5) and a 1 8–2 0 Gy equivalent dose of ∼100–120 Gy As a general

5) and a 1.8–2.0 Gy equivalent dose of ∼100–120 Gy. As a general rule, the prostate target volume with or without the seminal

vesicles should be covered by at least 95% of the prescription dose (i.e., V100 prostate >95%). Maintenance of dose constraints to OARs is equally important. The urethra maximum dose should be below 110% (ideally V100 urethra <90%). We recommend further reduction to 105% for patients who have had a TURP; and it is advisable to wait for wound healing at least 3 months between TURP and prostate brachytherapy. SP600125 order The rectal dose constraints should be 75–80% (e.g., V75 rectum <1%). Bladder dosimetry should be considered in terms of minimum and maximum so the dose to bladder wall (surrogate for the peripheral base of the prostate) does not receive <80% nor the bladder neck and trigone >80% (V80 bladder neck <1%). Updated European

and American guidelines for HDR prostate brachytherapy that include normal tissue dose constraints have been recently published PD-0332991 mw [37] and [38]. A summary of the clinical experience with HDR monotherapy can be found in Table 1 (the treatment protocols), Table 2 (late toxicity), and Table 3 (clinical outcomes). In May 1995, the first trial of prostate cancer HDR brachytherapy as monotherapy was opened at the University of Osaka, Japan and reported by Yoshioka et al. in 2000 (11). The original treatment regimen was 48 Gy in eight fractions and five consecutive days delivered with a single implant. In November 1996, the radiation dose was increased to 54 Gy in nine fractions over 5 days. The treatments were delivered

twice daily with an interfraction time of 6 h. Interestingly, 19/22 patients had high-risk features, either T3–4 disease or prostate-specific antigen (PSA) >20 ng/mL, and they OSBPL9 received hormonal therapy. They reported their results in 112 patients (68 high-risk) in 2011 (39). Intermediate-risk patients and those patients with prostate volumes >40 cm3 received 6–12 months of neoadjuvant ADT, and high-risk patients were treated adjuvant ADT for 3 years to life. The 5-year PSA disease–free survival was 83% (low 85%, intermediate 93%, and high 79%), local control 97%, disease–free survival 87%, and overall survival 96%. Initial PSA and younger age were the only significant prognostic variables. Most toxicity was genitourinary (GU). Acute Grade 3 “Common Toxicity Criteria for Adverse Events” (CTCAE) toxicity was observed in 6 patients. There were thirteen Grade 2 and three Grade 3 toxicities reported. A detailed dosimetry analysis of late toxicity in 83 patients treated with 54 Gy in nine fractions (median followup 3 years) was reported in 2009 (40). Toxicity correlations with dose volume histogram parameters revealed greatest difference for rectal toxicity were the V40 (volume of rectum that receives 40% of the prescription dose) and the D5 (the dose to 5 cm3 of the rectum). Rectal toxicity (V40 ≥ 8 cm3 vs.

This has particular significance for countries with high burdens

This has particular significance for countries with high burdens of TTIs. The importance of VNRBD has been reaffirmed by several World Health Assembly resolutions and declarations (including WHA28.72, WHA58.13 and WHA63.12) [3]. The click here issue of self-sufficiency in blood and blood products generated much interests and discussion among the Member States during the 126th WHO Executive Board (resolution EB126.R14) and the 63rd World Health Assembly adopted the resolution WHA 63.12 on the ‘Availability, safety and quality of blood products’. The WHA resolutions, The Melbourne Declaration on 100% Voluntary Non-Remunerated Donation of Blood and Blood Components

(June 2009) [4] and the recommendations of the WHO Global Blood Safety Network [5] and [6] have reaffirmed the achievement of self-sufficiency in blood and blood products based on VNRBD and the CYC202 security of that supply as the important national policy direction for ensuring a safe, secure and sufficient supply of blood and blood products. WHA 63.12, thereby, urges the WHO Member States “to take all the necessary steps to establish, implement and support nationally-coordinated, efficiently-managed and sustainable blood and plasma programmes

according to availability of resources, with the aim of achieving self-sufficiency”. Despite some successes, self-sufficiency is not yet a reality in many countries. A consultation of experts, convened by the World Health Organization (WHO) in September 2011 in Geneva, Switzerland, addressed the urgent need to establish strategies and mechanisms for achieving self-sufficiency. Information on the current situation, and country perspectives and experiences were shared. Factors influencing the global implementation of self-sufficiency, including safety, ethics, security and sustainability of supply, trade and its potential impact on public health, availability and access for patients, were analysed

to define strategies and mechanisms and provide practical guidance on buy RG7420 achieving self-sufficiency. Experts developed a consensus statement outlining the rationale and definition of self-sufficiency in safe blood and blood products based on VNRBD and made recommendations to national health authorities and WHO [7]. Experts Consensus Statement also defines that self-sufficiency in safe blood and blood products based on VNRBD means that the national needs of patients for safe blood and blood products, as assessed within the framework of the national health system, are met in a timely manner, that patients have equitable access to transfusion services and blood products, and that these products are obtained from VNRBD of national and, where needed, of regional origin, such as from neighbouring countries.

Enzymes for wound debridement, trypsin, elase, and granulase are

Enzymes for wound debridement, trypsin, elase, and granulase are commonly used in the wound healing ABT-737 cost process. Nathan et al.30 investigated the effect of trypsin and suggested that enzymes are a natural part of host defenses in the wound-healing process and that application of enzymes could potentially aid in the wound-healing process and the proteolytic

activity of enzyme is supportive to digest the dressings in the burn wound. This study also concluded that wound enzyme activity and bacterial contamination are not related. Elase, or fibrinolysin and deoxyribonuclease, has been used in everything from treatment of monilial vulvovaginitis to chronic leg ulcers and burn wounds.31 In cases in which the use of elase has been reported to facilitate and extend the necrotic process, its use is selleck highly contraindicated.32 Debriding preparations presently available must be used with caution as bacteremia has been reported in human patients after enzymatic debridement.33 A live yeast cell derivative is a water-soluble extract of yeast reported to stimulate angiogenesis, epithelialization, and collagen formation.34 It has been connected with improved wound healing in dogs. However, in horses, it prolonged wound healing by delaying wound contraction

and resulted in excessive granulation tissue formation.32 Honey has many potentially useful properties, including broad-spectrum antimicrobial activity, anti-inflammatory

action, and stimulation of new tissue growth.35 Even though the exact mechanisms of honey’s bacterial inhibition are unknown, possible mechanisms include osmotic action, low pH, its viscous nature, and production of hydrogen peroxide.36 A review of randomized controlled trials involving honey in superficial burns and wounds concluded that confidence in honey as a useful treatment for superficial wounds and burns was low, although there appears to be some biological plausibility for its use.37 See other topical agents in Figure 2. Silver therapy, in principle, has many benefits, such as (1) a multilevel antibacterial effect on cells, which considerably reduces the organism’s chances of developing resistance; (2) effectiveness against Uroporphyrinogen III synthase multi-drug-resistant organisms; and (3) low systemic toxicity. However, silver compounds such as silver nitrate and silver sulfadiazine are used for topical applications because they may be neutralized by anions (chloride, bicarbonate, and protein) in body fluids or cause cosmetic abnormality (argyria, or blue-gray coloration) on prolonged use, and they can arrest the healing process via fibroblast and epithelial cell toxicity. Despite these shortcomings, silver sulfadiazine is the most popular topical antimicrobial silver delivery system in use because safer alternatives are unavailable.

Diese Symptome treten nicht auf bei therapeutischen oder prophyla

Diese Symptome treten nicht auf bei therapeutischen oder prophylaktischen Dosen, da der NOAEL für akute Eisenintoxikation bei 10 bis 20 mg Fe/kg Körpergewicht liegt [127] and [154]. Die möglichen Einflüsse des Eisens auf das kardiovaskuläre Risiko werden höchst kontrovers diskutiert [136] and [155], was zum Teil an der Schwierigkeit liegt, bei den zu Grunde liegenden pathogenen Feedback-Mechanismen zwischen Ursache und Wirkung zu unterscheiden. Selbst eine signifikante Korrelation zwischen Atherosklerose und Serumferritin [156] lässt offen, ob das Ferritin in diesem Fall

gut gefüllte Eisenspeicher repräsentiert oder ob es als Antwort auf die entzündungsauslösende Ribociclib solubility dmso Wirkung der Atherosklerose erhöht

wurde. So NVP-BKM120 price kann eine Ursache-Wirkungs-Beziehung weder bewiesen noch widerlegt werden. Die Diskussion begann mit der Beobachtung eines 2,2-fach höheren relativen Risikos für akuten Myokardinfarkt (= AMI) in Ostfinnland bei Ferritinkonzentrationen im Serum von mehr als 200 mg/L. Solche Ferritinkonzentrationen werden bei etwa 18% der Männer in den USA und in Europa gefunden [8] and [73]. Follow-up-Studien ergaben widersprüchliche Resultate. In den meisten Folgestudien korrelierte das kardiovaskuläre Risiko mit dem Füllstand der Eisenspeicher, obwohl oft keine Signifikanz erreicht wurde [73], nicht einmal dann, wenn die entsprechenden Daten einer Metaanalyse unterworfen wurden [159]. Die Transferrinsättigung und die Eisenkonzentration im Serum als Maß für die Eisenspeicher reagieren weniger auf Veränderungen der Eisenbeladung als vielmehr auf den Turnover

des erythrozytären Eisenpools; alle diese Faktoren korrelieren kaum mit dem kardiovaskulären Risiko [160]. Dagegen spiegelt die Ferritinkonzentration im Serum die Eisenspeicher direkt wider, wenn sie nicht durch Entzündungsprozesse beeinflusst wird. Deshalb wurden bei den besser kontrollierten Studien die Eisenspeicher anhand des Serumferritins zusammen mit Entzündungsparametern wie CRP, Blutbild (WBC), Blutsenkungsgeschwindigkeit und Leberenzymen bestimmt [160]. Der Serum-Transferrinrezeptor these (= TfR) wird weniger stark von Entzündungen beeinflusst als das Serumferritin. Dieser Parameter reagiert eher auf Eisenmangel anstatt auf Eisenüberladung und kann deshalb verwendet werden, um nachzuprüfen, ob erhöhte Serumferritinspiegel aufgrund einer Entzündung oder infolge gut gefüllter Eisenspeicher vorliegen [161]. Serumferritin und TfR wurden zusammen mit CRP und der Blutsenkungsgeschwindigkeit in zwei Studien gemessen, bei denen eine signifikante Korrelation zwischen hohen Eisenspeichern und dem kardiovaskulären Risiko gezeigt wurde [160] and [162].

Inhaled antibiotics have already been used in the treatment of ot

Inhaled antibiotics have already been used in the treatment of other respiratory tract conditions, including cystic fibrosis (CF)67 and 68 and bronchiectasis.91 and 92 Administration of aerosolised antibiotics plays a particularly important role in CF, since patients with the condition suffer from diminished mucociliary

clearance, increasing their susceptibility to colonisation and infection by bacterial pathogens, including P. aeruginosa. 93 In this population, intermittent inhaled tobramycin has been shown to improve pulmonary function and decrease the density of P. aeruginosa in sputum, leading to significant reductions in respiratory hospitalisations. 67 and 68 Inhaled gentamycin has recently been shown to have a beneficial effect on outcomes in bronchiectasis, reducing the number of exacerbations and decreasing P. aeruginosa in the sputum. 72 In addition, use of inhaled dry powder ciprofloxacin Rapamycin cost in bronchiectasis patients has been associated with improved quality of life, which is likely to be due to reductions in bacterial load and improved eradication (of approximately

35%). 91 Inhaled antibiotics appear to be well tolerated in most of the above studies, reducing the risks Pexidartinib of adverse effects associated with systemic exposure. While wheezing and localised irritation (e.g. cough, bronchospasm) have been reported in some studies,92, 94 and 95 most report minimal side effects.67, 68 and 91 Choice of antimicrobial is dependent on pharmacokinetics/pharmacodynamics

in the bronchopulmonary tree, with the ability to achieve high Cmax values favouring concentration-killing drugs, while the applied delivery system influences particle size distribution and hence deposition and exposure. 96 and 97 Although the optimal dosing regimen (e.g. continuous or pulsed) for inhaled antibiotics in COPD has not been determined, their administration in aerosolised form has the ability to achieve high, microbiologically relevant concentrations in respiratory secretions in excess of the MIC of the infecting organism(s). 98 In COPD patients with chronic bacterial infection, delivery of a high concentration of antibiotic in Ribonucleotide reductase the airway through inhalation may lead to a reduction in chronic inflammation via a reduction in bacterial load, potentially reducing the frequency of exacerbations. Nevertheless, evidence for a reduction in airway inflammation following the use of aerosolised antibiotics is limited. The pharmacodynamic/pharmacokinetic profile of inhaled antibiotic therapy in the lower respiratory tract are quite different from systemic antibiotic use. The measured concentrations of various antibiotics (gentamycin, sisomycin, amikacin, tobramycin) in various locations in the respiratory tract following inhalation exceeded the highest MICs of the prevalent pathogens by between 50 and 125 times.

The system integrates the central components of RNPC, with inform

The system integrates the central components of RNPC, with information on research studies at each network centre that are either complete, underway, in recruitment or in the planning phase. These databases will facilitate the recruitment of research subjects and researchers in the areas of interest. 4) Design “Research Methodology” teaching modules to enable the

online recruitment and training of health professionals. To contribute to the preparation of research projects, 12 teaching modules on applied scientific research methodology and evaluation in the health sciences were developed (Ferreira Junior et al., 2008) for professionals involved in basic research and clinical research. These modules are available free of cost on the SAVPC website and include video lessons, text, online assessments and directed study. 5) Customise and deploy tools for tele-education and tele-care Hydroxychloroquine chemical structure to facilitate interactions among the RNPC centres. Multi-centre studies such as “Treatment of selleck chemical venous ulcers with fibrin sealant derived from snake venom” are available in two interactive forms: 1. Asynchronous interaction in the virtual learning environment, Moodle®. This environment contains specific information on the study, such

as a brochure provided by the researcher, the study protocol and good clinical practices for the researchers involved in the trial. Moreover, this information can only be accessed using a login and password. 2. Synchronise interactions via internet tele-conferencing tools. Tele-conferencing tools were made available, via the internet, that can be used at pre-scheduled times to integrate research centres, researchers and sponsors and to empower each of these participants during the clinical trials. It is widely claimed that the discovery and development of new pharmaceutical products entail high costs and Selleckchem HA-1077 risks in a decidedly competitive market, with few advantages for the companies that act in this scenario. However, Light and

Warburton (2011) have suggested that with public funding, companies can develop and produce clinically superior medicines at low prices with minimal risk. Due to the indifference of the pharmaceutical market for developing new, strategic bioproducts for the Brazilian health system, a public–public partnership (PuP) was established for developing our fibrin sealant. The fibrin sealant developed by CEVAP-UNESP demonstrated a huge translational potential based on the large number of academic studies conducted over the last 20 years (Barros et al., 2009). According to Morgan et al. (2011), evaluating the translational potential of a product requires one to consider the quality of the related research and the product’s appropriateness, stage, timespan and commercialisation potential as well as the clarity of the path ahead. The fibrin sealant was deemed a strong contender in each of these areas, thus warranting further investment in the subsequent development stages.

The second susceptibility occurs under distributing pumping condi

The second susceptibility occurs under distributing pumping conditions, during which significant reductions in groundwater elevations are apparent in narrow valleys (Fig. 8D). Again, this is most likely associated with the aquifer geometry and area of contributing recharge. As demonstrated in Fig. 7, increases in both development density and water volume per pad elicit heightened water table responses; this trend was shared by all sources. Although water table change was still undetectable for stream withdrawals at the maximum development tested,

heightened resolution and smaller scale models might allow for Staurosporine better understanding of the connection between streams and groundwater. Changes to stream flow in response to high-volume water withdrawals are spatially selleck products variable. The most significant reduction to stream flow is concentrated in one region of the model (Fig. 9, cross-sections 7, 8, and 9). Other areas of the model respond relatively uniformly to extraction scenarios, with the percent reduction in stream flow increasing with increasing development density and water volume per pad. Within the minimum development range, extracting water from both municipal pumping wells and streams

reduces stream flow by less than 2% throughout most of the stream network (Fig. 9A). At the maximum density of development, stream flow is reduced by up to 13% in a localized region (Fig. 9D). Under those same development conditions, however, stream flow reduction still remains under 3% throughout most of the stream network. Although the magnitude of stream flow reduction changes N-acetylglucosamine-1-phosphate transferase based on water source, the general spatial distribution persists (Fig. 10). Streams throughout the model respond consistently to applied withdrawal scenarios with the exception of stream cross-sections 7, 8, and 9, which exhibit nearly three times the stream flow reduction as compared to the rest of the stream segments. The combination source and stream withdrawals produced the greatest response in stream flow whereas distributed

pumping scenario results in a less dramatic response (Fig. 10). Extracting from municipal wells causes more spatial variability in stream flow reduction as compared to the combination source (Fig. 10, cross-section 8). There is a positive relationship between stream flow reduction and volume of extracted water which is determined by both well pad density and water volume per pad. Relatively uniform response throughout most of the stream segments emphasizes the markedly greater response at cross-sections 7, 8, and 9 (Fig. 9). These locations are in narrow valleys and represent streams with lesser annual discharge. These two factors dictate the capacity of groundwater–surface water exchange when withdrawals from either the aquifer or the streams are applied. Downstream parts of the stream network (Fig.

Each of the 102 samples was run on the same plate in triplicate

Each of the 102 samples was run on the same plate in triplicate. All mRNA levels are presented relative to the geometric mean of the three control genes. PHLDA2 expression levels were quantified by Real-time PCR (QPCR) against three reference genes: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide (YWHAZ), ubiquitin C (UBC) and topoisomerase

(TOP1) [28]. Summary data are presented as mean (SD) or median (inter-quartile range) depending on whether or not the data were normally distributed. Variables not normally distributed were transformed logarithmically. To investigate associations between PHLDA2 expression and parental body composition, fetal growth rates and infants body composition, Pearson’s and Spearman’s Erastin cell line AG 14699 correlation coefficients were calculated where appropriate. Differences in PHLDA2 expression levels between different categories of maternal lifestyle were tested by t-test or one-way

analysis of variance. Neonatal anthropometric measurements were adjusted for sex and gestational age and neonatal DXA measurements were adjusted for sex, gestational age and age at DXA. As there was a question regarding sex differences in mRNA levels between male and female placentas all mRNA data were adjusted for the sex of the baby [29]. Within group Z-scores were generated for femur length and abdominal circumference at 19 and 34 weeks. Royston models were fitted to fetal measurements to create z-scores for size and conditional growth rates [30]. To investigate whether there were sex differences in the relationship between PHLDA2 expression and the variables sex was included in regression analyses as appropriate and where an interaction was found data were analyzed separately by sex. Data were analyzed using Stata

version 11.0 (Statacorp, Texas, USA). In this study, PHLDA2 gene expression was examined in the placentas from 102 infants collected as part of the Southampton Women’s Survey. All were singleton, term deliveries (37 weeks gestation or greater). 53 of the infants were male and 49 were female. Descriptive statistics are given in Table 1. Within this cohort of 102 infants, no association was click here found between the placental expression level of PHLDA2 and birth weight, placental weight or other neonatal anthropometric or body composition measurements at birth ( Table 2). Longitudinal fetal ultrasound data was available at both 19 and 34 weeks for 58 fetuses within the cohort of 102 infants. There were no differences in the birth parameters between this subset of 58 pregnancies and the 43 pregnancies without full fetal scan data (data not shown). A lower 19–34 week femur length z-score change (linear growth velocity) was significantly associated with higher term placental PHLDA2 mRNA levels ( Table 3, Fig. 1).

16 The justifications

for this sample size are based on r

16 The justifications

for this sample size are based on rationale about feasibility, precision about the mean, and variance. 16 Median bleeding times were 41.5 seconds (IQR 27.25-67.5 seconds) for Autophagy inhibitor FNA compared with 7.5 seconds (IQR 5.5-10.25 seconds) for CB and 7.5 seconds (IQR 5.5-10 seconds) for TC biopsy specimens. Bleeding time was significantly longer for FNA compared with CB (P = .0006) and was indifferent between CB and TC biopsy specimens (P = .86) ( Fig. 3). The median scoring for artifacts was 5.5 (IQR 2-6) for FNA compared with 2 (IQR 2-2) for CB and 2 (IQR 0.5-2.75) for TC biopsy specimens. CBs showed fewer artifacts than did FNAs (P = .016) and were comparable to TC biopsy specimens (P = .53) ( Fig. 4). Retrieval of CBs with a sheath did not result in more artifacts compared with direct puncture CBs (CB-1) (cryo vs cryo + sheath 2.53: P = .16, cryo vs cryo + sheath 1.75: P = .074, cryo vs cryo + sheath 1.6: P = .27) ( Fig. 4). Transduodenal CBs displayed more artifacts than did direct puncture CBs (P = .028). Histopathologic assessability was given a median score of 1 (IQR 1-2) for FNA compared with 6 (IQR 6-6) for CB and 6 (IQR 6-6) for TC biopsy specimens. The histologic assessability of CBs (CB-1) was superior over FNAs (P < .0001) and as good as that of TC biopsy specimens (P = .98) and transduodenal CBs (P = .54)

( Fig. AZD6738 5). The use of sheaths decreased the histologic assessability in comparison with direct puncture CB (CB-1) (cryo vs cryo + sheath 2.53: P = .0088, cryo vs cryo + sheath 1.75: P = .0023, cryo vs cryo + sheath 1.6: P = .0076) ( Fig. 5). CB specimens (CB-1) were larger than FNA biopsy specimens (P those = .010) but smaller than TC biopsy specimens (P = .0011) ( Fig. 6). Smaller biopsy specimens also were obtained when CB specimens were retrieved by transduodenal puncture (P = .0005) or with sheaths (cryo vs cryo + sheath 2.53: P < .0001, cryo vs cryo + sheath 1.75: P = .0001, cryo vs cryo + sheath 1.6: P < .0001) ( Fig. 6). Sample histology images are provided in Figure 7. Handling of the CB probe with standard endoscopic equipment was performed

without technical difficulties (no increased stiffness through cooling of the probe, no abnormal friction between the probe and the channel, maneuverability was not different in comparison to a 19-gauge FNA needle based on subjective impressions of the 3 examiners). Tissue could be extracted with a single pass of the CB probe for transgastric and transduodenal EUS-CB punctures in all cases. During EUS the frozen tissue appears with a discrete hyperechogenic signal and can be discriminated from the surrounding tissue endosonographically because of its different density. This can be seen as echo enhancement in the EUS image. The echo enhancement lasts as long as freezing is activated. As soon as the freezing process is deactivated, the visible EUS effect disappears.

While the precise locus of such an effect is a matter of current

While the precise locus of such an effect is a matter of current debate [30], under this perspective, it seems plausible that specific types of outcome are not represented in OFC to control selleckchem choices directly, but instead to facilitate rapid updating of stimulus-based associations

by allowing animals to accurately assign credit to a particular stimulus or choice that produced them. This in turn will enable accurate stimulus-based value estimates to be passed on to structures involved in choosing what option to select. If correct, the next pressing question is to determine what exact computations OFC performs and how the OFC resolves which elements of the world are relevant for learning. Some potential clues ATM inhibitor can be found in the study by Walton and colleagues discussed above [28]. One consequence of the loss in appropriate credit assignment observed in the OFC-lesioned animals was that it unmasked a separate, intact learning mechanism that could approximate stimulus-outcome associations by using recent choice and reward histories. It is important to note that this faculty was not a novel learning strategy acquired after the lesion; logistic regression analyses showed that these

recency-weighted choice and reward histories affected choices to an almost equal extent pre-operatively and post-operatively in the control and lesion groups. However, in the non-lesioned animals, their Aprepitant impact on behaviour was dwarfed by the much stronger influence of specific stimulus-outcome pairings. This implies that the way the OFC promotes appropriate credit assignment might therefore be to enhance current task-relevant associations rather than to suppress irrelevant ones. A number of studies have provided evidence for a role of OFC in such a faculty. For instance,

excitotoxic OFC lesions in rats cause them to have abnormally persistent latent inhibition [31]. The lesion rendered them slower to respond to a stimulus relative to unlesioned control animals when it switched from being neutral to becoming reinforced; in other words, the OFC group were impaired at upregulating attention to a familiar but previously behaviourally irrelevant stimulus once it became a useful predictor of future events. By contrast, there is little evidence that OFC lesions that spare medial OFC directly disrupt extinction learning, implying no role for this region in disengaging with a stimulus when it no longer predicts reward 15• and 32]. There is also evidence that OFC might play a role in identifying the type of decision environment the agent currently faces, a sort of ‘relevance filter’ over the vast stimulus (decision) space available to an agent at any given time [6••].