Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Moody Music Generator: Characterising Control Parameters Using Crowdsourcing.

Abstract. We characterise the expressive effects of a music generator capable of varying its moods through two control parameters. The two control parameters were constructed on the basis of existing work on va-lence and arousal in music, and intended to provide control over those two mood factors. In this paper we conduct a listener study to determine how people actually perceive the various moods the generator can produce. Rather than directly attempting to validate that our two control param-eters represent arousal and valence, instead we conduct an open-ended study to crowd-source labels characterising different parts of this two-dimensional control space. Our aim is to characterise perception of the generator’s expressive space, without constraining listeners ’ responses to labels specifically aimed at validating the original arousal/valence moti-vation. Subjects were asked to listen to clips of generated music over the Internet, and to describe the moods with free-text labels. We find that the arousal parameter does roughly map to perceived arousal, but that the nominal “valence ” parameter has strong interaction with the arousal parameter, and produces different effects in different parts of the con-trol space. We believe that the characterisation methodology described here is general and could be used to map the expressive range of other parameterisable generators.

Embracing additive manufacture: implications for foot and ankle orthosis design

<p>Abstract</p> <p>Background</p> <p>The design of foot and ankle orthoses is currently limited by the methods used to fabricate the devices, particularly in terms of geometric freedom and potential to include innovative new features. Additive manufacturing (AM) technologies, where objects are constructed via a series of sub-millimetre layers of a substrate material, may present the opportunity to overcome these limitations and allow novel devices to be produced that are highly personalised for the individual, both in terms of fit and functionality.</p> <p>Two novel devices, a foot orthosis (FO) designed to include adjustable elements to relieve pressure at the metatarsal heads, and an ankle foot orthosis (AFO) designed to have adjustable stiffness levels in the sagittal plane, were developed and fabricated using AM. The devices were then tested on a healthy participant to determine if the intended biomechanical modes of action were achieved.</p> <p>Results</p> <p>The adjustable, pressure relieving FO was found to be able to significantly reduce pressure under the targeted metatarsal heads. The AFO was shown to have distinct effects on ankle kinematics which could be varied by adjusting the stiffness level of the device.</p> <p>Conclusions</p> <p>The results presented here demonstrate the potential design freedom made available by AM, and suggest that it may allow novel personalised orthotic devices to be produced which are beyond the current state of the art.</p

Water dispersible microbicidal cellulose acetate phthalate film

BACKGROUND: Cellulose acetate phthalate (CAP) has been used for several decades in the pharmaceutical industry for enteric film coating of oral tablets and capsules. Micronized CAP, available commercially as "Aquateric" and containing additional ingredients required for micronization, used for tablet coating from water dispersions, was shown to adsorb and inactivate the human immunodeficiency virus (HIV-1), herpesviruses (HSV) and other sexually transmitted disease (STD) pathogens. Earlier studies indicate that a gel formulation of micronized CAP has a potential as a topical microbicide for prevention of STDs including the acquired immunodeficiency syndrome (AIDS). The objective of endeavors described here was to develop a water dispersible CAP film amenable to inexpensive industrial mass production. METHODS: CAP and hydroxypropyl cellulose (HPC) were dissolved in different organic solvent mixtures, poured into dishes, and the solvents evaporated. Graded quantities of a resulting selected film were mixed for 5 min at 37°C with HIV-1, HSV and other STD pathogens, respectively. Residual infectivity of the treated viruses and bacteria was determined. RESULTS: The prerequisites for producing CAP films which are soft, flexible and dispersible in water, resulting in smooth gels, are combining CAP with HPC (other cellulose derivatives are unsuitable), and casting from organic solvent mixtures containing ≈50 to ≈65% ethanol (EtOH). The films are ≈100 µ thick and have a textured surface with alternating protrusions and depressions revealed by scanning electron microscopy. The films, before complete conversion into a gel, rapidly inactivated HIV-1 and HSV and reduced the infectivity of non-viral STD pathogens >1,000-fold. CONCLUSIONS: Soft pliable CAP-HPC composite films can be generated by casting from organic solvent mixtures containing EtOH. The films rapidly reduce the infectivity of several STD pathogens, including HIV-1. They are converted into gels and thus do not have to be removed following application and use. In addition to their potential as topical microbicides, the films have promise for mucosal delivery of pharmaceuticals other than CAP

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Magnetism, FeS colloids, and Origins of Life

A number of features of living systems: reversible interactions and weak bonds underlying motor-dynamics; gel-sol transitions; cellular connected fractal organization; asymmetry in interactions and organization; quantum coherent phenomena; to name some, can have a natural accounting via $physical$ interactions, which we therefore seek to incorporate by expanding the horizons of `chemistry-only' approaches to the origins of life. It is suggested that the magnetic 'face' of the minerals from the inorganic world, recognized to have played a pivotal role in initiating Life, may throw light on some of these issues. A magnetic environment in the form of rocks in the Hadean Ocean could have enabled the accretion and therefore an ordered confinement of super-paramagnetic colloids within a structured phase. A moderate H-field can help magnetic nano-particles to not only overcome thermal fluctuations but also harness them. Such controlled dynamics brings in the possibility of accessing quantum effects, which together with frustrations in magnetic ordering and hysteresis (a natural mechanism for a primitive memory) could throw light on the birth of biological information which, as Abel argues, requires a combination of order and complexity. This scenario gains strength from observations of scale-free framboidal forms of the greigite mineral, with a magnetic basis of assembly. And greigite's metabolic potential plays a key role in the mound scenario of Russell and coworkers-an expansion of which is suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed Krishnaswami Alladi, Springer 201

The influence of minimum sitting period of the ActivPAL™ on the measurement of breaks in sitting in young children

Sitting time and breaks in sitting influence cardio-metabolic health. New monitors (e.g. activPAL™) may be more accurate for measurement of sitting time and breaks in sitting although how to optimize measurement accuracy is not yet clear. One important issue is the minimum sitting/upright period (MSUP) to define a new posture. Using the activPAL™, we investigated the effect of variations in MSUP on total sitting time and breaks in sitting, and also determined the criterion validity of different activPAL™ settings for both construct

The rise and fall of the British comedy magazine

Although humorous magazines have existed internationally for over a century, 1994 saw the publication in the UK of the first magazine about comedy. This article reviews the rise and decline of a specific type of professional comedy sub-culture, the comedy magazine. It describes and evaluates the genesis and production of the UK’s first magazine about comedy, Deadpan, and its successors. The review contains reflections from two key contributors and creators (Deadpan’s editor and Comedy Review’s staff writer) and provides an analysis of the motivation behind these publications, their subsequent evolution, and their ultimate failure. Their rise is discussed in the context of societal changes in the UK in the 1990s, the development of lads’ mags and their influence on comedy magazines, and the televisual and stand-up performance comedy output of the decade

A Very Peculiar Practice: a very modern campus comedy, 35 years on

On May 21st 1986, the BBC broadcast the first episode of Andrew Davies’s black campus comedy A Very Peculiar Practice. 2021 celebrated the series’ 35th anniversary. This article provides an analysis of the contribution of the series to the genre of campus comedy. It provides an evaluation of the major themes, plots and characters introduced throughout the series and how these reflected, and reacted to, the political environment and ideology of the time. The series is discussed in the broader context of the campus novel, the genre of fiction in which staff, students and university management are satirised, and its contribution to the genre of television and film medicine/hospital comedy is also discussed

Are horror film scores un (der) appreciated? A review of their function, perception and professional recognition

Horror, as a genre, has traditionally suffered from being regarded as less serious or prestigious than are other film genres. There is some evidence that the under-appreciation may also extend to horror film scores.This paper reviews the nature and purpose of horror film scores in the context of the function of film scores generally, and evaluates whether one specific metric of professional recognition -the AMPAS award for best original score (Oscar)- reflects the anecdotal lack of recognition for horror. In terms of Oscar recognition, 664 films not categorised as musicals have been nominated for an Oscar for best score since 1935 and 1.65% of these have been horror films. Scores from two horror films have won an Oscar. The genre most likely to win an award is drama with 54 wins. Apart from documentary and biopic, which have received no award, the genres least likely to win are thriller, family, crime and horror. The article discusses these findings in the context of composers’ views of horror film, how music is used as a device to support or amplify cinematic objectives, and whether there are features of horror film and horror film scores which distinguish them from other genres. Three possible explanations for the attitudes towards horror scores are discussed: that they are (i) more functional/pedestrian, (ii) more experimental and/or (iii) not considered to be conventional musical compositions