Decision criterion dynamics in animals performing an auditory detection task

Classical signal detection theory attributes bias in perceptual decisions to a threshold criterion, against which sensory excitation is compared. The optimal criterion setting depends on the signal level, which may vary over time, and about which the subject is naïve. Consequently, the subject must optimise its threshold by responding appropriately to feedback. Here a series of experiments was conducted, and a computational model applied, to determine how the decision bias of the ferret in an auditory signal detection task tracks changes in the stimulus level. The time scales of criterion dynamics were investigated by means of a yes-no signal-in-noise detection task, in which trials were grouped into blocks that alternately contained easy- and hard-to-detect signals. The responses of the ferrets implied both long- and short-term criterion dynamics. The animals exhibited a bias in favour of responding “yes” during blocks of harder trials, and vice versa. Moreover, the outcome of each single trial had a strong influence on the decision at the next trial. We demonstrate that the single-trial and block-level changes in bias are a manifestation of the same criterion update policy by fitting a model, in which the criterion is shifted by fixed amounts according to the outcome of the previous trial and decays strongly towards a resting value. The apparent block-level stabilisation of bias arises as the probabilities of outcomes and shifts on single trials mutually interact to establish equilibrium. To gain an intuition into how stable criterion distributions arise from specific parameter sets we develop a Markov model which accounts for the dynamic effects of criterion shifts. Our approach provides a framework for investigating the dynamics of decisions at different timescales in other species (e.g., humans) and in other psychological domains (e.g., vision, memory

Classification Criteria for Intermediate Uveitis, Non–Pars Planitis Type

Purpose: To determine classification criteria for intermediate uveitis, non-pars planitis type (IU- NPP, also known as undifferentiated intermediate uveitis) / Design: Machine learning of cases with IU-NPP and 4 other intermediate uveitides. / Methods: Cases of intermediate uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated on the validation set. / Results: Five hundred eighty-nine of cases of intermediate uveitides, including 114 cases of IU-NPP, were evaluated by machine learning. The overall accuracy for intermediate uveitides was 99.8% in the training set and 99.3% in the validation set (95% confidence interval 96.1, 99.9). Key criteria for IU-NPP included unilateral or bilateral intermediate uveitis with neither 1) snowballs in the vitreous nor 2) snowbanks on the pars plana. Other key exclusions included: 1) multiple sclerosis, 2) sarcoidosis, and 3) syphilis. The misclassification rates for pars planitis were 0 % in the training set and 0% in the validation set, respectively. / Conclusions: The criteria for IU-NPP had a low misclassification rate and appeared to perform well enough for use in clinical and translational research

Classification Criteria for Multiple Sclerosis-Associated Intermediate Uveitis

PURPOSE: The purpose of this study was to determine classification criteria for multiple sclerosis-associated intermediate uveitis. DESIGN: Machine learning of cases with multiple sclerosis-associated intermediate uveitis and 4 other intermediate uveitides. METHODS: Cases of intermediate uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used in the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated in the validation set. RESULTS: A total of 589 cases of intermediate uveitides, including 112 cases of multiple sclerosis-associated intermediate uveitis, were evaluated by machine learning. The overall accuracy for intermediate uveitides was 99.8% in the training set and 99.3% in the validation set (95% confidence interval: 96.1-99.9). Key criteria for multiple sclerosis-associated intermediate uveitis included unilateral or bilateral intermediate uveitis and multiple sclerosis diagnosed by the McDonald criteria. Key exclusions included syphilis and sarcoidosis. The misclassification rates for multiple sclerosis-associated intermediate uveitis were 0 % in the training set and 0% in the validation set. CONCLUSIONS: The criteria for multiple sclerosis-associated intermediate uveitis had a low misclassification rate and appeared to perform sufficiently well enough for use in clinical and translational research

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

A qualitative study of independent fast food vendors near secondary schools in disadvantaged Scottish neighbourhoods

Background: Preventing and reducing childhood and adolescent obesity is a growing priority in many countries. Recent UK data suggest that children in more deprived areas have higher rates of obesity and poorer diet quality than those in less deprived areas. As adolescents spend a large proportion of time in school, interventions to improve the food environment in and around schools are being considered. Nutrient standards for school meals are mandatory in the UK, but many secondary pupils purchase foods outside schools at break or lunchtime that may not meet these standards. Methods: Qualitative interviews were conducted with fast food shop managers to explore barriers to offering healthier menu options. Recruitment targeted independently-owned shops near secondary schools (pupils aged c.12-17) in low-income areas of three Scottish cities. Ten interviews were completed, recorded, and transcribed for analysis. An inductive qualitative approach was used to analyse the data in NVivo 10. Results: Five themes emerged from the data: pride in what is sold; individual autonomy and responsibility; customer demand; profit margin; and neighbourhood context. Interviewees consistently expressed pride in the foods they sold, most of which were homemade. They felt that healthy eating and general wellbeing are the responsibility of the individual and that offering what customers want to eat, not necessarily what they should eat, was the only way to stay in business. Most vendors felt they were struggling to maintain a profit, and that many aspects of the low-income neighbourhood context would make change difficult or impossible. Conclusions: Independent food shops in low-income areas face barriers to offering healthy food choices, and interventions and policies that target the food environment around schools should take the neighbourhood context into consideration

Doyne lecture 2016:intraocular health and the many faces of inflammation

Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses

Arsenic on the Hands of Children after Playing in Playgrounds

Increasing concerns over the use of wood treated with chromated copper arsenate (CCA) in playground structures arise from potential exposure to arsenic of children playing in these playgrounds. Limited data from previous studies analyzing arsenic levels in sand samples collected from CCA playgrounds are inconsistent and cannot be directly translated to the amount of children’s exposure to arsenic. The objective of this study was to determine the quantitative amounts of arsenic on the hands of children in contact with CCA-treated wood structures or sand in playgrounds. We compared arsenic levels on the hands of 66 children playing in eight CCA playgrounds with levels of arsenic found on the hands of 64 children playing in another eight playgrounds not constructed with CCA-treated wood. The children’s age and duration of playtime were recorded at each playground. After play, children’s hands were washed in a bag containing 150 mL of deionized water. Arsenic levels in the hand-washing water were quantified by inductively coupled plasma mass spectrometry. Our results show that the ages of the children sampled and the duration of play in the playgrounds were similar between the groups of CCA and non-CCA playgrounds. The mean amount of water-soluble arsenic on children’s hands from CCA playgrounds was 0.50 μg (range, 0.0078–3.5 μg). This was significantly higher (p < 0.001) than the mean amount of water-soluble arsenic on children’s hands from non-CCA playgrounds, which was 0.095 μg (range, 0.011–0.41 μg). There was no significant difference in the amount of sand on the children’s hands and the concentration of arsenic in the sand between the CCA and non-CCA groups. The higher values of arsenic on the hands of children playing in the CCA playgrounds are probably due to direct contact with CCA-treated wood. Washing hands after play would reduce the levels of potential exposure because most of the arsenic on children’s hands was washed off with water. The maximum amount of arsenic on children’s hands from the entire group of study participants was < 4 μg, which is lower than the average daily intake of arsenic from water and food

Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking

Rationale GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. Objective We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure. Methods α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). Results No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Conclusions Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking

Measuring quality of life in ALS/MND: validation of the WHOQOL-BREF

Objectives: The World Health Organization Quality of Life-BREF Scale (WHOQOL-BREF) is a generic QOL measure with four domains covering Physical, Psychological, Social and Environment. Providing the opportunity to contrast QoL with other conditions, or with population norms, the current study had three aims: 1) can the established domains of the WHOQOL-BREF be validated within a large ALS/MND population; 2) can a total score be validated and 3) can they provide interval level measurement? / Methods: Data were obtained from the Trajectories of Outcomes in Neurological Conditions study. Internal construct validity was determined by fit of the data to the Rasch measurement model. / Results: 636 participants with ALS/MND were included. All domains, except the Social domain, showed satisfactory fit to the Rasch model. All were unidimensional, and showed no Differential Item Functioning by age, gender, or onset type. Finally, a total score was validated from a bi-factor perspective. / Conclusions: The WHOQOL-BREF is valid for use in populations with ALS/MND and can be analyzed to yield interval level measurement: It offers a range of domains that reflect QOL, which can be used for parametric analysis and for comparison with other conditions or general populations, two advantages for its inclusion as a trial outcome measure and for observational studies

ALDH Activity Selectively Defines an Enhanced Tumor-Initiating Cell Population Relative to CD133 Expression in Human Pancreatic Adenocarcinoma

Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends. cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice. phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy