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Short-term feeding studies have highlighted a phenomenon in Ca regulation that raises concerns around Ca absorption in dogs that may make an impact on commercial diets near to the maximum recommended level. A recent study to determine responses in dogs fed one of two diets differing in dietary Ca over 40 weeks found no evidence to suggest a concern across a range of biological parameters hypothesised to be affected by Ca. Unforeseen consequences of dietary Ca could have occurred and metabolic profiling was deemed a suitable data-driven approach to identify effects of dietary Ca. The objectives were to compare the fasted plasma metabolome (sampled at 8-week intervals over 40 weeks) of dogs fed one of two diets, near to the minimum and maximum recommended levels of dietary Ca. Comparisons with the control diet were also investigated across the postprandial time course (1–4 h) following acute (1 d) and long-term (24 weeks) feeding of the test diet. Comparing fasted plasma samples at each time point, no significant effect (adjusted P < 0·05) of diet on metabolites was observed. In the postprandial state, only phosphate was consistently different between diets and was explained by additional dietary P to maintain Ca:P. Metabolic profiling analysis supports the view that the dietary Ca upper limit is safe. Additionally, the canine plasma metabolome was characterised, providing insights into the stability of individual profiles across 40 weeks, the response to consumption of a nutritionally complete meal over a 4 h postprandial time course and different kinetic categories of postprandial absorption.
Renal disease has a high incidence in cats, and some evidence implicates dietary P as well. To investigate this further, two studies in healthy adult cats were conducted. Study 1 (36 weeks) included forty-eight cats, stratified to control or test diets providing 1·2 or 4·8 g/1000 kcal (4184 kJ) P (0 or approximately 3·6 g/1000 kcal (4184 kJ) inorganic P, Ca:P 1·2, 0·6). Study 2 (29 weeks) included fifty cats, stratified to control or test diets, providing 1·3 or 3·6 g/1000 kcal (4184 kJ) P (0 or approximately 1·5 g/1000 kcal (4184 kJ) inorganic P, Ca:P 1·2, 0·9). Health markers, glomerular filtration rate (GFR) and mineral balance were measured regularly, with abdominal ultrasound. Study 1 was halted after 4 weeks as the test group GFR reduced by 0·4 (95 % CI 0·3, 0·5) ml/min per kg, and ultrasound revealed changes in renal echogenicity. In study 2, at week 28, no change in mean GFR was observed (P >0·05); however, altered renal echogenicity was detected in 36 % of test cats. In agreement with previous studies, feeding a diet with Ca:P <1·0, a high total and inorganic P inclusion resulted in loss of renal function and changes in echogenicity suggestive of renal pathology. Feeding a diet containing lower total and inorganic P with Ca:P close to 1·0 led to more subtle structural changes in a third of test cats; however, nephrolithiasis occurred in both diet groups, complicating data interpretation. We conclude that the no observed adverse effects level for total dietary P in adult cats is lower than 3·6 g/1000 kcal (4184 kJ), however the effect of inorganic P sources and Ca:P require further investigation.
In this paper we review the design and development of a 100 J, 10 Hz nanosecond pulsed laser, codenamed DiPOLE100X, being built at the Central Laser Facility (CLF). This 1 kW average power diode-pumped solid-state laser (DPSSL) is based on a master oscillator power amplifier (MOPA) design, which includes two cryogenic gas cooled amplifier stages based on DiPOLE multi-slab ceramic Yb:YAG amplifier technology developed at the CLF. The laser will produce pulses between 2 and 15 ns in duration with precise, arbitrarily selectable shapes, at pulse repetition rates up to 10 Hz, allowing real-time shape optimization for compression experiments. Once completed, the laser will be delivered to the European X-ray Free Electron Laser (XFEL) facility in Germany as a UK-funded contribution in kind, where it will be used to study extreme states of matter at the High Energy Density (HED) instrument.
Patient-reported outcome measures (PROMs) provide a way to measure the impact of a disease and its associated treatments on the quality of life from the patients’ perspective. The aim of this review was to identify PROMs that have been developed and/or validated in patients with carotid artery disease (CAD) undergoing revascularization, and to assess their psychometric properties and examine suitability for research and clinical use.
Eight electronic databases including MEDLINE and CINAHL were searched from inception to May 2015 and updated in the MEDLINE database to February 2017. A two-stage search approach was used to identify studies reporting the development and/or validation of relevant PROMs in patients with CAD undergoing revascularization. Supplementary citation searching and hand-searching reference lists of included studies were also undertaken. The Consensus-based standards for the selection of health measurement instruments (COSMIN) and Oxford criteria were used to assess the methodological quality of the included studies, and the psychometric properties of the PROMs were evaluated using established assessment criteria.
Six PROMs, reported in five studies, were identified: 36-Item Short Form Health Survey (SF-36), Euro-QoL-5-Dimension Scale (EQ-5D), Hospital Anxiety and Depression Scale (HADS), Dizziness Handicap Inventory (DHI), Quality of life for CAD scale by Ivanova 2015 and a disease-specific PROM designed by Stolker 2010. The rigour of the psychometric assessment of the PROMs were variable with most only attempting to assess a single psychometric criterion. No study reported evidence on criterion validity and test-retest reliability. The overall psychometric evaluation of all included PROMs was rated as poor.
This review highlighted a lack of evidence in validated PROMs used for patients undergoing carotid artery revascularization. As a result, the development and validation of a new PROM for this patient population is warranted in order to provide data which can supplement traditional clinical outcomes (stroke >30 days post-procedural, myocardial infarction and death), and capture changes in health status and quality of life in patients to help inform treatment decisions.
Although the implications of long-term high Ca intakes have been well documented in growing dogs, the health consequences of Ca excess in adult dogs remain to be established. To evaluate the impact of feeding a diet containing 7·1 g/4184 kJ (1000 kcal) Ca for 40 weeks on Ca balance and health parameters in adult dogs, eighteen neutered adult Labrador Retrievers, (nine males and nine females) aged 2·5–7·4 years were randomised to one of two customised diets for 40 weeks. The diets were manufactured according to similar nutritional specifications, with the exception of Ca and P levels. The diets provided 1·7 and 7·1 g/4184 kJ (1000 kcal) (200(SD26) and 881(SD145) mg/kg body weight0·75 per d, respectively) Ca, respectively, with a Ca:P ratio of 1·6. Clinical examinations, ultrasound scans, radiographs, health parameters, metabolic effects and mineral balance were recorded at baseline and at 8-week intervals throughout the study. Dogs in both groups were healthy throughout the trial without evidence of urinary, renal or orthopaedic disease. In addition, there were no clinically relevant changes in any of the measures made in either group (all P>0·05). The high-Ca diet resulted in a 3·3-fold increase in faecal Ca excretion (P<0·001), whereas apparent Ca digestibility (%) and net Ca balance (g/d) did not significantly change from baseline or differ between the groups at any time point (both P>0·05). Ca intakes of up to 7·1 g/4184 kJ (1000 kcal) are well tolerated over a period of 40 weeks, with no adverse effects that could be attributed to the diet or to a high mineral intake.
Because horsenettle and tall ironweed are difficult to control in cool-season grass pastures, research was conducted in Tennessee and Kentucky in 2010 and 2011 to examine the efficacy of aminocyclopyrachlor on these weeds. Aminocyclopyrachlor was evaluated at 49 and 98 g ai ha−1 alone and in mixtures with 2,4-D amine at 371 and 742 g ae ha−1. Aminopyralid was also included as a comparison treatment at 88 g ai ha−1. Treatments were applied at three POST timings to horsenettle and two POST timings to tall ironweed. By 1 yr after treatment (YAT) horsenettle was controlled 74% with aminocyclopyrachlor plus 2,4-D applied late POST (LPOST) at 98 + 742 g ha−1. By 1 YAT, tall ironweed was controlled ≥ 93% by aminocyclopyrachlor applied early POST (EPOST) or LPOST, at rates as low as 49 g ha−1. Similar control was achieved with aminopyralid applied LPOST. Both aminocyclopyrachlor and aminopyralid were found to reduce horsenettle and tall ironweed biomass the following year. Moreover, all LPOST applications of aminocyclopyrachlor alone or in mixtures with 2,4-D prevented regrowth of tall ironweed at 1 YAT. Based on these studies, a LPOST herbicide application in August or September when soil moisture is adequate is recommended for control of horsenettle and tall ironweed in cool-season grass pastures.
The Second Crusade (1145-9) was, for the most part, a failure. One of its few successes was the capture of the Muslim-held city of Lisbon by contingents of Anglo-Normans, Flemings, and northern Rhinelanders travelling via the Iberian peninsula en route to the Holy Land. At its full extent the Second Crusade consisted of campaigns in the Levant, the Baltic, and the east coast of Spain, as well as the Lisbon expedition. By far the largest forces went to the Holy Land but, following a calamitous crossing of Asia Minor, the combined armies of the kings of France and Germany, along with the troops of the Latin settlers, retreated from the walls of Damascus after only five days. Because the crusade to the Levant had been preached so successfully by Abbot Bernard of Clairvaux, this dismal outcome attracted bitter criticism from contemporaries. The defeat was ascribed to the treachery of (variously) the Greeks, the Templars, the count of Flanders, and the Latin settlers, or the incompetence of King Louis VII of France and the papal legates. Some commentators believed the crusade to have been the work of the devil. Bernard himself argued that it was the judgement of God that had caused the expedition to fail. Other writers blamed the participants’ motives, most relevantly here the contemporary historian, Henry, Archdeacon of Huntingdon. He wrote:
In the same year  the armies of the emperor of Germany and the French king, which marched out with great pride under illustrious commanders, came to nothing because God despised them…. Meanwhile, a naval force that was made up of ordinary, rather than powerful, men, and was not supported by any great leader, except Almighty God, prospered a great deal better because they set out in humility. Truly ‘God resists the proud, but gives grace to the humble’. For the armies of the French king and the emperor had been more splendid and larger than that which earlier had conquered Jerusalem, and yet were crushed by very much smaller forces and were destroyed like a spider’s web. But no host had been able to withstand the poor men of whom I spoke above, and the large forces who attacked them were reduced to weakness.
Drug development is notoriously slow and arduous in comparison to other high-tech industries. The raw nature of biology makes it very difficult to rapidly prototype and iterate in ways that are normally much faster in other technology spaces. Layer on top of the lengthy screening processes and multi-year, multi-million dollar clinical trials an enormous regulatory burden and you end up with development times in excess of 10 years on average from concept to product (Lipsky and Sharp, 2001). Contrast this to the smartphone industry, where a new hardware prototype can be in stores within nine months from the first mockup. Even faster, OS releases can sometimes turn around in 90 days. Granted, the improvement increments may be measured on different scales in pharmaceuticals and consumer electronics, but the key driver of innovation is the iterative cycle.
It is not surprising that the pharmaceutical industry has turned to computational approaches in order to compress the lag experienced between bench and bedside. With so much riding on a single molecule to perform in clinical trials and deliver the most promising product possible, early characterization of drug candidates can make or break the next blockbuster. Drug candidate identification and optimization has seen benefit from process automation, but prediction of which targets and drugs will perform well enough to provide a positive risk–benefit is still not possible.
Biomarkers are tools applied to study exploratory pharmaceuticals, which help scientists and clinicians better understand the trajectory of a developing drug. Historically, drugs were developed almost exclusively using empirical data to evaluate the risk–benefit profile. The use of biomarkers in drug development has driven a trend toward more quantitative, evidence-based drug development. This trend has also fueled the promises of personalized medicine and the companion diagnostics industry. Importantly, incorporating biomarker information throughout the drug development process has led to an increase in confidence to accelerate or abandon certain experimental therapeutics. The FDA's Critical Path Initiative has driven regulatory interest in using biomarker evidence to add greater confidence in bringing new therapeutics to unmet medical needs (Woodcock and Woosley, 2008). While the emerging trend to use biomarkers has provided plenty of buzz around precision medicine, sifting through all the information to find the right conclusions can be a new challenge stemming from the mountains of data being generated in response. Here is where “Big Data” meets “Big Pharma.”
When developing an artifact, designers must first understand the problem. This includes the benefits that the artifact must deliver and the user variation that is present. Each user has a unique set of human factors, preferences, personal knowledge, and solution constraints that could potentially influence the characteristics of the artifact. Currently, there is little work supporting the process of how to formally generate user-specific design specifications, resulting in ad hoc or a priori decisions when generating design specifications. Further, because most design processes generate design specifications manually, the number of design specifications is not typically addressed at the user level. This research presents an affordance-based approach for use in the early stages of design to help designers establish user-specific design specifications. This information can then be used in the creation of a system or set of systems that meets the demands of both the user(s) and the organization that is developing the artifact. An affordance-based approach is leveraged because it maintains the relational field of view among the user, existing artifacts, and the artifact(s) being designed. Once individual design specifications are generated, designers can use this information in later stages of the design process.
This essay will explore a few of the myriad competing tensions of motive, ideology and practicality that were created by, and existed during, the time of the Crusades. The First Crusade was launched in 1095 when Pope Urban II called for the liberation of Jerusalem from the Muslims of the Near East. Four years later, the knights of Western Europe captured the holy city and established a series of territories in the Levant. Over time the Muslims began to fight back and by 1187, under the leadership of Saladin, they defeated the Franks (as the settlers were known) and recovered Jerusalem. The particular focus here is on the Third Crusade (1187—92), the campaign called in the aftermath of this seismic event. Popular history books often characterize this as the great clash between Richard the Lionheart and Saladin, and between Christianity and Islam. They describe battles and sieges; they might also highlight the divisions between Richard and Philip Augustus, and the failure of the crusade to recover Jerusalem. Such points are certainly central to a discussion of the Third Crusade but they are symptomatic of more detailed treatments of the expedition that have not, to date, placed the subject in a fuller context. One aspect of this broader approach is to emphasize the diversity of participants within the Christian and Muslim forces, to take the crusade beyond the Richard and Saladin binary.