general pediatrician or pediatric subspecialist has successfully completed accredited training and fulfills the continuous evaluation requirements that encompass the 6 core competencies of the Accreditation Council for Graduate Medical Education (ACGME) and the American Board of Medical Specialties (ABMS). The ABP’s quest for excellence is evident in its rigorous evaluation process and in new initiatives undertaken that not only continually improve the standards of its certification but also advance the science, education, study, and practice of pediatrics. The ABP’s responsibilities and authorities in standard setting and evaluation overlap through interest and influence the responsibilities and authorities assumed by the ACGME through its Pediatric Review Committee in the area of training, as well as those of the American Academy of Pediatrics and the subspecialty societies with respect to advocacy and education. Although the respective organizations have distinct missions and roles, they often work in collaboration and synergy regarding training and advocacy. Nonetheless, standard setting, evaluation, and certification remain the sole purview of the ABP. Because of the centrality of accredited training to certification, a decision by the ABP to offer a subspecialty certificate leads to a petition to the ACGME to accredit training programs. The ABP provides substantial input to the development of initial subspecialty program requirements and periodic revisions through its respective subboards, and the ABP standards for certification heavily influence the content of program requirements. In the late 1990s, the ACGME and ABMS introduced the concept of competency-based medical education (CBME) with the establishment of 6 domains of competence: patient care, medical knowledge, practice-based … Address correspondence to David K. Stevenson, MD, Harold K. Faber Professor of Pediatrics, Stanford University School of Medicine, Medical School Office Building, 1265 Welch Rd, X157, Stanford, CA 94305. E-mail: dstevenson{at}stanford.edu

Introduction Interleukin-12 (IL-12) is a potent cytokine that augments anti-tumor immune responses by promoting CD4 T cell Th1 differentiation, increasing CD8 T cell and NK cell cytotoxicity, inducing MHC expression on antigen presenting cells, and reprogramming myeloid-derived suppressor cells. However, the clinical utility of IL-12 administered systemically or produced by genetically engineered tumor-specific T cells has been limited by toxicities. DeepTM IL-12 is a fusion protein between IL-12 and a Fab antibody against CD45, an abundant surface receptor on T cells. This tethers IL-12 onto tumor-specific T cells prior to adoptive cell transfer (ACT) with the aim of reducing systemic exposure and focusing IL-12 function on the tumor microenvironment. Here, we describe the superior safety and efficacy profiles of Deep IL-12 tethered T cells in an immune competent adoptive cell therapy model for solid tumors. Methods The safety and efficacy of Deep IL-12 Primed T cells were evaluated in the PMEL/B16-F10 cancer model. CD8 PMEL T cells contain a TCR that recognizes the gp100 antigen expressed in B16-F10 melanoma cells. Deep IL-12 was loaded onto PMEL CD8 T cells to generate Deep IL-12 Primed PMEL T cells which were then adoptively transferred into mice bearing B16-F10 tumors. We compared tumor size, body weight change, cytokine release, circulating toxicity biomarkers, immune cell activity and histopathology in mice treated with Deep IL-12 Primed T cells and PMEL T cells alone or co-administered with recombinant IL-12. Results Deep IL-12 Primed PMEL T cells significantly improved tumor growth inhibition and overall survival in mice bearing established B16-F10 tumors as compared with PMEL T cell therapy alone or combined with systemic co-administration of IL-12. Deep IL-12 Primed PMEL T cells were well-tolerated, as administration of at least 40 million Deep IL-12 Primed PMEL T cells did not cause overt toxicities in non-tumor bearing mice. Deep IL-12 Primed PMEL T cells, but not PMEL T cells combined with systemic IL-12, resulted in elevated and sustained induction of IFNγ in the tumor microenvironment. In contrast, IFNγ induction in serum was transient and returned to baseline levels within four days of ACT. Interestingly, Deep IL-12 Priming increased both accumulation and activity of the adoptively transferred PMEL T cells in the tumor microenvironment but not in off-target healthy tissues such as the spleen. Further toxicological analysis of Deep IL-12 Primed tumor-reactive T cells will be discussed. Conclusions Deep IL-12 Priming enables tethering of IL-12 to the surface of tumor-specific T cells prior to ACT. This improves anti-tumor efficacy by promoting T cell function selectively in the tumor microenvironment and avoids toxicity by limiting systemic IL-12 exposure, resulting in a highly favorable benefit-risk profile for Deep IL-12 Primed T cells. Citation Format: De-Kuan Chang, Gulzar Ahmad, Jonathan Nardozzi, Katharine Sackton, Jesse Lyons, Karsten Sauer, Thomas Andresen, Douglas Jones. Surface-tethered IL-12 improves tumor-specific T-cell therapy and enhances inflammatory activity in tumors without inducing systemic toxicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 933.

Interleukin-12 (IL-12) is a potent pro-inflammatory cytokine that augments anti-tumor immune responses by promoting CD4 T cell Th1 differentiation, increasing CD8 T cell and NK cell cytotoxicity, inducing MHC expression on antigen presenting cells, and reprogramming myeloid-derived suppressor cells. However, the clinical utility of IL-12 has been limited by systemic toxicities. DeepTM IL-12 is a fusion protein between IL-12 and a Fab antibody against CD45, an abundant surface receptor on T cells. This enables tethering of IL-12 onto T cells prior to adoptive cell transfer (ACT). We report here the superior safety and efficacy of ACT with tumor-specific Deep IL- 12 Primed T cells which carry surface-tethered IL-12. The PMEL/B16-F10 cancer model utilizes adoptively transferred PMEL CD8 T cells that contain a TCR specific for the gp100 antigen expressed in B16-F10 melanoma cells. Deep IL-12 tethering to PMEL T cells significantly improved tumor growth inhibition and survival in tumor-bearing mice compared to PMEL T cell therapy alone or combined with systemically delivered IL-12. Doses up to 40 million Deep IL-12 Primed T cells did not result in overt toxicities. Thus, in contrast to systemically delivered free IL-12, T cell tethered IL-12 is well-tolerated. Deep IL-12 Primed PMEL T cells additionally resulted in elevated and sustained induction of IFNγ in the tumor microenvironment. In contrast, IFNγ induction in serum was transient and returned to baseline levels within four days of ACT. Further toxicological analyses will be discussed. In conclusion, ACT with Deep IL-12 Primed T cells delivers a favorable therapeutic profile by promoting T cell function selectively in the tumor microenvironment while limiting systemic IL-12 exposure.