Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.

BackgroundThis retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.MethodsEighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.ResultsRetreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).ConclusionOur data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed

The experience of enchantment in human-computer interaction

Improving user experience is becoming something of a rallying call in human–computer interaction but experience is not a unitary thing. There are varieties of experiences, good and bad, and we need to characterise these varieties if we are to improve user experience. In this paper we argue that enchantment is a useful concept to facilitate closer relationships between people and technology. But enchantment is a complex concept in need of some clarification. So we explore how enchantment has been used in the discussions of technology and examine experiences of film and cell phones to see how enchantment with technology is possible. Based on these cases, we identify the sensibilities that help designers design for enchantment, including the specific sensuousness of a thing, senses of play, paradox and openness, and the potential for transformation. We use these to analyse digital jewellery in order to suggest how it can be made more enchanting. We conclude by relating enchantment to varieties of experience.</p

[89Zr]Oxinate4 for long-term in vivo cell tracking by positron emission tomography

Purpose 111In (typically as [111In]oxinate3) is a gold standard radiolabel for cell tracking in humans by scintigraphy. A long half-life positron-emitting radiolabel to serve the same purpose using positron emission tomography (PET) has long been sought. We aimed to develop an 89Zr PET tracer for cell labelling and compare it with [111In]oxinate3 single photon emission computed tomography (SPECT). Methods [89Zr]Oxinate4 was synthesised and its uptake and efflux were measured in vitro in three cell lines and in human leukocytes. The in vivo biodistribution of eGFP-5T33 murine myeloma cells labelled using [89Zr]oxinate4 or [111In]oxinate3 was monitored for up to 14 days. 89Zr retention by living radiolabelled eGFP-positive cells in vivo was monitored by FACS sorting of liver, spleen and bone marrow cells followed by gamma counting. Results Zr labelling was effective in all cell types with yields comparable with 111In labelling. Retention of 89Zr in cells in vitro after 24 h was significantly better (range 71 to >90 %) than 111In (43–52 %). eGFP-5T33 cells in vivo showed the same early biodistribution whether labelled with 111In or 89Zr (initial pulmonary accumulation followed by migration to liver, spleen and bone marrow), but later translocation of radioactivity to kidneys was much greater for 111In. In liver, spleen and bone marrow at least 92 % of 89Zr remained associated with eGFP-positive cells after 7 days in vivo. Conclusion [89Zr]Oxinate4 offers a potential solution to the emerging need for a long half-life PET tracer for cell tracking in vivo and deserves further evaluation of its effects on survival and behaviour of different cell types

Latent Print Proficiency Testing: An Examination of Test Respondents, Test‐Taking Procedures, and Test Characteristics

Proficiency testing is a key component of quality assurance programs within crime laboratories and can help improve laboratory practices. However, current proficiency testing procedures contain significant limitations and can be misinterpreted by examiners and court personnel (Garrett & Mitchell, 2018). To evaluate some of these limitations, we surveyed latent print examiners (n = 198) after they completed a Collaborative Testing Services, Inc. proficiency test. Additionally, we evaluated test performance and used a quality metric algorithm to evaluate the quality of test prints. Results do not suggest that respondents are dissimilar to the broader examiner population, although they may engage in different behaviors when completing tests versus casework. Findings show that proficiency testing contains prints of high quality and is perceived as both relatively easy and representative of casework. The test discriminated between inexperienced and experienced respondents, and verification procedures were largely ineffective in reducing errors. Objective quality metrics may provide a path forward to improving proficiency testing in a measurable manner

Impacts of climate change on plant diseases – opinions and trends

There has been a remarkable scientific output on the topic of how climate change is likely to affect plant diseases in the coming decades. This review addresses the need for review of this burgeoning literature by summarizing opinions of previous reviews and trends in recent studies on the impacts of climate change on plant health. Sudden Oak Death is used as an introductory case study: Californian forests could become even more susceptible to this emerging plant disease, if spring precipitations will be accompanied by warmer temperatures, although climate shifts may also affect the current synchronicity between host cambium activity and pathogen colonization rate. A summary of observed and predicted climate changes, as well as of direct effects of climate change on pathosystems, is provided. Prediction and management of climate change effects on plant health are complicated by indirect effects and the interactions with global change drivers. Uncertainty in models of plant disease development under climate change calls for a diversity of management strategies, from more participatory approaches to interdisciplinary science. Involvement of stakeholders and scientists from outside plant pathology shows the importance of trade-offs, for example in the land-sharing vs. sparing debate. Further research is needed on climate change and plant health in mountain, boreal, Mediterranean and tropical regions, with multiple climate change factors and scenarios (including our responses to it, e.g. the assisted migration of plants), in relation to endophytes, viruses and mycorrhiza, using long-term and large-scale datasets and considering various plant disease control methods

Energy- and flux-budget turbulence closure model for stably stratified flows. Part II: the role of internal gravity waves

We advance our prior energy- and flux-budget turbulence closure model (Zilitinkevich et al., 2007, 2008) for the stably stratified atmospheric flows and extend it accounting for additional vertical flux of momentum and additional productions of turbulent kinetic energy, turbulent potential energy (TPE) and turbulent flux of potential temperature due to large-scale internal gravity waves (IGW). Main effects of IGW are following: the maximal value of the flux Richardson number (universal constant 0.2-0.25 in the no-IGW regime) becomes strongly variable. In the vertically homogeneous stratification, it increases with increasing wave energy and can even exceed 1. In the heterogeneous stratification, when IGW propagate towards stronger stratification, the maximal flux Richardson number decreases with increasing wave energy, reaches zero and then becomes negative. In other words, the vertical flux of potential temperature becomes counter-gradient. IGW also reduce anisotropy of turbulence and increase the share of TPE in the turbulent total energy. Depending on the direction (downward or upward), IGW either strengthen or weaken the total vertical flux of momentum. Predictions from the proposed model are consistent with available data from atmospheric and laboratory experiments, direct numerical simulations and large-eddy simulations.Comment: 37 pages, 5 figures, revised versio

Long term in-vivo studies of a photo-oxidized bovine osteochondral transplant in sheep

BACKGROUND: Articular cartilage has limited capacity to repair. Defects greater than 3 mm heal with formation of inferior fibrous cartilage. Therefore, many attempts have been made to find the ideal graft for larger cartilage lesions. Different grafts, such as untreated or cryopreserved osteochondral transplants, have been used with variable success. METHODS: Photo-oxidized osteochondral grafts were implanted in both femoral condyles of one ovine knee. Untreated xenogeneic and autogeneic grafts served as controls. Three groups of 8 sheep each were formed and they were sacrificed 6, 12 or 18 months after surgery. RESULTS: The macroscopic evaluation of the condyle and graft showed a well-maintained cartilage surface in most grafts at all time points. However, the host cartilage matrix deteriorated considerably in all xenogeneic, most autogeneic and fewer of the photo-oxidized grafts at 12 and 18 months, respectively. The blue colour of the photo-oxidized grafts resulting from the process of photo-oxidation was visible in all grafts at 6 months, had diminished at 12 months and had completely disappeared at 18 months after surgery. Histologically a loss of matrix staining was almost never noticed in untreated xenografts, transiently at 6 months in photo-oxidized grafts and increased at 12 and 18 months. Fusion between graft and host cartilage could be seen in photo-oxidized grafts at 12 and 18 months, but was never seen in autografts and xenografts. CONCLUSIONS: The photo-oxidation of osteochondral grafts and its use as transplant appears to have a beneficial effect on cartilage and bone remodelling. Osteochondral grafts pre-treated with photo-oxidation may be considered for articular cartilage replacement and therefore may delay artificial joint replacements in human patients

Structural basis for the photoconversion of a phytochrome to the activated far-red light-absorbing form

Phytochromes are a collection of bilin-containing photoreceptors that regulate numerous photoresponses in plants and microorganisms through their ability to photointerconvert between a red light-absorbing, ground state Pr and a far-red light-absorbing, photoactivated state Pfr1,2. While the structures of several phytochromes as Pr have been determined3-7, little is known about the structure of Pfr and how it initiates signaling. Here, we describe the three-dimensional solution structure of the bilin-binding domain as Pfr using the cyanobacterial phytochrome from Synechococcus OSB’. Contrary to predictions, light-induced rotation of the A but not the D pyrrole ring is the primary motion of the chromophore during photoconversion. Subsequent rearrangements within the protein then affect intra- and interdomain contact sites within the phytochrome dimer. From our models, we propose that phytochromes act by propagating reversible light-driven conformational changes in the bilin to altered contacts between the adjacent output domains, which in most phytochromes direct differential phosphotransfer

Young people's views on the potential use of telemedicine consultations for sexual health: results of a national survey

<p>Abstract</p> <p>Background</p> <p>Young people are disproportionately affected by sexually transmissible infections in Australia but face barriers to accessing sexual health services, including concerns over confidentiality and, for some, geographic remoteness. A possible innovation to increase access to services is the use of telemedicine.</p> <p>Methods</p> <p>Young people's (aged 16-24) pre-use views on telephone and webcam consultations for sexual health were investigated through a widely-advertised national online survey in Australia. Descriptive statistics were used to describe the study sample and chi-square, Mann-Whitney U test, or t-tests were used to assess associations. Multinomial logistic regression was used to explore the association between the three-level outcome variable (first preference in person, telephone or webcam, and demographic and behavioural variables); odds ratios and 95%CI were calculated using in person as the reference category. Free text responses were analysed thematically.</p> <p>Results</p> <p>A total of 662 people completed the questionnaire. Overall, 85% of the sample indicated they would be willing to have an in-person consultation with a doctor, 63% a telephone consultation, and 29% a webcam consultation. Men, respondents with same-sex partners, and respondents reporting three or more partners in the previous year were more willing to have a webcam consultation. Imagining they lived 20 minutes from a doctor, 83% of respondents reported that their first preference would be an in-person consultation with a doctor; if imagining they lived two hours from a doctor, 51% preferred a telephone consultation. The main objections to webcam consultations in the free text responses were privacy and security concerns relating to the possibility of the webcam consultation being recorded, saved, and potentially searchable and retrievable online.</p> <p>Conclusions</p> <p>This study is the first we are aware of that seeks the views of young people on telemedicine and access to sexual health services. Although only 29% of respondents were willing to have a webcam consultation, such a service may benefit youth who may not otherwise access a sexual health service. The acceptability of webcam consultations may be increased if medical clinics provide clear and accessible privacy policies ensuring that consultations will not be recorded or saved.</p