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Research on the capacity to understand others’ minds has tended to focus on representations of beliefs, which are widely taken to be among the most central and basic theory of mind representations. Representations of knowledge, by contrast, have received comparatively little attention and have often been understood as depending on prior representations of belief. After all, how could one represent someone as knowing something if one doesn't even represent them as believing it? Drawing on a wide range of methods across cognitive science, we ask whether belief or knowledge is the more basic kind of representation. The evidence indicates that non-human primates attribute knowledge but not belief, that knowledge representations arise earlier in human development than belief representations, that the capacity to represent knowledge may remain intact in patient populations even when belief representation is disrupted, that knowledge (but not belief) attributions are likely automatic, and that explicit knowledge attributions are made more quickly than equivalent belief attributions. Critically, the theory of mind representations uncovered by these various methods exhibit a set of signature features clearly indicative of knowledge: they are not modality-specific, they are factive, they are not just true belief, and they allow for representations of egocentric ignorance. We argue that these signature features elucidate the primary function of knowledge representation: facilitating learning from others about the external world. This suggests a new way of understanding theory of mind—one that is focused on understanding others’ minds in relation to the actual world, rather than independent from it.
In the course of the 1170s Saladin worked assiduously to develop his power and authority in Egypt and then into Syria and the Jazira. To the Franks of Jerusalem (amongst others) this was a cause of profound concern and William of Tyre, the great chronicler of the Latin East, offered a contemporary assessment of the sultan's progress. His analysis went beyond matters of rising military strength:
Wise in counsel, valiant in war, and generous beyond measure. All the more, for this very reason, he was distrusted by those of our nobles who had keener foresight. Even in our day there is no better means by which princes can win the hearts of their subject, or for that matter, of others, than by showing generosity (munificentia) toward them; and nothing more readily attracts the eye of strangers, especially when it proceeds from princes.
The sultan's qadi and close confidant, Baha’ al-Din, wrote of him:
Saladin's generosity was too public to need to be recorded and too famous to need to be recounted … in times of shortage he would be generous, just as he would in easy circumstances. The officials from the royal chest used to hide a certain amount of money from him as a precaution in case some crisis surprised them because they knew that if he learnt of it, he would spend it.
Baha’ al-Din provided a theological endorsement for such behaviour: ‘[The Prophet] (God bless him and give him peace) said: ‘When a generous man stumbles, God takes him by the hand. There are many hadiths concerning generosity.’
From these two comments it is clear that the lavish giving of gifts and rewards was a central element of Saladin's modus operandi, his character and his reputation. Gift-giving was a fundamental aspect of contemporary culture in both the Near East and Western Europe. Saladin, as the skilled and flexible operator that he was, adapted to this practice; he certainly embraced it and to some extent, may be said to have raised it to a new level. While, as William of Tyre observed, it was a way to exercise power, matters could go awry.
We report on the successful demonstration of a 150 J nanosecond pulsed cryogenic gas cooled, diode-pumped multi-slab Yb:YAG laser operating at 1 Hz. To the best of our knowledge, this is the highest energy ever recorded for a diode-pumped laser system.
The foetal programming hypothesis posits that optimising early life factors e.g. maternal diets can help avert the burden of adverse childhood outcomes e.g. childhood obesity. To improve applicability to public health messaging, we investigated whether maternal whole diet quality and inflammatory potential influence childhood adiposity in a large consortium.
We harmonized and pooled individual participant data from up to 8,769 mother-child pairs in 7 European mother-offspring cohorts. Maternal early-, late-, and whole-pregnancy dietary quality and inflammatory potential were assessed with Dietary Approaches to Stop Hypertension (DASH) and energy-adjusted Dietary Inflammatory Index (E-DII), respectively. Primary outcome was childhood overweight and obesity (OWOB), defined as age- and sex-specific body-mass-index-z score (BMIz) > 85th percentile based on WHO growth standard. Secondary outcomes were sum-of-skinfold-thickness (SST), fat-mass-index (FMI) and fat-free-mass-index (FFMI) in available cohorts. Outcomes were assessed in early- [mean (SD) age: 2.8 (0.3) y], mid- [6.2 (0.6) y], and late-childhood [10.6 (1.2) y]. We used multivariable regression analyses to assess the associations of maternal E-DII and DASH with offspring adiposity outcomes in cohort-specific analyses, with subsequent random-effects meta-analyses. Analyses were adjusted for maternal age, pre-pregnancy BMI, parity, lifestyle factors, energy intake, educational attainment, offspring age and sex.
A more pro-inflammatory maternal diet, indicated by higher E-DII, was associated with a higher risk of offspring late-childhood OWOB [pooled-OR (95% CI) comparing highest vs. lowest E-DII quartiles: 1.22 (1.01,1.47) for whole-pregnancy and 1.38 (1.05,1.83) for early-pregnancy; both P < 0.05]. Moreover, higher late-pregnancy E-DII was associated with higher mid-childhood FMI [pooled-β (95% CI): 0.11 (0.003,0.22) kg/m2; P < 0.05]; trending association was observed for whole-pregnancy E-DII [0.12 (-0.01,0.25) kg/m2; P = 0.07]. A higher maternal dietary quality, indicated by higher DASH score, showed a trending inverse association with late-childhood OWOB (pooled-OR (95% CI) comparing highest vs. lowest DASH quartiles: 0.58 (0.32,1.02; P = 0.06). Higher early-pregnancy DASH was associated with lower late-childhood SST [pooled-β (95% CI): -1.9 (-3.6,-0.1) cm; P < 0.05] and tended to be associated with lower late-childhood FMI [-0.34 (-0.71,0.04) kg/m2; P = 0.08]. Higher whole-pregnancy DASH tended to associate with lower early-childhood SST [-0.33 (-0.72,0.06) cm; P = 0.10]. Results were similar when modelling DASH and E-DII continuously.
Analysis of pooled data suggests that pro-inflammatory, low-quality maternal antenatal diets may influence offspring body composition and obesity risk, especially during mid- or late-childhood. Due to variation of data availability at each timepoint, our results should be interpreted with caution. Because most associations were observed at mid-childhood or later, future studies will benefit from a longer follow-up.
In framing investment treaty claims against host states, foreign investors routinely assert that the state’s conduct was ‘politically’ motivated. Arbitral tribunals must then grapple with these allegations. Yet, tribunals lack both a coherent conception of what constitutes politically motivated conduct and a consistent understanding of the relevance, if any, of such motivations for the disposition of an investor’s legal claims. This uncertainty points to an underlying tension within the investment treaty regime between the protection of investors’ interests on the one hand, and the legitimate scope for democratic decision-making and responsive politics on the other.
Using concepts drawn from political science, we develop a new framework to map the variety of conduct that tribunals characterize as ‘political’. Our framework draws attention to different types of influence over government decision-making, as well as differences between government actors responsible for the conduct. We use this framework to show that tribunals have adopted different conceptions of what constitutes illegitimate political influence over government decision-making in factually similar cases. We then evaluate tribunals’ competing approaches in light of normative theories spanning both public law and private law. Engaging with multiple normative theories allows us to examine whether tribunals’ different approaches to politically motivated conduct might reflect diverse underlying normative commitments. We argue, however, that many arbitral tribunals demonstrate a reflexive distrust of domestic political contestation that is difficult to justify within any of the theories that we consider.
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.
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.
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.
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.
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.