The correction of errors committed with high confidence.

Abstract Most theories predict that when people indicate that they are highly confident they are producing their strongest responses. Hence, if such a high confidence response is in error it should be overwritten only with great difficulty. In contrast to this prediction, we have found that people easily correct erroneous responses to general information questions endorsed as correct with highconfidence, so long as the correct answer is given as feedback. Three potential explanations for this unexpected hypercorrection effect are summarized. The explanation that is tested here, in two experiments, is that after a person commits a high-confidence error the correct answer feedback, being surprising or unexpected, is given more attention than is accorded to the feedback to low-confidence errors. This enhanced attentional capture leads to better memory. In both experiments, a tone detection task was presented concurrently with the corrective feedback to assess the attentional capture of feedback stimuli. In both, tone detection was selectively impaired during the feedback to high confidence errors. It was also negatively related to final performance, indicating that the attention not devoted to the tone detection was effectively engaged by the corrective feedback. These data support the attentional explanation of the high-confidence hypercorrection effect

Neural Correlates of People's Hypercorrection of Their False Beliefs

Despite the intuition that strongly held beliefs are particularly difficult to change, the data on error correction indicate that general information errors that people commit with a high degree of belief are especially easy to correct. This finding is called the hypercorrection effect. The hypothesis was tested that the reason for hypercorrection stems from enhanced attention and encoding that results from a metacognitive mismatch between the person's confidence in their responses and the true answer. This experiment, which is the first to use imaging to investigate the hypercorrection effect, provided support for this hypothesis, showing that both metacognitive mismatch conditions—that in which high confidence accompanies a wrong answer and that in which low confidence accompanies a correct answer—revealed anterior cingulate and medial frontal gyrus activations. Only in the high confidence error condition, however, was an error that conflicted with the true answer mentally present. And only the high confidence error condition yielded activations in the right TPJ and the right dorsolateral pFC. These activations suggested that, during the correction process after error commission, people (1) were entertaining both the false belief as well as the true belief (as in theory of mind tasks, which also manifest the right TPJ activation) and (2) may have been suppressing the unwanted, incorrect information that they had, themselves, produced (as in think/no-think tasks, which also manifest dorsolateral pFC activation). These error-specific processes as well as enhanced attention because of metacognitive mismatch appear to be implicated

l-carnitine and cancer cachexia: Clinical and experimental aspects

Cancer cachexia is a multifaceted syndrome characterized, among many symptoms, by extensive muscle wasting. Chronic systemic inflammation, partly triggered and sustained by cytokines, as well as increased oxidative stress contributes to the pathogenesis of this complex metabolic disorder. l-carnitine plays a central role in the metabolism of fatty acids and shows important antioxidant and anti-inflammatory properties. Systemic carnitine depletion has been described in several diseases, and it is characterized by fatigue, muscle weakness, and decreased tolerance to metabolic stress. In cachectic cancer patients, low serum carnitine levels have been reported, and this change has been suggested to play an important contributory role in the development of cachexia. Based on these data, carnitine supplementation has been tested in preliminary studies concerning human cachexia, resulting in improved fatigue and quality of life. We present here a review of clinical and experimental evidence regarding the use of carnitine supplementation in the management of cancer cachexia

Less is Different: Emergence and Reduction Reconciled

This is a companion to another paper. Together they rebut two widespread philosophical doctrines about emergence. The first, and main, doctrine is that emergence is incompatible with reduction. The second is that emergence is supervenience; or more exactly, supervenience without reduction. In the other paper, I develop these rebuttals in general terms, emphasising the second rebuttal. Here I discuss the situation in physics, emphasising the first rebuttal. I focus on limiting relations between theories and illustrate my claims with four examples, each of them a model or a framework for modelling, from well-established mathematics or physics. I take emergence as behaviour that is novel and robust relative to some comparison class. I take reduction as, essentially, deduction. The main idea of my first rebuttal will be to perform the deduction after taking a limit of some parameter. Thus my first main claim will be that in my four examples (and many others), we can deduce a novel and robust behaviour, by taking the limit, N goes to infinity, of a parameter N. But on the other hand, this does not show that that the infinite limit is "physically real", as some authors have alleged. For my second main claim is that in these same examples, there is a weaker, yet still vivid, novel and robust behaviour that occurs before we get to the limit, i.e. for finite N. And it is this weaker behaviour which is physically real. My examples are: the method of arbitrary functions (in probability theory); fractals (in geometry); superselection for infinite systems (in quantum theory); and phase transitions for infinite systems (in statistical mechanics).Comment: 75 p

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies

Earth: Atmospheric Evolution of a Habitable Planet

Our present-day atmosphere is often used as an analog for potentially habitable exoplanets, but Earth's atmosphere has changed dramatically throughout its 4.5 billion year history. For example, molecular oxygen is abundant in the atmosphere today but was absent on the early Earth. Meanwhile, the physical and chemical evolution of Earth's atmosphere has also resulted in major swings in surface temperature, at times resulting in extreme glaciation or warm greenhouse climates. Despite this dynamic and occasionally dramatic history, the Earth has been persistently habitable--and, in fact, inhabited--for roughly 4 billion years. Understanding Earth's momentous changes and its enduring habitability is essential as a guide to the diversity of habitable planetary environments that may exist beyond our solar system and for ultimately recognizing spectroscopic fingerprints of life elsewhere in the Universe. Here, we review long-term trends in the composition of Earth's atmosphere as it relates to both planetary habitability and inhabitation. We focus on gases that may serve as habitability markers (CO2, N2) or biosignatures (CH4, O2), especially as related to the redox evolution of the atmosphere and the coupled evolution of Earth's climate system. We emphasize that in the search for Earth-like planets we must be mindful that the example provided by the modern atmosphere merely represents a single snapshot of Earth's long-term evolution. In exploring the many former states of our own planet, we emphasize Earth's atmospheric evolution during the Archean, Proterozoic, and Phanerozoic eons, but we conclude with a brief discussion of potential atmospheric trajectories into the distant future, many millions to billions of years from now. All of these 'Alternative Earth' scenarios provide insight to the potential diversity of Earth-like, habitable, and inhabited worlds.Comment: 34 pages, 4 figures, 4 tables. Review chapter to appear in Handbook of Exoplanet

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Objective Metamemory Testing Captures Awareness of Deficit in Alzheimer's Disease

For reasons that remain unknown, there is marked inter-person variability in awareness of episodic memory loss in patients with Alzheimer’s disease (AD). Existing research designs, primarily subjective in nature, have been at a relative disadvantage for evaluating disordered metamemory and its relation to the clinical and neuropathological heterogeneity of AD, as well as its prognosis for various disease outcomes. The current study sought to establish an objective means of evaluating metamemory in AD by modifying traditional metacognitive paradigms in which participants are asked to make predictions regarding their own memory performance. Variables derived from this measure were analyzed in relation to clinically rated awareness for memory loss. As predicted, a range of awareness levels existed across patients with mild to moderate AD (n = 24) and clinical ratings of awareness were significantly associated with verbal episodic memory monitoring (r = .46, p = .03). Further, patients who were rated as aware of their memory loss remained well calibrated over the course of the task whereas those rated as relatively unaware grew over-confident in their predictions F (1, 33) = 4.19, p = .02. Findings suggest that over-confidence may be related to impaired online error recognition and compromised use of metamemory strategies such as the Memory for Past Test heuristic. Importantly, clinically rated awareness did not vary as a function of demographic variables, global cognition, or verbal memory. However, participants characterized as relatively unaware were impaired on a nonverbal memory task as compared to aware participants, F (1, 20) = 6.98, p = .02. The current study provides preliminary support for the use of a recognition-based verbal episodic memory monitoring task as a quantitative measure of awareness for memory loss in AD, and offers insight into the manner in which metamemory breaks down. Discrepancies in nonverbal memory across the two awareness groups provide partial support for the idea that metamemory variability in AD may be related to the neuroanatomic presentation of the disease, with disordered awareness potentially reflective of a critical level of right hemisphere involvement