Author response image 1. Re-plotting of panels from figures 2A, 2D, 3D and 3E from the main manuscript, using two-tailed rather than one-tailed tests on signal build-up rates (significance indicated by black running markers).

The ability to revise one's certainty or confidence in a preceding choice is a critical feature of adaptive decision-making but the neural mechanisms underpinning this metacognitive process have yet to be characterized. In the present study, we demonstrate that the same build-to-threshold decision variable signal that triggers an initial choice continues to evolve after commitment, and determines the timing and accuracy of self-initiated error detection reports by selectively representing accumulated evidence that the preceding choice was incorrect. We also show that a peri-choice signal generated in medial frontal cortex provides a source of input to this post-decision accumulation process, indicating that metacognitive judgments are not solely based on the accumulation of feedforward sensory evidence. These findings impart novel insights into the generative mechanisms of metacognition

Plasmid-Cured Chlamydia caviae Activates TLR2-Dependent Signaling and Retains Virulence in the Guinea Pig Model of Genital Tract Infection

Loss of the conserved “cryptic” plasmid from C. trachomatis and C. muridarum is pleiotropic, resulting in reduced innate inflammatory activation via TLR2, glycogen accumulation and infectivity. The more genetically distant C. caviae GPIC is a natural pathogen of guinea pigs and induces upper genital tract pathology when inoculated intravaginally, modeling human disease. To examine the contribution of pCpGP1 to C. caviae pathogenesis, a cured derivative of GPIC, strain CC13, was derived and evaluated in vitro and in vivo. Transcriptional profiling of CC13 revealed only partial conservation of previously identified plasmid-responsive chromosomal loci (PRCL) in C. caviae. However, 2-deoxyglucose (2DG) treatment of GPIC and CC13 resulted in reduced transcription of all identified PRCL, including glgA, indicating the presence of a plasmid-independent glucose response in this species. In contrast to plasmid-cured C. muridarum and C. trachomatis, plasmid-cured C. caviae strain CC13 signaled via TLR2 in vitro and elicited cytokine production in vivo similar to wild-type C. caviae. Furthermore, inflammatory pathology induced by infection of guinea pigs with CC13 was similar to that induced by GPIC, although we observed more rapid resolution of CC13 infection in estrogen-treated guinea pigs. These data indicate that either the plasmid is not involved in expression or regulation of virulence in C. caviae or that redundant effectors prevent these phenotypic changes from being observed in C. caviae plasmid-cured strains

Action planning and the timescale of evidence accumulation

Perceptual decisions are based on the temporal integration of sensory evidence for different states of the outside world. The timescale of this integration process varies widely across behavioral contexts and individuals, and it is diagnostic for the underlying neural mechanisms. In many situations, the decision-maker knows the required mapping between perceptual evidence and motor response (henceforth termed “sensory-motor contingency”) before decision formation. Here, the integrated evidence can be directly translated into a motor plan and, indeed, neural signatures of the integration process are evident as build-up activity in premotor brain regions. In other situations, however, the sensory-motor contingencies are unknown at the time of decision formation. We used behavioral psychophysics and computational modeling to test if knowledge about sensory-motor contingencies affects the timescale of perceptual evidence integration. We asked human observers to perform the same motion discrimination task, with or without trial-to-trial variations of the mapping between perceptual choice and motor response. When the mapping varied, it was either instructed before or after the stimulus presentation. We quantified the timescale of evidence integration under these different sensory-motor mapping conditions by means of two approaches. First, we analyzed subjects’ discrimination threshold as a function of stimulus duration. Second, we fitted a dynamical decision-making model to subjects’ choice behavior. The results from both approaches indicated that observers (i) integrated motion information for several hundred ms, (ii) used a shorter than optimal integration timescale, and (iii) used the same integration timescale under all sensory-motor mappings. We conclude that the mechanisms limiting the timescale of perceptual decisions are largely independent from long-term learning (under fixed mapping) or rapid acquisition (under variable mapping) of sensory-motor contingencies. This conclusion has implications for neurophysiological and neuroimaging studies of perceptual decision-making

The workload of web-based consultations with atopic eczema patients at home

Abstract Background Atopic eczema is a chronic inflammatory non-contagious skin disease characterised by intensive itch and inflamed skin. Due to its chronic and relapsing course atopic eczema imposes a great burden on affected families. Review articles about home care telemedicine have indicated advantageous effects of home telehealth. However, few studies have investigated how home care telemedicine applications affect the workload of the clinician. Methods The use of a web-based counselling system was recorded through computerised logging. The doctor who answered the requests sent via the Internet recorded the amount of time needed for reading and answering 93 consecutive requests. Results The time needed by the physician to read and answer a request was less than 5 minutes in 60% of the cases. The doctor spent significantly more time to answer requests that had photographs attached compared to requests without photographs (P = 0.005). The time needed to answer requests received during the winter season (October-March) was significantly longer than the rest of the year (P = 0.023). There was no correlation between the answering time and the age of the patient. Conclusions Individual web-based follow-up of atopic eczema patients at home is feasible. The amount of time needed for the doctor to respond to a request from the patient appears to be small. The answering time seems to depend on whether photographs are supplied and also on seasonal variations of disease activity. Since the management of atopic eczema is complex involving many different types of treatments and educational aspects, we expect this type of communication to be useful also to other chronic disease patients requiring close follow-up.</p

Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage

<p>Abstract</p> <p>Background</p> <p>Phase I/II placebo-controlled clinical trials of recombinant Factor VIIa (rFVIIa) suggested that administration of rFVIIa within 4 hours after onset of intracerebral hemorrhage (ICH) is safe, limits ICH growth, and improves outcomes. We sought to determine the cost-effectiveness of rFVIIa for acute ICH treatment, using published Phase II data. We hypothesized that rFVIIa would have a low marginal cost-effectiveness ratio (mCER) given the poor neurologic outcomes after ICH with conventional management.</p> <p>Methods</p> <p>We performed an incremental cost-effectiveness analysis from the societal perspective, considering conventional management vs. 80 ug/kg rFVIIa treatment for acute ICH cases meeting Phase II inclusion criteria. The time frame for the analysis was 1. 25 years: data from the Phase II trial was used for 90 day outcomes and rFVIIa complications – arterial thromboembolic events (ATE). We assumed no substantial cost differences in care between the two strategies except: 1) cost of rFVIIa (for an 80 mcg/kg dose in an 80 kg patient, assumed cost of $6,408); 2) cost of ATE side effects from rFVIIa (which also decrease quality of life and increase the chance of death); and 3) differential monetary costs of outcomes and their impact on quality of life, including disposition (home vs. nursing home), and outpatient vs. inpatient rehabilitation. Sensitivity analyses were performed to explore uncertainty in parameter estimates, impact of rFVIIa cost, direct cost of neurologic outcomes, probability of ATE, and outcomes after ATE.</p> <p>Results</p> <p>In the "base case", treating ICH with rFVIIa dominates the usual care strategy by being more effective and less costly. rFVIIa maintained a mCER <$50,000/QALY over a wide range of sensitivity analyses. Sensitivity analyses showed that the cost of rFVIIa must exceed $14,500, or the frequency of ATE exceed 29$50,000/QALY. Varying the cost and/or reducing the utility of health states following ATE did not impact results.</p> <p>Conclusion</p> <p>Based on data from preliminary trials, treating selected ICH patients with rFVIIa results in lower cost and improved clinical outcomes. This potential cost-effectiveness must be considered in light of the Phase III trial results.</p

Time dependent ethnic convergence in colorectal cancer survival in hawaii

BACKGROUND: Although colorectal cancer death rates have been declining, this trend is not consistent across all ethnic groups. Biological, environmental, behavioral and socioeconomic explanations exist, but the reason for this discrepancy remains inconclusive. We examined the hypothesis that improved cancer screening across all ethnic groups will reduce ethnic differences in colorectal cancer survival. METHODS: Through the Hawaii Tumor Registry 16,424 patients diagnosed with colorectal cancer were identified during the years 1960–2000. Cox regression analyses were performed for each of three cohorts stratified by ethnicity (Caucasian, Japanese, Hawaiian, Filipino, and Chinese). The models included stage of diagnosis, year of diagnosis, age, and sex as predictors of survival. RESULTS: Mortality rates improved significantly for all ethnic groups. Moreover, with the exception of Hawaiians, rates for all ethnic groups converged over time. Persistently lower survival for Hawaiians appeared linked with more cancer treatment. CONCLUSION: Ethnic disparities in colorectal cancer mortality rates appear primarily the result of differential utilization of health care. If modern screening procedures can be provided equally to all ethnic groups, ethnic outcome differences can be virtually eliminated

Replication of Association between ADAM33 Polymorphisms and Psoriasis

Polymorphisms in ADAM33, the first gene identified in asthma by positional cloning, have been recently associated with psoriasis. No replication study of this association has been published so far. Data available in the French EGEA study (Epidemiological study on Genetics and Environment of Asthma, bronchial hyperresponsivensess and Atopy) give the opportunity to attempt to replicate the association between ADAM33 and psoriasis in 2002 individuals. Psoriasis (n = 150) has been assessed by questionnaire administered by an interviewer and a sub-sample of subjects with early-onset psoriasis (n = 74) has been identified based on the age of the subjects at time of interview (<40 years). Nine SNPs in ADAM33 and 11 SNPs in PSORS1 were genotyped. Association analysis was conducted by using two methods, GEE regression-based method and a likelihood-based method (LAMP program). The rs512625 SNP in ADAM33 was found associated with psoriasis at p = 0.01, the usual threshold required for replication (OR [95% CI] for heterozygotes compared to the reference group of homozygotes for the most frequent allele = 0.61 [0.42;0.89]). The rs628977 SNP, which was not in linkage disequilibrium with rs512625, was significantly associated with early-onset psoriasis (p = 0.01, OR [95% CI] for homozygotes for the minor allele compared to the reference group = 2.52 [1.31;4.86]). Adjustment for age, sex, asthma and a PSORS1 SNP associated with psoriasis in the EGEA data did not change the significance of these associations. This suggests independent effects of ADAM33 and PSORS1 on psoriasis. This is the first study that replicates an association between genetic variants in ADAM33 and psoriasis. Interestingly, the 2 ADAM33 SNPs associated with psoriasis in the present analysis were part of the 3-SNPs haplotypes showing the strongest associations in the initial study. The identification of a pleiotropic effect of ADAM33 on asthma and psoriasis may contribute to the understanding of these common immune-mediated diseases

Using Goal- and Grip-Related Information for Understanding the Correctness of Other’s Actions: An ERP Study

Detecting errors in other’s actions is of pivotal importance for joint action, competitive behavior and observational learning. Although many studies have focused on the neural mechanisms involved in detecting low-level errors, relatively little is known about error-detection in everyday situations. The present study aimed to identify the functional and neural mechanisms whereby we understand the correctness of other’s actions involving well-known objects (e.g. pouring coffee in a cup). Participants observed action sequences in which the correctness of the object grasped and the grip applied to a pair of objects were independently manipulated. Observation of object violations (e.g. grasping the empty cup instead of the coffee pot) resulted in a stronger P3-effect than observation of grip errors (e.g. grasping the coffee pot at the upper part instead of the handle), likely reflecting a reorienting response, directing attention to the relevant location. Following the P3-effect, a parietal slow wave positivity was observed that persisted for grip-errors, likely reflecting the detection of an incorrect hand-object interaction. These findings provide new insight in the functional significance of the neurophysiological markers associated with the observation of incorrect actions and suggest that the P3-effect and the subsequent parietal slow wave positivity may reflect the detection of errors at different levels in the action hierarchy. Thereby this study elucidates the cognitive processes that support the detection of action violations in the selection of objects and grips

Internal and external information in error processing

<p>Abstract</p> <p>Background</p> <p>The use of self-generated and externally provided information in performance monitoring is reflected by the appearance of error-related and feedback-related negativities (ERN and FRN), respectively. Several authors proposed that ERN and FRN are supported by similar neural mechanisms residing in the anterior cingulate cortex (ACC) and the mesolimbic dopaminergic system. The present study is aimed to test the functional relationship between ERN and FRN. Using an Eriksen-Flanker task with a moving response deadline we tested 17 young healthy subjects. Subjects received feedback with respect to their response accuracy and response speed. To fulfill both requirements of the task, they had to press the correct button and had to respond in time to give a valid response.</p> <p>Results</p> <p>When performance monitoring based on self-generated information was sufficient to detect a criterion violation an ERN was released, while the subsequent feedback became redundant and therefore failed to trigger an FRN. In contrast, an FRN was released if the feedback contained information which was not available before and action monitoring processes based on self-generated information failed to detect an error.</p> <p>Conclusion</p> <p>The described pattern of results indicates a functional interrelationship of response and feedback related negativities in performance monitoring.</p

Dissociation of Subjectively Reported and Behaviorally Indexed Mind Wandering by EEG Rhythmic Activity

Inattention to current activity is ubiquitous in everyday situations. Mind wandering is an example of such a state, and its related brain areas have been examined in the literature. However, there is no clear evidence regarding neural rhythmic activities linked to mind wandering. Using a vigilance task with thought sampling and electroencephalography recording, the current study simultaneously examined neural oscillatory activities related to subjectively reported and behaviorally indexed mind wandering. By implementing time-frequency analysis, we found that subjectively reported mind wandering, relative to behaviorally indexed, showed increased gamma band activity at bilateral frontal-central areas. By means of beamformer source imaging, we found subjectively reported mind wandering within the gamma band to be characterized by increased activation in bilateral frontal cortices, supplemental motor area, paracentral cortex and right inferior temporal cortex in comparison to behaviorally indexed mind wandering. These findings dissociate subjectively reported and behaviorally indexed mind wandering and suggest that a higher degree of executive control processes are engaged in subjectively reported mind wandering