Pharmacological Fingerprints of Contextual Uncertainty

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses. \ua9 2016 Marshall et al

Age, Information Processing Speed, and Intelligence

Entry tower with "arrow slots" and broch construction details; Benson & Forsyth (Gordon Benson and Alan Forysth) were nominated for the Stirling Prize in 1999 for the Museum of Scotland design, their first major building (winning competition design, 1991). The spaces and shapes echo Modernism and Le Corbusier, but also reference the context of Old Town. The yellow Moray sandstone cladding also speaks to Scottish history. The main feature is the circular entrance tower, which echoes the Edinburgh castle battery (the Half Moon Battery). The center has a dramatic seven story high triangular glass atrium flooded with daylight. Stairs and walkways connect the galleries on the different levels. The building was controversial in part because it adjoins the (former) Royal Museum, a very notable Victorian Italianate building (1861-1888). The two collections (Museum of Scotland and Royal Museum) were formally merged under the name National Museum of Scotland in 2006. The collections in the 1998 building cover Scottish history in an essentially chronological arrangement, beginning with prehistory to the early medieval period at the lowest level, with later periods in the higher levels. Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 6/27/2012

A review of nocturnal leg cramps in older people

Nocturnal leg cramps are common and troublesome, especially in later life, and have a significant impact on quality of life, particularly sleep quality. This article reviews the current state of knowledge regarding the diagnosis, frequency, pathophysiology and management of cramps. Recent evidence suggests that diuretic and long-acting beta-agonist therapy predispose to leg cramps. There is conflicting evidence regarding the efficacy of prophylactic stretching exercises in preventing cramps. Quinine remains the only medication proven to reduce the frequency and intensity of leg cramps. However, the degree of benefit from quinine is modest and the risks include rare but serious immune-mediated reactions and, especially in older people, dose-related side effects. Quinine treatment should be restricted to those with severe symptoms, should be subject to regular review and requires discussion of the risks and benefits with patients

A review of nocturnal leg cramps in older people

Nocturnal leg cramps are common and troublesome, especially in later life, and have a significant impact on quality of life, particularly sleep quality. This article reviews the current state of knowledge regarding the diagnosis, frequency, pathophysiology and management of cramps. Recent evidence suggests that diuretic and long-acting beta-agonist therapy predispose to leg cramps. There is conflicting evidence regarding the efficacy of prophylactic stretching exercises in preventing cramps. Quinine remains the only medication proven to reduce the frequency and intensity of leg cramps. However, the degree of benefit from quinine is modest and the risks include rare but serious immune-mediated reactions and, especially in older people, dose-related side effects. Quinine treatment should be restricted to those with severe symptoms, should be subject to regular review and requires discussion of the risks and benefits with patients

Regiodivergent Synthesis of 4- and 5-Sulfenyl Oxazoles from Alkynyl Thioethers

The regiodivergent synthesis of 4- and 5-sulfenyl oxazoles from 1,4,2-dioxazoles and alkynyl thioethers has been achieved. Gold-catalysed conditions are used to favour the formation of 5-sulfenyl oxazoles via β-selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4-sulfenyl oxazoles are formed by α-selective reaction under Brønsted acid conditions from the same substrates. The nature of stabilising gold-sulfur interactions have been investigated by natural bond orbital analysis, showing that the S→Au interactions are significantly stronger in the intermediate that favours the 5-sulfenyl oxazoles. A kinetic survey identifies catalyst inhibition processes. This study into the regiodivergent methods includes the development of telescoped annulation-oxidation protocols for regioselective access to oxazole sulfoxides and sulfones

Regiodivergent Synthesis of 4- and 5-Sulfenyl Oxazoles from Alkynyl Thioethers

The regiodivergent synthesis of 4- and 5-sulfenyl oxazoles from 1,4,2-dioxazoles and alkynyl thioethers has been achieved. Gold-catalysed conditions are used to favour the formation of 5-sulfenyl oxazoles via β-selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4-sulfenyl oxazoles are formed by α-selective reaction under Brønsted acid conditions from the same substrates. The nature of stabilising gold-sulfur interactions have been investigated by natural bond orbital analysis, showing that the S→Au interactions are significantly stronger in the intermediate that favours the 5-sulfenyl oxazoles. A kinetic survey identifies catalyst inhibition processes. This study into the regiodivergent methods includes the development of telescoped annulation-oxidation protocols for regioselective access to oxazole sulfoxides and sulfones

Safety and efficacy of combining biologics or small molecules for inflammatory bowel disease or immune-mediated inflammatory diseases: A European retrospective observational study

Few data are available regarding the combination of biologics or small molecules in inflammatory bowel disease (IBD) patients. We report safety and efficacy of such combinations through a retrospective multicentre series.Combination therapy was defined as the concomitant use of two biologics or one biologic with a small molecule. Patient demographics, disease characteristics and types of combinations were recorded. Safety was evaluated according to the occurrence of serious infection, opportunistic infection, hospitalisation, life-threatening event, worsening of IBD or immune-mediated inflammatory diseases (IMID), cancer and death. Efficacy was evaluated as the physician global assessment of the combination and comparison of clinical/endoscopic scores of IBD/IMID activity prior and during combination.A total of 104 combinations were collected in 98 patients. Concomitant IMID were present in 41 patients. Reasons for starting combination therapy were active IBD (67%), active IMID or extra-intestinal manifestations (EIM) (22%), both (10%) and unclassified in 1. Median duration of combination was 8 months (interquartile range 5-16). During 122 patient-years of follow-up, 42 significant adverse events were observed, mostly related to uncontrolled IBD. There were 10 significant infections, 1 skin cancer and no death. IBD disease activity was clinically improved in 70% and IMID/EIM activity in 81% of the patients. Overall, combination was continued in 55% of the patients.Combination of biologics and small molecules in patients with IBD and IMID/EIM seems to be a promising therapeutic strategy but is also associated with a risk of opportunistic infections or infections leading to hospitalisation in 10%

Stress, coping, and psychological resilience among physicians

Abstract Background Recent research has demonstrated that burnout is widespread among physicians, and impacts their wellbeing, and that of patients. Such data have prompted efforts to teach resilience among physicians, but efforts are hampered by a lack of understanding of how physicians experience resilience and stress. This study aimed to contribute to knowledge regarding how physicians define resilience, the challenges posed by workplace stressors, and strategies which enable physicians to cope with these stressors. Methods A qualitative approach was adopted, with 68 semi-structured interviews conducted with Irish physicians. Data were analysed using deductive content-analysis. Results Five themes emerged from the interviews. The first theme, ‘The Nature of Resilience’ captured participants’ understanding of resilience. Many of the participants considered resilience to be “coping”, rather than “thriving” in instances of adversity. The second theme was ‘Challenges of the Profession’, as participants described workplace stressors which threatened their wellbeing, including long shifts, lack of resources, and heavy workloads. The third theme, ‘Job-related Gratification’, captured aspects of the workplace that support resilience, such as gratification from medical efficacy. ‘Resilience Strategies (Protective Practices)’ summarised coping behaviours that participants considered to be beneficial to their wellbeing, including spending time with family and friends, and the final theme, ‘Resilience Strategies (Attitudes)’, captured attitudes which protected against stress and burnout. Conclusions This study emphasised the need for further research the mechanisms of physician coping in the workplace and how we can capitalise on insights into physicians’ experiences of coping with system-level stressors to develop interventions to improve resilience