The human brain continuously generates predictions about the environment based on learned regularities in the world. These predictions actively and efficiently facilitate the interpretation of incoming sensory information. We review evidence that, as a result of this facilitation, predictions directly influence conscious experience. Specifically, we propose that predictions enable rapid generation of conscious percepts and bias the contents of awareness in situations of uncertainty. The possible neural mechanisms underlying this facilitation are discussed. Perception has evolved to transform raw sensory signals into information that can guide behavior. But perception is not a purely stimulus-driven phenomenon; the brain perceives the world proactively. Endogenous influences, such as attention, memory, and mood, guide perception to ensure that informative representations of the environment are generated as efficiently as possible.In this review, we focus on the influence of predictions on visual perception. The predictions we discuss are not analogous to the deliberate, elaborative foresight that individuals may engage in when planning for the future . Instead, we use the term “prediction” here to refer to expectations about the immediate sensory environment based on previous experience and learning. Through everyday experience, individuals learn many types of regularities in the world, such as associations among items or events. For example, a yellow traffic light is almost always followed by a red light. Insofar as the environment is generally regular, it is, to an extent, predictable. Expectations about the environment can be derived from these learned regularities and used to guide sensory processing, presumably via top-down (descending) projections linking brain regions involved in generating expectations with lower-level sensory regions.If predictions guide processing in visual areas, it follows that this facilitation may have consequences for conscious perceptionOne method for studying the influence of predictions on awareness is to show observers stimuli with multiple perceptual interpretations and determine if predictions affect what they see. The popular perceptual phenomenon known as binocular rivalry provides a convenient means to accomplish this. Binocular rivalry occurs when a unique image is presented to each eye; interpretation of the stimuli is inherently ambiguous because the two eyes provide conflicting information about the shared portion of the visual field. The brain must work out the most likely interpretation of this impossible input . Second, most of the studies cited below examined the influence of predictions on behavioral proxies of recognition such as reaction time rather than subjective reports of perception. However, it will be worthwhile for future research to determine if predictive facilitation of object recognition is due, at least in part, to faster and more accurate generation of object percepts.For instance, contextual facilitation of object recognition arises from the knowledge that certain objects often reliably co-occur in particular settings. Cubicles and copy machines, but not octopuses and cars, are found inside office buildings. Furthermore, objects within a context are often arranged in a regular manner: computer monitors rest on desks inside of cubicles. Over time, observers learn many sets of such regularities, termed schemata or “context frames” . Thus, associative processing seems to specifically engage these context network regions. Further support for this claim is provided by the fact that these regions are recruited in a variety of tasks that call on contextual associations, such as memory encoding , retrosplenial complex (RSC), and medial prefrontal cortex (mPFC) mediates these contextual associations Figure . To locaThere are several mechanisms by which contextual processing may modulate activity in regions related to visual perception. PHC itself is situated in the ventral visual stream and lesions of this region in the monkey severely impair object recognition , may play a critical role in generating predictions based on LSF information Bar, . In thisConsistent with this proposal, LSF images evoke activity in OFC prior to inferior temporal areas; thus, LSF information reaches prefrontal cortex quickly enough to influence recognition processes in the ventral visual stream (Bar et al., Facilitatory feedback originating in OFC has also been shown using stimuli designed to preferentially stimulate the dorsal magnocellular pathway (Kveraga et al., We have suggested that LSF representations in OFC trigger associations with object and category information stored in memory, which then serve as predictions that guide sensory processing. To activate memory representations, OFC should interact with hippocampal regions in the medial temporal lobe, known to support long-term memory (for a review, see Squire et al., We have reviewed evidence that predictions have consequences for conscious perception. When visual input is ambiguous, predictions may help select the contents of awareness, maintaining a coherent interpretation of the environment. Under less demanding conditions, predictions may still influence awareness, allowing percepts to be generated more quickly and with less interference by sensory noise. To support these arguments, we have drawn on observations from a wide variety of domains, including the resolution of binocular rivalry, perception of ambiguous figures, associative learning, and other phenomena. We suggest, however, that all of these studies index the fact that humans are highly adept at extracting consistencies in the world and using this knowledge to generate expectations about the immediate sensory environment. Although different instances of prediction may recruit different cortical regions, predictive mechanisms are likely instantiated as dynamic top-down modulation of sensory cortex by higher sensory and prefrontal areas engaged in comparatively abstract processing. Via this modulation, predictions about the environment generated in higher-level cortical regions can guide perception.Given that the specific neural processes that give rise to conscious perception remain unclear, it is difficult to conjecture precisely how predictive feedback influences the contents of awareness. However, it is intriguing that a number of prominent theories posit that top-down feedback may play an important role in generating the neural states postulated to account for consciousness (Tononi and Edelman, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In 2005, Kosfeld et al. published their now seminal paper showing that intranasal oxytocin (OXT) administration increased interpersonal trust , which try to reconcile its pro- and anti-social roles, but there have been no attempts to date to integrate these into a single viewpoint. A potential third factor, reward sensitivity might aid this integration. We propose a model that unites these perspectives, providing new avenues of research into OXT's efficacy in social and emotional neurodevelopmental conditions.This paradox gives rise to two questions. First, how can the beneficial effects of OXT on empathy, trust and affiliation be compatible with its seemingly contradictory anti-social effects? Second, what implication does this have for the therapeutic potential of OXT in social and emotional neurodevelopmental conditions? With regard to the first question, we provide a brief overview of the literature aiming to understand the mechanism(s) underlying OXT's efficacy. There are two main perspectives on how OXT affects social behavior  or GSAD this system might be disturbed, resulting in social interaction deficits. Recent research has shown hypoactivation in the reward circuitry in ASC during social reward processing (Delmonte et al., In individuals that do not experience heightened anxiety in social situations or experience reduced reward sensitivity, OXT might not necessarily show beneficial effects. Moreover, it might even impede social behavior. For example, by decreasing anxiety social vigilance might become blunted (Ebitz et al., In conclusion, over recent years it has become clear that the effects of OXT administration on human social behavior are not best framed in absolute terms such as pro- or antisocial. We aim to shift the focus to underlying core processes such as anxiety and reward sensitivity. When applied to studied contexts, the modulation of OXT on these core processes can lead to different behavioral outcomes dependent on person and situation, especially since reward processing and anxiety in specific contexts differs from person to person. More research is needed to investigate how the dynamics of OXT modulation on these core processes translates to different contexts and groups.


The Arctic is one of the ecosystems most affected by climate change; in particular, winter temperatures and precipitation are predicted to increase with consequent changes to snow cover depth and duration. Whether the snow-free period will be shortened or prolonged depends on the extent and temporal patterns of the temperature and precipitation rise; resulting changes will likely affect plant growth with cascading effects throughout the ecosystem. We experimentally manipulated snow regimes using snow fences and shoveling and assessed aboveground size of eight common high arctic plant species weekly throughout the summer. We demonstrated that plant growth responded to snow regime, and that air temperature sum during the snow free period was the best predictor for plant size. The majority of our studied species showed periodic growth; increases in plant size stopped after certain cumulative temperatures were obtained. Plants in early snow-free treatments without additional spring warming were smaller than controls. Response to deeper snow with later melt-out varied between species and categorizing responses by growth forms or habitat associations did not reveal generic trends. We therefore stress the importance of examining responses at the species level, since generalized predictions of aboveground growth responses to changing snow regimes cannot be made. Snow depth is one of the drivers governing growing season length in the Arctic http://igloo.atmos.uiuc.edu/IPCC/). However, the magnitude and direction of snow cover changes are not easily predictable since they strongly depend on how precipitation sums are distributed across the winter season and, in particular, the partitioning into snow and rain fractions Changes of temperature and precipitation regimes driven by climatic change will impact arctic and alpine snow cover and are hence expected to have profound direct (e.g. melt-out date and temperature sums) and indirect effects  on arctic and alpine ecosystems Depending on these factors, two possible scenarios are conceivable. (1) Due to rising temperatures in winter, the fraction of precipitation falling as rain could increase and hence reduce snow cover depth and duration leading to a longer growing season Over and above these uncertainties about the future of arctic snow regimes the likely ecosystem consequences of a changing snow pack are also variable. Studies in other arctic regions suggest an increase of net primary production (NPP) following a prolonged growing season, i.e. after early snowmelt In the light of these opposing scenarios and conjectures, generic predictions of how the future snow pack will affect arctic plant growth remain difficult. In this study we therefore searched for potential generic trends by exploring how a delayed and an earlier melt might affect the aboveground growth of several common high arctic plant species. To do so, we experimentally manipulated snow depth and thus melt dates in the field by means of snow fences  and shoveling , calculated how these manipulations changed the cumulative temperature sums received by the experimental plots, and studied growth responses of target plants to the treatments by measuring plant sizes weekly throughout a full growing-season.Normal; the opposite for late melt), and 2) patterns of response may be observed at the general , growth form  and habitat association  level We hypothesized that 1) melt out date and temperature sums would affect aboveground plant size , Svalbard, Norway, throughout summer 2011, from 1 May until 12 September. Annual mean air temperature during 2002–11 (Longyearbyen airport) was −3.7°C, and average temperatures of the coldest month (March), the warmest month (July) and annual mean precipitation were −13.5°C, 7.2°C and 177 mm, respectively Deep), and another one in the area of intermediate snow depth , both representing a climate scenario that predicts a moderate to pronounced delay of snowmelt and hence a shortened growing season. To account for a climate scenario that predicts less snow in favor of rain and hence an earlier melt-out we designated a subplot next to each fence on a small windblown ridge that melted out naturally earlier than average  and another one on which the snow was manually removed on 1 May . In contrast to the other snow regimes, Removed subplots were newly established in autumn 2010. We compared these regimes with current conditions in an unmodified Normal subplot for each fence, in an area representative for most of the valley's snow depth, approx. 10–35 cm. The average melt-out dates during 2008–2012 were 24 May in Shallow, 2 June in Normal, 12 June in Medium, 19 June in DeepRemoved, eight Shallow, nine Normal, seven Medium and nine Deep. The low number of Removed subplots is due to marker stick removal by reindeer during wintertime.The experimental setup is based on Morgner et al. 521) and the Longyearbyen Lokalstyre The land on which the field site is situated belongs to Store Norske Spitsbergen Grubekompani Normal and Deep, and from 1 June 2010 in Removed, Shallow, and Medium. Daily average soil temperatures of each logger were used for the entire block. Daily average air temperatures at two meters above the ground were taken from the new weather station of the University Centre in Svalbard in Adventdalen Before snowmelt, all subplots were observed every second day and were defined as snow free when 50% of their area had melted out. In each block (i.e. set of three fences) one data logger was installed  which recorded soil temperatures hourly at approximately two centimeters below the soil surface from 4 September 2007 in Removed subplots. In addition, we also calculated the number of days with a mean temperature above 5°C. TDD and number of days until the day of each growth measurement were then matched with the recorded plant size.From the temperature measurements we calculated nine different temperature variables for each subplot, three from air and six from soil measurements : these vAlopecurus magellanicus, Bistorta vivipara (syn. Polygonum viviparum), Cassiope tetragona, Dryas octopetala, Luzula arcuata subsp. confusa, Pedicularis hirsuta, Salix polaris and Stellaria crassipes  were measured. If the marked individual got lost due to grazing or wind removal of the marker, a new randomly chosen individual or ramet nearby was marked and observed from then on and treated as a replicate in order to avoid loss of data. 43.5% of the recorded individuals or ramets were followed throughout the complete season.As soon as a subplot had melted out, or individuals of a given species were visible, one randomly chosen individual or ramet per species was selected. For Alopecurus, Dryas, Luzula and Salix the summed length of all leaves per shoot (in mm) excluding the petiole or ligule (where applicable) was used. For Bistorta the length and width of each leaf was used to calculate the leaf areas as ellipses and single leaf values were then summed for each individual. For Pedicularis and Stellaria, plant length/height was measured from soil surface until the uppermost leaf. For Cassiope, the growth increment of a shoot of the year was used since the insertion of the youngest leaf on the caulis was not easily visible.For each species different measurements were taken according to their morphology . For AloSince the data was collected in a hierarchically organized experimental set up, we used linear mixed-effects models for analysis. We assumed a unimodal relationship between time and plant size since plants usually do not grow cumulatively throughout the vegetation period but with a peak during early to mid-season, followed by a decline of live plant tissue due to senescence and leaf drop. In the analysis, we hence fitted a second order polynomial of each of the nine different temperature variables to the size measurements  of each Treatment effects on (1) melt-out dates, (2) the different temperature variables, and (3) the average size of the species throughout the season were also evaluated by means of mixed effects models with the same group structure as defined above. Potential heteroscedasticity was considered for as much grouping levels as possible . With respect to plant size, these analyses were conducted for every species separately as well as for all species together to test for generic trends. In the latter case, we scaled all species-specific size measurement to a common range between 0 and 1 and added growth form and habitat association as predictor variables, as well as species identity as an additional (highest) group variable. Each model was then sequentially reduced and the one with the lowest AIC selected. All analyses were conducted with R Normal regime differed significantly from all other snow regimes  immediately following snowmelt, and dropped throughout the growing season (to 30–50% at end August). Soils in Deep and Medium were moister- and those in Shallow were drier- than Normal , and this gave rise to higher soil moisture during the growing season than in the Normal or Shallow regimes . For consistency, we have therefore used TDD since melt-out in all subsequent analyses of all species. The TDD after melt-out of individual subplots depends on melt-out dates only, since air temperatures were derived from one single weather station. Consequently, this variable differed between treatments in parallel to melt-out dates although the difference between Normal and Shallow subplots was not statistically significant (Thawing degree days of air temperatures since melt-out (TDD) was the temperature variable that explained plant size for all species best, due to its lowest AIC. For nificant , most prShallow had an effect on the aboveground growth when regarding all species together and led to decreased plant sizes  but led to smaller plants of Cassiope and Pedicularis.The species-specific results are summarized in Alopecurus were only significantly higher in Medium than in Normal plots, namely by 50% (Removed) and 363°C , where the species grew fastest after snowmelt . In parallel, plants reached a 12% higher maximum leaf length in Removed, but a 35% lower maximum in Shallow regime. Shortening the growing season did not affect the species' full-season leaf length significantly.Growth responses of nsistent . In RemoPedicularis. However, no significant effect was found in Deep, maybe because of scarcity of data for this treatment  had a significantly negative effect on the average total length of Salix leaves and reduced it by 11% compared to Normal conditions . Earlier snowmelt  did not affect the leaf length significantly.Only a very late snowmelt  in Medium and an increase of 64% (11.3 mm) in Shallow compared to Normal  since snowmelt was found to be the best predictor of aboveground plant size. Surprisingly, the cumulative soil temperatures at our site did not describe the plant size as well as the air temperatures 6 km away, and from our data it is not possible to tease out whether this is due to insufficient geographical resolution of microclimatic thermal variation Shallow snow regime). However, even this response was not common to all species, but driven by a relatively strong effect of Shallow on some of them. The detected species-specific variation of aboveground growth responses to different snow regimes is probably a consequence of niche specializations of each individual species. Chapin and Shaver Generalizations regarding aboveground growth responses of all vascular plants to changes in the snow regimes studied are hard to make. Responses were species-specific and not grouped to growth forms or habitat associations (snow bed vs. ridge species). Analysis of data across all eight species indicated just one trend; lower aboveground plant size on ridges  and a small increase of nitrate (NO3−) in soils under deep snow Normal regime by the end of the season Only some of our species followed the hypothesized response, i.e. an earlier growing season start and higher temperature sum increased plant size, and later melt/lower temperature sum reduced plant size, compared to Medium can thus lead to a beneficial trade-off for nutrient-, season length- and temperature limited high arctic vegetation Alopecurus magellanicus, Bistorta vivipara and Dryas octopetala in our study. A positive growth response to controlled nutrient addition in Ny-Ålesund, Svalbard, was also reported for B. viviparaD. octopetalaCassiope tetragona, Pedicularis hirsuta and Stellaria crassipes, which was what we expected when only taking season length into account. These species were probably not able to benefit enough from improved nutrient/soil moisture supply Pedicularis might have slow growing roots, and the same could hold for the slow growing dwarf shrub Cassiope. That could explain both species' inability to benefit from snow fence induced nutrient flushes Cassiope did not respond to fertilizer addition but to summer temperatures in relatively cold Svalbard with opposite responses in the warmer sub-arctic lowlands of Abisko, Sweden. They thereby suggest a co-limitation of temperature and nutrient availability for that species, where growing temperature demands have to be fulfilled before enhanced nutrients can be utilized.An intermediate increase of snow cover in Removed treatment, which may have gained additional nutrients washed in with the extra melt water from surrounding areas, which might, together with extra moisture, have contributed to the enhanced growth of Dryas and Luzula. Second, climate change may also ameliorate early season climatic conditions Shallow) only resulted in an increased biomass for Stellaria - in terms of average but for not for peak plant sizes. Cassiope, Luzula and Pedicularis even had lower average and peak sizes in Shallow compared to Normal. We assume that these results are due to a shift of the onset of growth and thus of the determination of leaf set towards climatic conditions which are cooler than expected under a future warmer climate Shallow snow cover at these sites might be representative for future average conditions and expose aboveground tissues to fluctuating air temperatures causing dehardening during winter warm spells, followed by exposure to cold winter temperatures. This potentially harms overwintering meristems and reduces growth in the following season, as has been observed in Vaccinium myrtillus in the sub-Arctic during winters with low snow cover Normal snow regime might only occur during growing seasons following exceptionally stable winters without dehardening periods. In addition, recent research has demonstrated that in contrast to aboveground growth, sexual reproduction of alpine and arctic plants may suffer severely even from episodic mild frost events during anthesis The highly variable, species-specific responses of arctic plants to changes in snow pack are a generic finding, which holds even if our experimental manipulations have some associated caveats. Indeed, the experimental treatments resulted in specific combinations of growing season length, microclimate during (early) growth and nutrient and water While our hypothesis 2 was rejected regarding the uniformity of species in their growth response to an earlier or later snowmelt, we could accept hypothesis 1 as cumulative temperature sums since the date of snow melt were indeed found to be a highly significant predictor of the size of arctic plants. In fact the critical role of temperature sums for plant life in cold-limited climates is not too surprising BistortaCassiope and Pedicularis the majority of individuals steadily grew until the end of season under most treatments, irrespective of accumulated temperature. These two species could therefore be categorized as aperiodic functional types, which grow until environmental conditions become unfavorable. However, all other observed species  stopped growing after a given temperature sum. These could therefore be categorized as periodic species with growth limited by internal factors. This also suggests that these species are unlikely to benefit greatly from an earlier or warmer spring and longer potential growing season, and that is likely to have knock-on effects for grazing herbivores relying on these plants as forage. However, we emphasize that we only measured one aspect of growth, while little is known about the dynamics of belowground or stem growth, which might well continue until after leaf growth ceased.Grouping species into plant functional types (PFTs) according to their physiology rather than growth form might simplify the analyses of community responses to environmental perturbations Bistorta vivipara), others were highly resistant ; still others seemed to respond negatively to any changes (e.g. Cassiope tetragona), and this may explain their occurrence in the landscape.We demonstrated that air temperature sums since melt-out best explained aboveground growth for all species in most snow regimes. We conclude that the response of high arctic plants to climate-driven changes in snow regimes is highly species-specific, and thus it is very important to study several common high arctic species instead of only one. Some species were very responsive  were unaffected by a moderate increase in snow depth. In contrast, a deep snow pack reduced the growth of certain species , most likely due to reducing the growing season length to under a threshold level; yet this regime increased the growth of other species , possibly due to 1) increased soil moisture in early summer and 2) enhanced mineralization rates during winter resulting in increased nutrient availability during summer Shallow snow regime that melted five days earlier than Normal, all plants (except Stellaria crassipes) were smaller, possibly as a result of decreased protection from cold winter air temperatures or start of growth early in the spring time whilst temperatures were still cold. The Removed regime enhanced the growth of Luzula arcuata and Dryas octopetala in contrast to their response to shallow snow, indicating that enhanced moisture and possibly in-washed nutrients (due to the influx of melt water from surrounding areas) were contributing factors.Certain species  realistic changes in temperature, especially during spring time, and (2) the confounding effects of altered moisture and nutrient supplies. Thus we recommend future studies to investigate these issues in more detail, for example by arranging snow fence experiments along ambient temperature gradients and measure nutrient and moisture supply rates as covariates. Nevertheless, climate change and its consequences for arctic snow regimes will certainly affect temperature conditions during the growing season and winter as well as nutrient and moisture supply simultaneously. The plant species studied responded differently to the various snow regimes, indicating that a changing climate is likely to result in a shift in species composition. Indirectly, such a shift in species composition will probably affect community, and finally ecosystem productivity.According to field-specific standards the data of this study is not deposited publicly but can be obtained directly from the authors upon request.Figure S1Soil moisture measured at the experimental site in Adventdalen throughout the growing season in 2011.(TIFF)Click here for additional data file.Table S1Climatic variables recorded in Adventdalen, Svalbard for June, July and August, 2002–2011; mean air temperatures (C), Thermal Degree Days  and accumulative precipitation (mm).(DOCX)Click here for additional data file.


Iodinated contrast agents are usually classified based upon their osmolality—high, low, and isosmolar. Iodinated contrast agents are also nephrotoxic in some but not all patients resulting in loss of glomerular filtration rate. Over the past 30 years, nephrotoxicity has been linked to osmolality although the precise mechanism underlying such a link has been elusive. Improvements in our understanding of the pathogenesis of nephrotoxicity and prospective randomized clinical trials have attempted to further explore the relationship between osmolality and nephrotoxicity. In this review, the basis for our current understanding that there are little if any differences in nephrotoxic potential between low and isosmolar contrast media will be detailed using data from clinical studies. Radiographic contrast agents have been in use for over 60 years. Based upon current data, 2.0 million cardiac catheterizations are performed annually in the USA  and nearOver the past decades, modifications in the organic molecule to which the iodine is bound have occurred and have resulted in changes in the physical properties of the product. These physical properties—ionicity, osmolality, and viscosity—are directly related to the number and size of the organic molecules needed to bind the iodine.In the mid-1950s, it was recognized that some patients develop a rise in serum creatinine (the definition of contrast-induced acute kidney injury or CIAKI) following the administration of high-osmolar contrast media. Most of these patients received intra-arterial infusions, for example, for coronary angiography. The development of CIAKI has been widely documented in the literature and the risk factors for developing such an injury are exhaustively described . It shouAs noted above, the size and number of organic molecules binding the iodine are the primary determinant of the ionicity, osmolality, and viscosity of the commercial product. Over the past 2 decades, we have moved in the development of contrast media from ionic monomers through nonionic monomers to nonionic dimers increasing the number of iodine atoms per molecule from 1.5 to 6.0 see . These call patients who receive them.Before delving into the multiple studies trying to address the relative nephrotoxicity of the contrast media with different physical properties, it is appropriate to first identify whether any of these differences in physical properties translates into something measureable in In general, the higher the osmolality of the contrast media, the greater the urine output in the first few hours following their administration. This makes sense physiologically as the contrast medium is a nonreabsorbable solute which acts like an osmotic diuretic, reducing electrolyte reabsorption along the nephron and obligating an increase in urine output. An increase in urine output has been observed when comparing high and low-osmolality contrast media as well as low and isoosmolality contrast media .A definite increase in urine viscosity is observed when using contrast medium that is of very large molecular size . This occurs as a result of the progressive concentration of the contrast medium as it travels down the nephron and 99% of the filtered water is reabsorbed. Urine viscosity can be directly measured and increases significantly only with isosmolar contrast media , 5.Could either of these effects contribute in some way to the decrease in glomerular filtration rate (CIAKI) observed in some patients following contrast administration?could result in extracellular volume contraction, stimulation of the intrarenal renin-angiotensin-aldosterone axis, and/or release of other vasoconstrictor hormones  that would augment the direct vasoconstrictor effects of contrast media and further exacerbate ischemia. The increase in urine viscosity could raise the pressure within the tubule lumen and reduce the net driving force for glomerular filtration (capillary hydrostatic pressure—(pressure within tubule + plasma oncotic pressure)) and thus directly decrease GFR. The degree to which these predictable effects contribute to the development of CIAKI will depend upon the amount of contrast medium administered and the unique physiologic environment of each patient. For example, the number of nephrons filtering the contrast media (reduced in chronic kidney disease) and the degree of reabsorption within the nephron (stimulated in extracellular volume depletion and congestive heart failure) might be expected to interact with these physiologic effects. As an example, when there is more reabsorption of filtrate because of volume depletion or heart failure, the viscosity in the urine following administration of a nonionic dimer would be greater. Similarly, if a patient is already volume depleted and receives a high-osmolality agent with subsequent increase in urine output, extracellular volume depletion would be exacerbated resulting in a greater stimulation of intrarenal vasoconstrictor factors.The osmotic diuresis with high- and low-osmolality contrast media Creatinine is not an ideal marker of GFR because it undergoes secretion and even reabsorption. Changes in serum creatinine could therefore reflect changes in secretion and/or reabsorption without a change in glomerular filtration .There is a lag phase of 1-2 days before creatinine will rise sufficiently to meet the threshold for CIAKI even when GFR is severely affected. This is because the retained creatinine must distribute in total body water resulting in a slow rise in serum levels. Because of the time lag, an acute reduction in GFR can be missed if serial creatinine levels are not determined for at least 72 hours [A true change in GFR might occur as a result of hemodynamic changes without any evidence of tubule injury. In this circumstance, an increase in serum creatinine sufficient to define CIAKI would not be associated with true injury.Likewise, tubule injury may not always be reflected in a change in GFR. In this circumstance, injury would be missed by reliance on serum creatinine .To date, the vast majority of clinical trials have used serum creatinine, a marker of glomerular filtration rate, to define CIAKI. The underlying assumption is that with injury to the tubules, there is a reduction in GFR mediated by a variety of mechanisms within the kidney. However, there are many problems with using creatinine as a measure of an acute change in GFR including the following.There was no difference in the incidence of CIAKI in patients who had normal kidney function.There was a 50% reduction in the incidence of CIAKI only in patients with an initial creatinine clearance less than 60 mL/min.The reduction in the incidence of CIAKI was seen only when the contrast was given intra-arterially but not intravenously.In the 1980–1990s, the development of nonionic contrast media  was quickly adopted because of a decrease in nonkidney side effects. In particular, the feelings of warmth, nausea, and itching were all diminished with low-osmolality contrast media (LOCM) compared to high-osmolality contrast media (HOCM). Many randomized controlled trials were performed to evaluate whether LOCM reduced the incidence of nephrotoxicity compared to HOCM. An important milestone was the meta-analysis of these trials performed by Barrett and Carlisle in 1993 [Despite these findings, this meta-analysis contributed significantly to the disuse of HOCM in all patients and HOCM subsequently faded from the market to be replaced with LOCM.In the late 1990s, a new class of contrast agent—isosmolar or IOCM—came into clinical use. Based upon the meta-analysis of Barrett and Carlisle that found that osmolality contributed to the nephrotoxicity of contrast media under certain circumstances, it was quite reasonable to hypothesize that the IOCM would be associated with less CIAKI compared to LOCM. A seminal study supporting this claim was the NEPHRIC trial. This was a 129-patient, randomized trial in patients with diabetes and chronic kidney disease (estimated creatinine clearance <60 mL/min) who were undergoing cardiac angiography . The IOCWhat followed the publication of the NEPHRIC trial in the New England Journal of Medicine in 2003 can aptly be described as a “war.” Manufacturers of LOCM other than the one studied in the NEPHRIC trial immediately set to work to replicate or repudiate the finding using their own LOCM. Multiple RCTs were conducted in high-risk populations undergoing cardiac angiography, peripheral angiography, or contrast-enhanced CT. Over the past decade, at least 4 meta-analyses of these trials were published with essentially similar findings –14 see . Some meWas NEPHRIC just wrong? It is always easy to argue that a study with only 129 subjects and in which the primary endpoint occurs in <10% is going to be underpowered and subject to a type-1 error. This is certainly one possibility. Was NEPHRIC correct but used as a comparator a particular LOCM (iohexol) with a higher with a higher incidence of CIAKI? The subsequent studies using other LOCMs would support this conclusion as well. If one refers to Thus, an overall summary of the current database, updated since previous guideline recommendations, is that strength and consistency of relationships between specific isosmolar or low-osmolar agents and CIAKI or renal failure are not sufficient to enable a guideline statement on selection among commonly used low-osmolar and isosmolar media.What are the limitations of these studies and the subsequent meta-analyses? These randomized prospective trials all used serum creatinine as the marker of injury. They assumed that any increase in creatinine following contrast exposure was caused by the contrast (no adjudication for other causes of a rise in serum creatinine). Katzberg et al. noted persistent global and focal nephrograms on CT performed 24 hours following administration of isosmolar contrast for coronary angiography . Such fidifferences in chronic comorbidities between those getting IV versus IA contrast media,differences in dose of contrast administered,ascertainment bias resulting from different follow-up protocols in those receiving IA versus IV contrast,bias resulting from acute hemodynamic instability, more likely in hospitalized versus nonhospitalized patients and thus more likely in IA versus IV contrast administration.What about differences between contrast media when given by the intravenous route? There is a significant body of literature suggesting an overall lower incidence of nephrotoxicity when iodinated contrast is given intravenously compared to intraarterially . The basWhen prospective randomized trials have specifically addressed patients undergoing contrast-enhanced CT, no differences have been found between IOCM and LOCM . A singlHowever, it should again be emphasized that the development of a rise in serum creatinine following a contrast-enhanced CT may not reflect kidney injury or specifically injury resulting from contrast (see above regarding limitation of using serum creatinine). Randomized controlled trials using specific injury markers that are known to increase after contrast induced injury. Even with injury markers such as NGAL, IL-18, and KIM-1, there is no specificity for contrast-induced injury.In addition, a number of authors have found that the incidence of a rise in serum creatinine following a non-contrast-enhanced CT is similar to that following a contrast-enhanced CT, particularly in those without severe reduction in GFR at baseline –22. ThisA few studies have focused on the thrombogenicity of different contrast agents. In vitro studies have suggested that ionic low-osmolar contrast is less thrombogenic compared to either isosmolar or low-osmolar nonionic contrast . ClinicaWhile the meta-analysis data seems clear regarding an absence of differences in nephrotoxicity between IOCM and LOCM, there is relatively little data regarding long-term consequences following contrast administration. Since the contrast is eliminated from the body almost completely within 24 hours, any long-term consequences related to contrast administration are likely related to acute kidney injury at the time of administration, for example, nephrotoxicity or the comorbidities present in patients who developed acute kidney injury. Again, the assumption has been that the acute kidney injury is related to the contrast and not some other mechanism. Many observational studies and retrospective reviews of databases have reported on the association between CIAKI and congestive heart failure, mortality, and the long-term loss of kidney function including the need for dialysis. It is beyond the scope of this review to discuss whether this association represents causality or not. The reader is referred to reviews of this topic .Reed et al.  in a metIn an observational study by Per Liss and collaborators, the risk of readmission to the hospital with a diagnosis of acute kidney injury within 1 year following the exposure to an isosmolar or low-osmolar contrast media is described using data from the Swedish Cardiovascular Registry . The SweThe CARE follow-up trial followed patients for one year who were enrolled in a prospective randomized trial comparing iopamidol (low-osmolar contrast media) to iodixanol (isosmolar contrast media) . PrespecContrast media are extremely safe but can precipitate acute kidney injury in a small number of high-risk patients. Based upon randomized trial data, there do not appear to be significant differences in the nephrotoxicity between contrast media that differ on the basis of ionicity, osmolality, or viscosity. This conclusion applies to both the intravenous and intra-arterial administration of contrast. Although a few trials have described long-term differences in outcomes based on viscosity and osmolality, further studies are clearly needed to define potential mechanisms and to confirm these preliminary findings.


The motor function is controlled by the motor system that comprises a series of cortical and subcortical areas interacting via anatomical connections. The motor function will be disturbed when the stroke lesion impairs either any of these areas or their connections. More and more evidence indicates that the reorganization of the motor network including both areas and their anatomical and functional connectivity might contribute to the motor recovery after stroke. Here, we review recent studies employing models of anatomical, functional, and effective connectivity on neuroimaging data to investigate how ischemic stroke influences the connectivity of motor areas and how changes in connectivity relate to impaired function and functional recovery. We suggest that connectivity changes constitute an important pathophysiological aspect of motor impairment after stroke and important mechanisms of motor recovery. We also demonstrate that therapeutic interventions may facilitate motor recovery after stroke by modulating the connectivity among the motor areas. In conclusion, connectivity analyses improved our understanding of the mechanisms of motor recovery after stroke and may help to design hypothesis-driven treatment strategies and sensitive measures for outcome prediction in stroke patients. Motor disability is the most common deficit after ischemic stroke. Following initial damage, stroke patients can usually recover to some extent, which may be related to structural and functional modifications in surviving brain tissue. Studies on stroke rats and patients have revealed that spontaneous recovery of the motor function after stroke is associated with brain plasticity –5. NeuroKnowing brain structural or functional alteration in a particular region does not tell us how this region interacts with other regions, which modulates behavior in concert . RecentlConnectivity models are based on the concept that the brain is organized by segregation of specialized and anatomically distinct brain regions which are functionally integrated in a network mediating motor, sensory, or cognitive processing . There ain vivo [Diffusion tensor imaging (DTI) is the most common method that can detect changes in anatomical connectivity in vivo . In normin vivo , 45. Anain vivo , 46. DTIin vivo –51. In din vivo –55. It is well recognized that diffusion-weighted imaging (DWI) is capable of yielding considerably more information than that contained in the diffusion metrics derived from DTI due to the fact that DTI is based upon a Gaussian approximation of the diffusion displacement probability function. However, non-Gaussian diffusion in the brain really exists , 57 and Functional connectivity is defined as temporal correlation between spatially remote neurophysiological events. The resting-state functional connectivity (rsFC) measures temporal coherence of low-frequency fluctuations (<0.1 Hz) of the blood oxygenation level-dependent (BOLD) signals between spatially remote brain regions. Correlation of these signals with underlying neural activity indicates that these fluctuations are of functional significance –67. StroA hypothesis-driven method has been extensively used to analyze rsFC changes. In this method, an ROI should be predefined based on hypotheses, and then the rsFC pattern of this ROI is obtained by computing correlations in the fMRI time courses between the ROI and every voxel of the whole brain . The indIn contrast to the nondirectional, correlative nature of functional connectivity, effective connectivity measures the causal influence that one brain area exerts over another under the assumption of a given mechanistic model. This approach can provide crucial knowledge about the direction of information flow and ultimately what kinds of computations are being performed in the system by showing which nodes in a network are driven by which other nodes , 41, 79.Effective connectivity is based on mathematical models that are usually applied to task-based neuroimaging data. The psychophysiological interactions (PPI) model is a relatively simple method to estimate effective connectivity from neuroimaging data . This exIn the framework of graph theory, the brain is described as a graph comprising a certain number of nodes (corresponding to brain regions) that are connected by edges  –88. The Brain reorganization after stroke is a dynamic process, which considerably differs across patients, depending on lesion location, time since stroke, severity of motor impairment, premorbid state, and even genetics. These contributing factors make it unlikely that one universal measure exists which is suitable for all patients. Consequently, a variety of connectivity analyses have been performed to investigate motor recovery mechanisms after ischemic stroke.DTI and DTT are powerful methods to detect not only impairments but also modifications in anatomical connectivity after stroke , 90. ThePannek et al.  investigAt subacute stage of stroke, decreased FA in ipsilesional white matter has been commonly reported, which reflects demyelination or axonal loss , 47, 94.The ipsilateral motor pathway from the unaffected motor cortex to the affected extremities has been regarded as one of the recovery mechanisms of stroke –106. HowThe pyramidal tract is known to possess collateral pathways in the human brain –116. TheIn a longitudinal rsFC study of rats after unilateral stroke , the autSimilar rsFC changes were also found in stroke patients. Immediately after stroke, significantly decreased rsFC of the ipsilesional primary sensorimotor cortex, especially the interhemispheric rsFC, was consistently reported , 124–126Besides the altered rsFCs within the motor network after stroke, reduced interhemispheric connectivity was also found between the attention-related areas in stroke patients with neglect , 128 andGrefkes et al. applied dynamic causal modeling to investigate changes of effective connectivity among the M1, lateral premotor cortex (PMC), and SMA in subacute stroke patients when they performed visually paced hand movements with their left, right, or both hands . IndepenThe temporal evolution of intra- and interhemispheric effective connectivity was also investigated during motor recovery from the acute to the early chronic phase after stroke , 132. ReThe effective connectivity can also be investigated during resting state. Using an SEM analysis, Inman and coauthors  focused The first preliminary study on the functional network efficiency changes after stroke was performed using graph theoretical measures on electroencephalography (EEG) data of 1 stroke patient and 8 healthy subjects when they performed a finger tapping task . The autThe poststroke longitudinal changes in motor network efficiency have been reported in a resting-state fMRI study in which the authors used graph theory to assess changes in the topological configuration of the motor network from the acute phase to the chronic phase after subcortical stroke . They foUsing DTT data, Crofts and colleagues  investigMuch evidence has suggested that stroke patients will benefit significantly from rehabilitative therapies beyond spontaneous recovery of function , 139. ReThe rsFC was assessed before and after a 12-week robot-aided motor rehabilitation program. The authors found that the rsFC between the ipsilesional and contralesional M1 reduced after a bout of motor rehabilitation. Greater reduction in the interhemispheric rsFC was associated with greater gains in motor function induced by the 12-week robotic therapy program. These findings suggest that greater reduction in interhemispheric rsFC in response to a bout of motor rehabilitation may predict greater efficacy of the full rehabilitation program . A recenResting-state fMRI data were analyzed using the SEM to evaluate therapy-related changes in motor network effective connectivity in stroke patients after 3 weeks of upper-extremity rehabilitation in the accelerated skill acquisition program (ASAP). The authors found that the behavioral improvement after training of the impaired upper extremity is accompanied by increased influence of the affected hemispheric PMC upon the unaffected hemispheric PMC and on the affected hemispheric M1 .The relationship between behavioral recovery and interhemispheric and intrahemispheric communication has been investigated by inhibiting the contralesional M1 using1-Hz repetitive transcranial magnetic stimulation (rTMS) . After iA growing body of evidence from connectivity-based analyses of functional imaging data has told us that a focal stroke lesion may affect not only the lesion site but also the network to which it belongs. Thus the connectivity-based analytic methods may be more appropriate for elucidating stroke-induced impairments from a network perspective and for clarifying the mechanisms of motor recovery after stroke. Moreover, connectivity analyses are likely to be better suited to investigate the mechanisms through which therapeutic interventions may facilitate the recovery of motor function and help us to develop new intervention therapies targeting the restoration of the function of the motor network. Finally, connectivity measures may serve to monitor the process of stroke recovery and to predict the outcomes of stroke patients at an early stage. However, conflicting findings exist and the exact mechanisms leading to changes in brain connectivity after stroke remain elucidated. Therefore, longitudinal studies with large sample size employing different neuroimaging modalities covering the whole period from the superacute stage to the late chronic stage are needed to further our understanding of how different types of brain connectivity evolve after stroke and how they relate to motor deficits and clinical outcome.


Online studies are increasingly utilized in applied research. However, lack of external diagnostic verification in many of these investigations is seen as a threat to the reliability of the data. The present study examined the robustness of internet studies on psychosis against simulation. We compared the psychometric properties of the Community Assessment of Psychic Experiences scale (CAPE), a self-report instrument measuring psychotic symptoms, across three independent samples: (1) participants with a confirmed diagnosis of schizophrenia, (2) participants with self-reported schizophrenia who were recruited over the internet, and (3) clinical experts on schizophrenia as well as students who were asked to simulate a person with schizophrenia when completing the CAPE. The CAPE was complemented by a newly developed 4-item psychosis lie scale. Results demonstrate that experts asked to simulate schizophrenia symptoms could be distinguished from real patients: simulators overreported positive symptoms and showed elevated scores on the psychosis lie scale. The present study suggests that simulated answers in online studies on psychosis can be distinguished from authentic responses. Researchers conducting clinical online studies are advised to adopt a number of methodological precautions and to compare the psychometric properties of online studies to established clinical indices to assert the validity of their results. Traditionally, psychological assessments administered by an interviewer are preferred over nonpersonal assessments such as questionnaires. Face-to-face (FTF) assessment may in some cases unveil hidden symptoms and/or partly compensate for a lack of reliable information provided by a patient alone . To illuOn the other hand, research assessing the correspondence between self- and observer ratings indicates that self-report of psychotic symptoms is more reliable than commonly thought. Studies have generally found satisfactory associations between self- and observer-based ratings for overall pathology , negativDespite the aforementioned merits, clinical assessment is not without weaknesses. The presence of an assessor may induce important biases , 10, espImportantly, findings obtained in clinical studies can by no means be extrapolated to the entire patient population as many patients are not willing to undergo personal assessment or treatment. In psychosis, at least one-third of individuals remain untreated , and patTo reach people with mental disorders who are unable, unwilling, or reluctant to engage in direct psychological or psychiatric contact, online assessment represents a low-threshold and economic means and may thus complement existing standard clinical assessments. However, even though studies on nonclinical samples assert that internet studies are usually as reliable as FTF contacts when certain precautions are met, many researchers still have reservations . InterneThe present study set out to examine the reliability of data on psychotic symptoms obtained over the internet and its robustness against simulation. To meet our purpose, we contrasted the performance of three different populations , individuals with schizophrenia with a likely diagnosis (online assessment), and “simulators” (online assessment)). In line with a prior study on OCD patients , we expen = 33) whose diagnoses were verified using the Mini Neuropsychiatric Interview , comple et al.,  and askeData for the second sample was derived from a recently published internet study on medication adherence . ParticWe recruited a sample of distinguished experts or students who were asked to simulate a diagnosis of either OCD  or psycThe Community Assessment of Psychic Experiences Scale  consistWith the aid of statistical procedures, scientific studies aim to generalize from a  sample to the entire population. As outlined in the introduction, results from neither clinical nor internet studies targeting mental disorders can claim full representativeness as, for example, patients seeking help  and those who do not (those more easily recruited via internet studies) seem to differ on important characteristics , 15. StiTherefore, the present study set out to test the robustness of internet-based research in schizophrenia against simulation. As expected, distinguished experts had a marked tendency to overreport positive (but not negative and depressed) symptoms and, unlike clinical samples, the positive syndrome did not correlate with negative and depressed symptoms . The mean scores of the schizophrenia samples were clearly above the values reported for nonclinical controls  in such studies. For example, the incorporation of lie scales as well as plausibility checks  may help to filter out simulators. Moreover, subjects who enter the same value for all items should be excluded. Overall, the consequences of false-positive judgments  are deemed more grave than false-negative assignments in internet studies. A nonmonetary compensation for participation  may also ward off simulators who are solely interested in financial reimbursement. Moreover, patients are best recruited from specific sources . As shown, several psychometric indices may serve as a proxy to determine the reliability of internet samples. If the psychometric properties of an internet sample are similar to established scores, this speaks for the validity of the results. Where possible, additional telephone interviews should be considered, which however raises the threshold of recruitment considerably. Another option is to ask in- and outpatients with a verified diagnosis for their email address before discharge and whether they are willing to participate in internet studies or to ask subjects to send blinded diagnostic information via fax or email .


Tools to support clinical or patient decision-making in the treatment/management of a health condition are used in a range of clinical settings for numerous preference-sensitive healthcare decisions. Their impact in clinical practice is largely dependent on their quality across a range of domains. We critically analysed currently available tools to support decision making or patient understanding in the treatment of acute ischaemic stroke with intravenous thrombolysis, as an exemplar to provide clinicians/researchers with practical guidance on development, evaluation and implementation of such tools for other preference-sensitive treatment options/decisions in different clinical contexts.Tools were identified from bibliographic databases, Internet searches and a survey of UK and North American stroke networks. Two reviewers critically analysed tools to establish: information on benefits/risks of thrombolysis included in tools, and the methods used to convey probabilistic information ; adherence to guidance on presenting outcome probabilities (IPDASi probabilities items) and information content (Picker Institute Checklist); readability (Fog Index); and the extent that tools had comprehensive development processes.Nine tools of 26 identified included information on a full range of benefits/risks of thrombolysis. Verbal descriptors, frequencies and percentages were used to convey probabilistic information in 20, 19 and 18 tools respectively, whilst nine used graphical methods. Shortcomings in presentation of outcome probabilities (e.g. omitting outcomes without treatment) were identified. Patient information tools had an aggregate median Fog index score of 10. None of the tools had comprehensive development processes.Tools to support decision making or patient understanding in the treatment of acute stroke with thrombolysis have been sub-optimally developed. Development of tools should utilise mixed methods and strategies to meaningfully involve clinicians, patients and their relatives in an iterative design process; include evidence-based methods to augment interpretability of textual and probabilistic information  on the full range of outcome states associated with available options; and address patients with different levels of health literacy. Implementation of tools will be enhanced when mechanisms are in place to periodically assess the relevance of tools and where necessary, update the mode of delivery, form and information content. Clinicians and patients are frequently faced with making a decision about medical or surgical treatment when there are multiple reasonable options (including where appropriate the option of doing nothing) with different balances of short- and long-term benefits, risks and resultant consequences, which are sensitive to individual patient preferences and values -3. ExampIn contrast to decisions about effective care, evidence-based tools such as clinical decision support tools , patientTools to support clinical and patient decision-making or patient understanding in the treatment/management of a health condition are used in a range of clinical settings for a myriad of preference-sensitive healthcare decisions, although their impact in clinical practice is largely dependent on their quality across a range of domains. Tools should be underpinned by a systematic development process, with reference to evidence-based methods, in order to establish the optimal mode of delivery (electronic or paper-based); form ; and information content  ,8-13.The decision to treat or not treat acute ischaemic stroke with intravenous thrombolysis  is a further example of a preference-sensitive healthcare decision, which presents unique challenges for development of tools to support patient understanding / decision making about treatment. Benefit from thrombolysis is time dependent and treatment must be administered within a maximal time window of 4.5 hours from onset of symptoms ,15. HoweGiven the extreme time dependent context and the gravity of the potential risks from thrombolysis, clinicians as well as patients (or their relatives/proxy in situations where a patient lacks capacity) are faced with making rapid decisions about treatment that involve deliberation of trade-offs between the increased likelihood of long-term benefit from thrombolysis (reduced risk of significant post-stroke disability) and the more immediate bleeding risks and consequences ,21. HealDespite evidence of effectiveness, thrombolytic treatment rates for acute stroke are below optimal levels . Other tA variety of tools may help: to support decision making about thrombolysis; clinicians to convey accurate information on benefits, risks and likely consequences of treating acute ischaemic stroke, with and without thrombolysis to patients/relatives in order to support informed consent; and (where appropriate) engagement of patients/relatives in shared decision making within the emergency (hyperacute) period of stroke.We critically analysed currently available tools to support decision making or patient understanding in the treatment of acute ischaemic stroke with intravenous thrombolysis, in order to provide clinicians and researchers with practical guidance on development, evaluation and implementation of such tools for other preference-sensitive treatment options/decisions in different clinical contexts.We included currently available paper-based or electronic tools to support decision making, patient understanding and risk communication in acute thrombolytic treatment. Eligible tools had to fulfil the following criteria: focus exclusively on intravenously-administered thrombolysis for treatment of acute ischaemic stroke; include textual or numerical information on risks and benefits of thrombolysis; and written in the English language. Tools were excluded if they focused on arterial thrombolysis or entry in clinical trials.Included tools were categorised as:Brief decision aids: designed to guide clinical decision making about thrombolysis, and/or engage patients/relatives in decision making by facilitating understanding of the available options and concomitant risks/benefits.•Risk communication tools: primarily focused on communication of probabilistic information to patients/relatives on risks/benefits of thrombolysis.•Patient information tools: primarily designed for patients/relatives to facilitate understanding of diagnosis, treatment, and management, but not specifically to engage them in decision making [•n making .Standardised information for clinicians: primarily designed to support clinicians in explaining the risks/benefits of thrombolysis to patients/relatives.•th August 2011) were conducted across five bibliographic databases  using a combination of keywords and MeSH headings. An example of the search strategy can be found in Additional file Searches  were contacted to disseminate a request to identify tools used nationally or locally to support decision making and risk communication in acute thrombolytic treatment. An Internet search using Google™ was also conducted.Tools identified were independently screened for eligibility by two reviewers . Disagreements were resolved through discussion.An iterative process, involving pilot testing and discussions between two reviewers , was used to develop a structured data extraction form.Data extraction was undertaken independently by both reviewers and disagreements resolved through discussion. The data extraction form captured: title, author(s), country of origin, publication/review date, type of tool , format ; length (number of A4 pages); and citations in tools to primary or secondary research evidence.Data were also extracted on: (i) numerical data or a description of acute stroke outcomes included in tools in terms of death; extent of disability ; risk oPatient information tools were assessed for: (i) readability using the Fog Index  - total Based on independent assessment by both reviewers, percentage (raw) agreement between raters was calculated for items in the IPDASi (probabilities), information content and development process checklists. Percentage agreement on the IPDASi (probabilities) items  and development process checklists indicated good/substantial agreement between raters (78% to 100%). Except for items relating to descriptions of the condition (67%) and authors’/developers’ credentials or qualifications (56%), there was a good level of agreement between raters on the information content (Picker Institute) checklist (72% to 100%).Twenty six tools were identified Figure . FourteeTools that included a description or numerical data on benefits , adverse outcomes (dependency or dependency and death combined), death, intracranial haemorrhage (ICH) and the impact of ICH following treatment with thrombolysis are shown in Table Five patient information tools ,41,45,48Numerical methods  used to convey probabilistic information on outcomes are shown in Table Nine tools used graphical methods. Graphical methods were used in all five risk communication tools -55, but Patient information tools were likely to be comprehensible to most patients/relatives with an aggregate median Fog index equivalent to 10 years of education required to understand the text Table . Only siRisk communication tools attracted the highest median IPDASi (probabilities) total scores Table , with twNone of the tools fulfilled all six development process criteria Table . Sourcesth to 6th grade reading levels [We critically analysed 26 tools that aimed to support decision making or patient understanding in the treatment of acute stroke with thrombolysis, and the majority demonstrated considerable deficiencies. Only nine tools included information on a full range of both benefits and risks of treatment with thrombolysis. The great majority of tools used frequencies to convey probabilistic information on acute stroke outcomes. However, a majority of tools also used verbal descriptors and percentages, which can cause difficulties with understanding and interpretation ,61. Furtg levels ,65, in oOur findings are not unique to tools designed to support decision-making and patient understanding in the treatment acute stroke with thrombolysis. They reflect those of previous studies in other clinical settings/domains that have identified deficiencies in information content, methods of conveying probabilistic information, and lack of comprehensive development processes ,66-70.The strengths of this review include a comprehensive search strategy and critical appraisal of tools across multiple relevant domains. The authors also have experience of developing and evaluating tools to support decision making about preference-sensitive treatment options, thus adding further context expertise to the review. In terms of weaknesses, we may have missed tools that are unpublished or unavailable via the Internet, although we also surveyed key clinical networks. We may have also missed unpublished information on development processes for tools.Our findings have implications that go beyond tools for this clinical setting to other contexts where decision support and risk presentation is being developed. In order to address the shortcomings of tools identified in this review, including analogous tools to support patient understanding and decision making about other preference-sensitive medical or surgical treatment options, tool development should adhere to a structured development process, recommendations of previous research -69 and pPatient decision aids utilising a structured development process have been described previously; for example to support decision-making about stroke prevention in atrial fibrillation ; managemDevelopment of tools should utilise mixed methods and appropriate strategies to meaningfully involve clinicians, patients and their relatives in an iterative design process to establish the optimal mode, form and content of tools in the specific context of the clinical setting. Evidence-based methods should also be utilised to augment interpretability of probabilistic information. In particular, presenting a balanced synopsis of the benefits/risks of treatment with and without the available options (and absolute difference in terms of likely benefit or harm) using natural frequencies ,74,75 wiGraphical displays provide a further mechanism for supporting accurate interpretation of probabilistic information , and theWe further advocate that researchers should investigate the potential value of tailoring outcome probabilities to individual patients  for enhaTools to support patient/carer understanding and decision-making in emergency care contexts are likely to differ from those designed for use in contexts where there is time for protracted discussions, and where patients/carers can access support and resources outside the consultation. In emergency care settings  usability testing should be undertaken to establish the optimal mode, form and information content of tools for a specific emergency context to enable rapid use by clinicians and patients/carers. Such tools could be used in parallel to other procedures across an emergency care pathway so as to negate/minimise any negative impact on time for decision making and receipt of treatment. In emergency settings, structured decision aids have been shown to be feasible for eliciting patients’ preferences and values about management and treatment options .The cultural sensitivity of tools to support patient understanding and decision making is a further area in need of research. Simply translating tools into multiple languages is unlikely to address the influence of cultural variation on patient preferences and values, or the applicability of tools to support involvement of patients in decision making with clinicians across cultural groups .The critical appraisal of tools to support decision making or patient understanding about thrombolytic treatment highlights several important implications for implementation of analogous tools in other clinical contexts. Tools with limitations across the multiple domains described in this review are unlikely to be sensitive to the needs of target users and the complexity of the clinical context. Tools with low scores on the IPDASi probabilities items checklist will limit their ability to support patients/carers to make informed values-based decisions. For example, tools that present unbalanced synopses of probabilistic information on outcome states, without appropriate methods of supporting health literacy, may cause clinicians and patients to over- or under-estimate benefits or adverse effects associated with the available options; for example as a result of using percentages to convey single event probabilities   as part of a structured development process has important benefits ; howeverNew tools to support patient understanding and decision making about preference-sensitive healthcare options/decisions are warranted when none currently exist. Tool development is a time- and resource-intensive process, and in cases where numerous tools already exist for a health condition of interest, an optimal strategy would be to adapt currently available tools so they fulfil quality standards , informeCurrently available tools to support decision-making or patient understanding in the treatment of acute stroke with thrombolysis have been sub-optimally developed. In particular, the great majority of tools lacked comprehensive development processes; failed to convey information on a full range of range of outcome states; and did not adhere to good practice on presentation of outcome probabilities. This has implications that go beyond tools for this clinical setting to other contexts where decision support and risk presentation is being developed.The potential impact of tools for supporting decision making and increasing patient understanding of preference-sensitive treatment options will be enhanced when they are (i) underpinned by an auditable structured development process that has meaningfully involved target users throughout the design and testing process; and (ii) utilised evidence-based methods to present a balanced synopsis of probabilistic information on the full range of outcome states, that is understandable and interpretable by patients with different levels of health literacy. Issues such as training/skills development for clinicians and dissemination plans, including strategies to sustain relevance and quality of information content over time, are also key elements in the equation for the effective implementation of tools in clinical settings.a please contact the corresponding author for copies of these tools.ICH: Intracranial haemorrhage; IPDASi: International patient decision aid standards instrument; rt-PA: Recombinant tissue plasminogen activator; SICH: Symptomatic intracranial haemorrhage.LS and MJM have no competing interests to declare. DF, GAF, HR and RGT have been involved in developing a computerised decision aid for thrombolytic treatment in acute stroke care. This may be made available for a cost payable to download the decision aid to cover the costs of technical maintenance and updating of the information content (predictive equations and user interface) in accordance with user feedback and availability of new data on the effectiveness of thrombolysis. GAF’s institution has received research grants from Boehringer Ingelheim (manufacturer of Alteplase), and honoraria from Lundbeck for stroke-related activities. GAF has also received personal remuneration for educational and advisory work from Boehringer Ingelheim and Lundbeck.RGT, GAF and HR conceived the study. DF conducted the electronic searches. DF and RGT assessed eligibility of tools for inclusion in the review, and conducted data extraction and quality appraisal. All authors provided input to the development of the methods and the drafting process. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/13/225/prepubElectronic search strategy for Medline. (keywords and MeSH terms).Click here for file


Under steady state conditions, billions of dead and dying cells are removed by extrusion from epithelial surfaces as well as by phagocytosis. Cells such as macrophages and dendritic cells have specialized receptors that directly recognize altered protein or lipids on apoptotic cells or opsonins that bind to the dying cell. Once engulfed, phagosomes containing apoptotic cells are rapidly acidified and the contents degraded by proteases and nucleases in lysozymes. During necrosis, cellular material is released prior to engulfment and extracellular nucleases as well as intracellular sensors dictate the inflammatory potential of the cellular debris. The outcome may be release of TNF-a, IL-1-b or interferon (IFN)-a depending upon the type of phagocyte, molecular nature of the cellular particle and the intracellular sensor engaged.In addition to responses by cells of the innate immune system, we have recently defined a link between processing of apoptotic cells and their debris to T cell activation . MFG-E8 These observations suggest that in addition to altering the rate of clearance of apoptotic cells, MFG-E8 deficiency promotes immune responses to self antigens by altered intracellular processing leading to enhanced antigen presentation. Thus, handling of dead and dying cells impacts both innate and adaptive immune responses to self antigens.


Gastro-oesophageal reflux disease is generally considered to be one of the commonest causes of chronic cough, however randomised controlled trials of proton pump inhibitors have often failed to support this notion. This article reviews the most recent studies investigating the mechanisms thought to link reflux and cough, namely laryngo-pharyngeal reflux, micro-aspiration and neuronal cross-organ sensitisation. How recent evidence might shed light on the failure of acid suppressing therapies and suggest new approaches to treating reflux related cough are also discussed. This waate data . Nonetheate data -9. The mi. GORD and chronic cough are both common conditions affecting similar populations but without a causal relationship, thus anecdotal reports of responses to acid suppression are just placebo responses,ii. a variety of criteria have been used for patient selection in studies of acid suppression, which may not have either targeted or allowed the sub-group of chronic cough patients to be identified that were most likely to respond to acid suppression,iii. the acidity of the refluxate may not be of major importance in the pathophysiological processes linking reflux and cough.Hence to better understand the association between GORD and cough requires a re-think of the possible mechanisms connecting these conditions, and how these might relate to sub-groups of patients with chronic cough. The aim of this article is to review recent evidence which might shed light on these mechanisms and thus identify more appropriate management strategies and treatment options for these patients along with possible avenues for drug development.laryngo-pharyngeal reflux) and/or bronchi (microaspiration) and ii) indirect stimulation by activation of neural pathways linking the oesophagus to the airway .Mechanisms whereby gastro-oesophageal reflux events can trigger coughing include i) direct stimulation of the nerve terminals responsible for evoking cough either in the larynx , allowing all reflux, whether liquid or gas, acidic or not, to be detected. Impedance rings allow measurement of the changes in conductance that occur with the movement of liquid (low impedance) and gas (high impedance) up into the oesophagus. In the larynx and pharynx reflux measurement using these technologies is more challenging. In the oesophagus, the baseline impedance level remains relatively stable as the impedance rings remain in contact with the oesophageal mucosa. In contrast, the pharynx is an air filled cavity and hence the baseline level of impedance is unstable, fluctuating depending on whether the impedance rings are in contact with the moist mucosa or in air. Moreover differentiating a retrograde reflux event in the pharynx from a swallow can be difficult and for both these reasons agreement is poor between different observers analysing the traces . DespiteOther techniques used to assess pharyngeal reflux include the Restech system, which detects changes in pH on exposure to aerosol and liquid reflux in the oropharynx and unlike standard pH electrodes can function in air. Unfortunately two studies comparing the Restech with simultaneous oesophageal MII/pH monitoring have found the majority of pharyngeal pH drops are not associated with oesophageal reflux events ,14. For In order to access the larynx and pharynx, refluxate must first traverse the length of the oesophagus and also breach the upper oesophageal sphincter. It could therefore be argued that the presence of excessive reflux in the proximal oesophagus may predispose subjects to LPR. However, the majority of studies both in unselected patients with chronic cough or those in whom extra-oesophageal causes have been excluded have shown that the number and acidity of proximal oesophageal reflux events is no different from healthy controls -21, who Failure of the upper oesophageal sphincter (UOS) may also increase the risk of refluxate reaching the larynx/pharynx and two recent studies have investigated the role of the UOS in cough. In a healthy control study, voluntary coughing evoked a dramatic contractile response of the UOS, assumed to be a protective reflex response to prevent refluxate entering the pharynx . InteresThe risk of food or refluxate entering the airway is likely to be a balance between the complex reflex responses that have evolved to protect the airway and pathological processes that increase pharyngeal/laryngeal exposure to food and refluxate, such as impaired co-ordination of swallowing, excessive laryngo-pharyngeal reflux and perhaps also oesophageal dysmotility, see Figure Studies infusing water into the hypopharynx of healthy controls show that several protective reflexes  are all provoked well before volumes are reached that are likely to spill into the airway . AlthougReflex glottal closure has also been studied in response to inhalation of the chemical irritant ammonia, measuring the threshold for evoking a ‘glottic stop’, which is a rapid transient glottal closure which can be detected by a sudden drop in inspiratory flow during inhalation of the vapour . UnselecNumerous studies have also documented that patients with chronic cough also have exaggerated cough responses to a variety of inhaled irritants (e.g. capsaicin and citric acid) when compared with healthy controls . Whilst As an alternative to exploring airway protective reflexes, several investigators have sought evidence of refluxate entering the airways by the detection of components of gastric fluid. Most commonly pepsin and bile acids have been measured in samples from the proximal (sputum) and more distal airways ). Whilst there is on-going debate about whether the assays are reliable and which enzymes in refluxate are most damaging to the airways, all studies that have included patients with chronic cough, have failed to demonstrate increased airway pepsin or bile acids compared with healthy controls in sputum or BAL ,35-37. OIn summary, current evidence supporting direct provocation of coughing by refluxate stimulating the pharynx/larynx or airways is scant in patients with chronic cough. Studies measuring the number of reflux events extending in to the proximal oesophagus or pharynx suggest that, as in healthy controls, very few such events occur. Pharyngeal and laryngeal reflex responses have rarely been studied in chronic cough patients, but it would seem unlikely that impairment of the laryngeal adductor reflex confers a significant aspiration risk, especially in the context of normal swallowing and heightened cough and glottic stop responses to chemical stimuli. Indeed several studies have indicated that very little pepsin or bile acid is present in the airways of patients with chronic cough.The shared vagal innervation of the oesophagus and airway and convergence of vagal afferents in the brainstem provides a means via which reflux events confined to the oesophagus may provoke airway responses in the form of bronchoconstriction and cough.Most recent studies using pH/MII monitoring have suggested that patients presenting with chronic cough have physiological numbers of reflux events and oesophageal acid exposure with the vast majority of events being confined to the distal oesophagus (80%) -21. NoneAs might be expected, studies using ambulatory acoustic systems to record cough sounds ,39 have R-C), 56% having a positive SAP for cough-reflux associations (SAPC-R), and 32% both, raising the possibility of a self-perpetuating cycle maintaining chronic cough [C-R than SAPR-C, those with a positive SAPC-R had fewer temporally linked events, suggesting that reflux triggering cough occurs more often than cough triggering reflux. Notably as in other studies, we also showed that the pH of the reflux event linked to cough was not important, and that non-acid events were as likely to be linked to cough as acid reflux events.We have recently shown using synchronized pH/impedance and objective acoustic cough recording that over 70% of patients exhibit temporal relationships between cough and distal oesophageal reflux, with 48% having a positive SAP for reflux-cough associations . This has previously often been described as the “oesophago-bronchial reflex”. Further evidence supporting the presence of such a mechanism comes from studies infusing acid into the distal oesophagus reporting increased cough frequency  and cougphagitis , but ideresponse . Other cExactly how vagal pathways might become modified to permit oesophageal-airway crosstalk is not known, but there is evidence that similar processes are also present in other conditions. For example, in asthma patients several studies found that oesophageal acid infusion can induce bronchoconstriction -54 and aSensitization within the nTS of the brain stem may also be responsible for the reverse association i.e. cough induced reflux. Vagal afferents from the proximal stomach are responsible for transient lower oesophageal sphincter relaxation (TLOSR), the main mechanism thought to be responsible for reflux events in both health and disease ,58. ThesIn summary, several studies from different laboratories using MII/pH monitoring agree that intra-oesophageal reflux in patients with chronic cough has similar characteristics to that in healthy populations. However these same studies have found statistically significant temporal associations, suggesting cough follows reflux events more frequently than would be expected by chance alone in up to 50% of patients and independent of pH of the refluxate. The most likely explanation for these associations is crosstalk between airway and oesophageal afferents at their site of convergence in the brainstem, suggesting in such patients, central nervous system mechanisms are responsible for chronic cough.Given the available evidence, it is not surprising that acid suppressants have demonstrated little overall therapeutic effect in most patients with chronic cough. Reducing the acidity of reflux events in patients with positive reflux-cough associations may be insufficient to prevent these events provoking cough. Nonetheless, it remains possible that a sub-group of patients might respond to an appropriate dosing regimen and duration of treatment with such medications; the trials of PPIs performed to date have all been of insufficient size to identify such a sub-group. A recent systematic review re-evaluated the response of chronic cough to antacid therapy in trials that included objective evidence of oesophageal acid exposure on 24 hr pH monitoring . TherapeIt remains to be seen whether patients with excessive oesophageal acid exposure and positive reflux-cough associations have the best chance of responding to PPI treatment. Future studies need also to be cognisant of the problems with carryover effects observed in crossover studies of PPIs  and thatB) receptor agonism and metabotropic glutamate receptor 5 (mGlu5) antagonists. The most extensively investigated reflux inhibitor has been the GABAB receptor agonist Lesogaberan, but unfortunately efficacy has been disappointing as an add-on therapy to PPIs in patients with typical symptoms of GORD [Several novel compounds have recently been shown to reduce the number of gastro-oesophageal reflux events in both healthy controls and patients with reflux disease by inhibition of TLOSRs  but none of GORD ,63. Leso of GORD ,65, whic of GORD  and/or b of GORD . Recent  of GORD . It is c(NMDA) receptor has been implicated in the development of central sensitisation. Whilst dextromethorphan, a NMDA receptor antagonist, is one of the commonest over the counter medicines used to treat cough, its efficacy is poor [Perhaps the most logical approach to treating reflux related cough might be to target the central neuronal sensitisation responsible for reflux-cough associations, but at present we know little about the relevant neuronal targets. In pain hypersensitivity states, the N-Methyl-D-aspartate  is poor . Interes is poor  and we h is poor . It is p is poor ,73, may Laparoscopic fundoplication is as effective as long term pharmacological treatment for patients with typical symptoms of reflux disease responsive to PPI treatment . SurgicaConsiderable progress has been made in recent years towards a better understand of the processes which may permit gastro-oesophageal reflux events to influence cough. Similar work is needed in other respiratory conditions if we are to begin to understand whether reflux disease has a significant influence. The current body of evidence largely supports the concept that neuronal crosstalk between the oesophagus and airway drives the relationships between gastro-oesophageal reflux and cough, however present technologies limit our ability to accurately detect refluxate reaching the larynx, pharynx and lower airways. Future strategies for treating patients with cough reflux associations are likely to include treatments to modulate the numbers of reflux events or the underlying neuronal hypersensitivity.JAS is a named inventor on a patent describing novel methods for cough detection and collaborates with a medical device company in the development of a cough monitoring system . LAH has no competing interests.JAS and LAH both contributed to writing the manuscript and all authors read and reviewed the final version.MRC Clinician Scientist Award G0701918.


Case reports on the development of toxic epidermal necrolysis (TEN) associated with concurrent administration of phenytoin with cranial radiation therapy (Ahmed (2004), Criton et al. (1997), and Rzany et al. (1996)), but reports about erythema multiforme, which can develop in patients treated with levetiracetam and cranial irradiation, are very limited. This paper presents evidence that TEN may be induced by concurrent use of radiation with both phenytoin and levetiracetam. Our case is a 42-year-old male patient, a case of gliosarcoma who developed purpuric dermatitis associated with phenytoin when combined with cranial radiation therapy; although phenytoin was discontinued and switched to levetiracetam, the patient had more severe symptoms of toxic epidermal necrolysis (TEN) on levetiracetam; the patient improved with aggressive symptom management, discontinuation of antiepileptic drugs (AEDs), and holding radiotherapy. Although TEN is a rare toxicity, physicians should pay a special attention to the monitoring of brain tumor patients on antiepileptic prophylaxis during cranial irradiation; furthermore, patients should be counselled to notify their physicians if they develop any new or unusual symptoms. Toxic epidermal necrolysis  is a potentially life-threatening condition associated with considerable morbidity and mortality; it is an exfoliative disease and results in full-thickness damage to the epidermis, characterized by a widespread bullae formation with epidermal necrosis and idiosyncratic of the skin and mucous membranes. TEN mainly occurs in adults and is often attributable to drug sensitivity and considered to be a severe form of Stevens-Johnson syndrome (SJS) or erythema multiforme . TEN is Intracranial malignancy is a condition that can be complicated by seizure activity. Antiepileptic drugs (AEDs) are typically employed as a prophylactic anticonvulsant agent; phenytoin and levetiracetam are the most common AED used for patients with intracranial malignancies and it is not uncommon for those patients to receive those drugs in conjunction with cranial radiation therapy. Toxic epidermal necrolysis (TEN) can develop in such patients during or soon after cranial radiation and can rapidly progress to erythema multiforme (EM) major .2 po daily with radiotherapy (RT) daily (for 6 weeks); a regimen of dexamethasone (12 mg/day) and Trimethoprim/sulfamethoxazole DS was started for him, and on October 5 (after 5 days of chemotherapy/radiotherapy) he presented to urgent care with severe rash on the arms and shoulders; he stated that he started to have rash on his shoulders after 2 weeks on phenytoin but started to spread to his arms, back, chest, and both legs which became more generalized and associated with itching after he was started on radiotherapy. In urgent care he received antihistaminic and corticosteroids, phenytoin was discontinued and switched to levetiracetam 500 mg po twice daily, his rash improved, and he was discharged home. On October 7, he reported back to urgent care with erythema, pruritis, facial swelling, exfoliative dermatitis, and exanthematous rash on the face, arms, thighs, chest, and back with minimal mucosal involvement  Temozolomide 75 mg/molvement  along wiSJS and TEN are severe, acute, mucocutaneous reactions that are commonly induced by drugs. Drug-induced SJS and TEN typically begin 1 to 3 weeks after the initiation of therapy but occur more rapidly with drug rechallenge or in the presence of provoking factors. More than 100 different compounds have been implicated in both syndromes; barbiturates are some of the most common among them . A case-Risks for serious skin reactions vary considerably among AEDs . A case-Because of the variety and the rarity of adverse systemic reactions to AEDs, physicians initiating AEDs should counsel patients to notify their physician if they develop any new or unusual symptoms. The wide variety of adverse reactions of AEDs which highlights the number of body systems other than the CNS gives emphasis to the importance for physicians to evaluate all aspects of a patient's physical functioning during usage of AEDs.Written consent was obtained from the patient for publication of this case report and any associated photograph. Although toxic epidermal necrolysis is a rare toxicity, it should always be considered with concurrent administration of phenytoin with cranial radiation therapy.The need for prophylactic anticonvulsant therapy in patients undergoing cranial radiation therapy should be assessed on a case by case basis. If anticonvulsants are employed, then they must be administered with caution, and all cutaneous reactions developing subsequently within the radiation site must be promptly evaluated with a high index of suspicion for erythema multiforme. As the first suspicious sign is seen, antiepileptic drugs should be discontinued immediately and aggressive medical management should be started .Because of the variety and the rarity of adverse systemic reactions to antiepileptic drugs (AEDs), physicians initiating antiepileptic drugs (AEDs) should counsel patients on the importance of notifying their physician if they develop any new or unusual symptoms.


To characterise the regulatory architecture of genomic loci in vivo, we have developed GROMIT (Genome Regulatory Organisation Mapping with Integrated Transposons) [Over the past years it has become apparent that a substantial part of mammalian gene regulation is achieved through the concerted action of long-range elements. Technical advances have greatly improved our ability to identify such elements, but still little is known about how they regulate gene expression mechanistically. It is particularly unclear to what extent genomic context influences the activity of regulatory elements, and therefore how authentically sposons) . GROMIT Using GROMIT we have generated more than 1000 insertions, and determined the regulatory activities associated with approximately 700, distributed along all autosomes. This data revealed that tissue-specific regulatory activity is widely present throughout the genome, and is frequently organised into regulatory landscapes, large intervals of tens to hundreds of kilobases, within which insertions share expression patterns. By correlating the identified landscapes with published landmarks of gene regulation, as well as HiC data, we found that landscapes largely overlap with previously identified topological domains. In addition, since enhancers can activate the GROMIT sensor freely within, but not outside these landscapes, this indicates that conformational constraints may influence their activity.Sonic hedgehog locus allowed us to zoom-in on a single large landscape, and dissect the factors that influence enhancer activity. We produced a series of duplications and inversions that modify the distance and order of regulatory elements, without changing their primary sequence, and identified multiple configurations that led to mis-expression of Sonic hedgehog. This showed that communication between genes and their enhancers is greatly influenced by the genomic context. We speculate that the genomic structural rearrangements induce changes in epigenetic marks and three-dimensional organisation of the region that are predictive of the observed expression changes.Complementing this approach, a detailed study of the in vivo experimental framework to manipulate the regulatory organisation of the mouse genome, which together with biochemical studies will shed light on how gene expression is precisely regulated in space and time.GROMIT provides an