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Previous studies of artificial intelligence (AI) applied to dermatology have shown AI to have higher diagnostic classification accuracy than expert dermatologists; however, these studies did not adequately assess clinically realistic scenarios, such as how AI systems behave when presented with images of disease categories that are not included in the training dataset or images drawn from statistical distributions with significant shifts from training distributions. We aimed to simulate these real-world scenarios and evaluate the effects of image source institution, diagnoses outside of the training set, and other image artifacts on classification accuracy, with the goal of informing clinicians and regulatory agencies about safety and real-world accuracy.We designed a large dermoscopic image classification challenge to quantify the performance of machine learning algorithms for the task of skin cancer classification from dermoscopic images, and how this performance is affected by shifts in statistical distributions of data, disease categories not represented in training datasets, and imaging or lesion artifacts. Factors that might be beneficial to performance, such as clinical metadata and external training data collected by challenge participants, were also evaluated. 25 331 training images collected from two datasets (in Vienna [HAM10000] and Barcelona [BCN20000]) between Jan 1, 2000, and Dec 31, 2018, across eight skin diseases, were provided to challenge participants to design appropriate algorithms. The trained algorithms were then tested for balanced accuracy against the HAM10000 and BCN20000 test datasets and data from countries not included in the training dataset (Turkey, New Zealand, Sweden, and Argentina). Test datasets contained images of all diagnostic categories available in training plus other diagnoses not included in training data (not trained category). We compared the performance of the algorithms against that of 18 dermatologists in a simulated setting that reflected intended clinical use.64 teams submitted 129 state-of-the-art algorithm predictions on a test set of 8238 images. The best performing algorithm achieved 58·8% balanced accuracy on the BCN20000 data, which was designed to better reflect realistic clinical scenarios, compared with 82·0% balanced accuracy on HAM10000, which was used in a previously published benchmark. Shifted statistical distributions and disease categories not included in training data contributed to decreases in accuracy. Image artifacts, including hair, pen markings, ulceration, and imaging source institution, decreased accuracy in a complex manner that varied based on the underlying diagnosis. When comparing algorithms to expert dermatologists (2460 ratings on 1269 images), algorithms performed better than experts in most categories, except for actinic keratoses (similar accuracy on average) and images from categories not included in training data (26% correct for experts vs 6% correct for algorithms, p0·0001). For the top 25 submitted algorithms, 47·1% of the images from categories not included in training data were misclassified as malignant diagnoses, which would lead to a substantial number of unnecessary biopsies if current state-of-the-art AI technologies were clinically deployed.We have identified specific deficiencies and safety issues in AI diagnostic systems for skin cancer that should be addressed in future diagnostic evaluation protocols to improve safety and reliability in clinical practice.Melanoma Research Alliance and La Marató de TV3.

For the analysis of a time-to-event endpoint in a single-arm or randomized clinical trial it is generally perceived that interpretation of a given estimate of the survival function, or the comparison between two groups, hinges on some quantification of the amount of follow-up. Typically, a median of some loosely defined quantity is reported. However, whatever median is reported, is typically not answering the question(s) trialists actually have in terms of follow-up quantification. In this paper, inspired by the estimand framework, we formulate a comprehensive list of relevant scientific questions that trialists have when reporting time-to-event data. We illustrate how these questions should be answered, and that reference to an unclearly defined follow-up quantity is not needed at all. In drug development, key decisions are made based on randomized controlled trials, and we therefore also discuss relevant scientific questions not only when looking at a time-to-event endpoint in one group, but also for comparisons. We find that different thinking about some of the relevant scientific questions around follow-up is required depending on whether a proportional hazards assumption can be made or other patterns of survival functions are anticipated, e.g. delayed separation, crossing survival functions, or the potential for cure. We conclude the paper with practical recommendations., Comment: 31 pages

For a future sustainable hydrogen economy, the electrocatalysis of hydrogen oxidation/evolution reactions (HOR/HER) needs to be better understood. In order to describe the strong alteration of HOR/HER rates on platinum group metals (PGM) in acidic and alkaline media, at least two prominent descriptors based on a Pt–Had binding energy model and a bifunctional model are frequently discussed in the literature. A clear discrimination of these both descriptors for PGM-based multi-metallic materials, yet, remains a critical challenge. To solve this dilemma, we have made use of the oxophilic and structural properties of cobalt atoms in Pt-based nano-materials to tune their catalytic HOR performance in alkaline media. More precisely, we have designed PtxCo1−x nanoparticles with various structural motifs. Remarkably, the surface rearrangement of PtxCo1−x nanoparticles along the uniform alloy, Pt-rich shell, and Co-segregated core–shell motifs is controlled by the electrochemical environment. To identify the elemental distribution of Co and Pt atoms, a new descriptor is presented in this work, the so-called Q(Hupd)/Q(Coz+) ratio. The coverage of OHad species can be controlled by the coverage of oxophilic Co surface atoms to investigate the bifunctional mechanism on the HOR kinetics in alkaline media. Thus, we are able to correlate the HOR exchange current densities with tuneable Co coverage on the particle surface to mimic e.g. the coverage of “Co(hydr)oxide clusters”. On the other hand, the strain effect to modify the Pt–Had binding energy is solely investigated on a Pt-rich shell induced by a Co-rich particle core. Despite the separation of these critical model parameters, cobalt as an oxophilic component strongly bonds OHad species at the bimetallic particle surface and modifies the HOR kinetics. In contrast, the induced lattice strain in the Pt-enriched shell of dealloyed core–shell nanoparticles leads to an increase of the Pt surface area-based specific exchange current density j0spec by a factor of ∼2 compared to pure Pt. Based on our results, we provide deeper insights into the kinetics and mechanism of the HOR on PtxCo1−x catalysts with different structural nanoparticle motifs in an alkaline environment.

Prior skin image datasets have not addressed patient-level information obtained from multiple skin lesions from the same patient. Though artificial intelligence classification algorithms have achieved expert-level performance in controlled studies examining single images, in practice dermatologists base their judgment holistically from multiple lesions on the same patient. The 2020 SIIM-ISIC Melanoma Classification challenge dataset described herein was constructed to address this discrepancy between prior challenges and clinical practice, providing for each image in the dataset an identifier allowing lesions from the same patient to be mapped to one another. This patient-level contextual information is frequently used by clinicians to diagnose melanoma and is especially useful in ruling out false positives in patients with many atypical nevi. The dataset represents 2,056 patients (20.8% with at least one melanoma, 79.2% with zero melanomas) from three continents with an average of 16 lesions per patient, consisting of 33,126 dermoscopic images and 584 (1.8%) histopathologically confirmed melanomas compared with benign melanoma mimickers., Measurement(s) melanoma • Skin Lesion Technology Type(s) Dermoscopy • digital curation Factor Type(s) approximate age • sex • anatomic site Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.13070345

Human memory is strongly influenced by brain states occurring before an event, yet we know little about the underlying mechanisms. We found that activity in the cingulo-opercular network (including bilateral anterior insula [aI] and anterior prefrontal cortex [aPFC]) seconds before an event begins can predict whether this event will subsequently be remembered. We then tested how activity in the cingulo-opercular network shapes memory performance. Our findings indicate that prestimulus cingulo-opercular activity affects memory performance by opposingly modulating subsequent activity in two sets of regions previously linked to encoding and retrieval of episodic information. Specifically, higher prestimulus cingulo-opercular activity was associated with a subsequent increase in activity in temporal regions previously linked to encoding and with a subsequent reduction in activity within a set of regions thought to play a role in retrieval and self-referential processing. Together, these findings suggest that prestimulus attentional states modulate memory for real-life events by enhancing encoding and possibly by dampening interference from competing memory substrates.

Mindfulness training ameliorates clinical and self-report measures of depression and chronic pain, but its use as an emotion regulation strategy—in individuals who do not meditate—remains understudied. As such, whether it (i) down-regulates early affective brain processes or (ii) depends on cognitive control systems remains unclear. We exposed meditation-naïve participants to two kinds of stimuli: negative vs. neutral images and painful vs. warm temperatures. On alternating blocks, we asked participants to either react naturally or exercise mindful acceptance. Emotion regulation using mindful acceptance was associated with reductions in reported pain and negative affect, reduced amygdala responses to negative images and reduced heat-evoked responses in medial and lateral pain systems. Critically, mindful acceptance significantly reduced activity in a distributed, a priori neurologic signature that is sensitive and specific to experimentally induced pain. In addition, these changes occurred in the absence of detectable increases in prefrontal control systems. The findings support the idea that momentary mindful acceptance regulates emotional intensity by changing initial appraisals of the affective significance of stimuli, which has consequences for clinical treatment of pain and emotion.

Introduction: Siremadlin is an oral (PO), potent and selective 2 nd generation inhibitor of Murine Double Minute-2 (MDM2i), resulting in a p53-dependent anti-proliferative effect. Siremadlin has a well-characterized safety profile and encouraging single-agent anti-leukemic activity in relapsed refractory (R/R) acute myeloid leukemia (AML) (Stein 2021, provisionally accepted, NCT02143635). More recently, MDM2i including siremadlin, have been shown to possess potent immunomodulatory effects (IME) in murine AML and solid tumor models (Wang 2021, Fang 2019). These data suggest that IME of siremadlin could be exploited to prevent relapse in AML patients (pts) in remission after allogeneic stem cell transplantation (SCT). Here we report the results of an exploratory post-hoc analysis of safety and preliminary efficacy in a subset of pts with relapsed AML post SCT and subsequently treated with siremadlin monotherapy. Methods: From the first-in-human study, CHDM201X2101 (NCT02143635), among 91 R/R AML pts treated with siremadlin monotherapy, a subset of pts (n= 19) who had undergone SCT before study entry were identified for inclusion in this analysis. Eligible pts were ≥ 18 years with wild-type TP53 AML have failed prior therapies. Siremadlin was administered PO according to 4 treatment regimens: 1A, 250 mg or 350 mg or 400 mg on day 1 of a 3-week (-W) cycle (n= 6); 1B, 120 mg or 150 mg on days 1 and 8 of a 4-W cycle (n= 4); 2A, 20 mg or 30 mg daily for the first 2 weeks of a 4-W cycle (n= 2); and 2C, 45 mg daily for the first week of a 4-W cycle (n= 7). Grading of adverse events (AEs) was per CTCAE version 4.03. Response evaluation was per investigator's assessment based on the International Working Group for AML (Cheson 2003). Results: Nineteen pts with R/R AML after ≥1 SCT had received siremadlin as salvage therapy for active disease. The median age was 64 years (range: 30-72), and median interval from most recent SCT to start of siremadlin was 308 days (range, 119-1105). Median number of prior lines of antineoplastic therapy between most recent SCT and study entry was 1 (range, 0-3), 3 patients had received prior donor lymphocyte infusion [Table 1]. The median duration of exposure to siremadlin was 60 days (range, 21-203), median dose intensity was 52.5 mg/day (range, 13.4-200), and the median cumulative dose was 630 mg (range, 250-1710). Sixteen (84.2%) and 14 (73.7%) pts experienced grade (G) ≥3 AEs and treatment-related AEs, respectively; 14 (73.7%) and 12 (63.2%) pts experienced serious AEs (SAEs) and treatment-related SAEs, respectively. Nine pts had AEs leading to siremadlin dose adjustment or interruption, and 1 pt had an AE leading to treatment discontinuation (fungal sinusitis, G3, not suspected to be related to siremadlin). The most common G 3/4 non-hematological AEs were febrile neutropenia (n=11, 57.9%), hypokalemia (n=5, 26.3%), and tumor lysis syndrome (n=3, 15.8%). Graft vs host disease (GvHD) was observed in 4 pts (21.1%): G3, n=2 (10.5%); G2 and G1, each n=1 (5.3%) [Table 2]. Three of these 4 pts had a history of GvHD prior to commencement of siremadlin. Siremadlin was continued safely at full dose (n=3) or dose-reduced (n=1) in all four pts. For 1 pt treated with 400 mg in Reg 1A, chronic GvHD was declared a dose-limiting toxicity. Overall, the safety profile was consistent with what was observed in the overall X2101 study population of hematologic malignancies (n=93) including n=91 R/R AML pts [Table 3]. Of note, 3 out of 19 patients achieved a major clinical response: 2 achieved complete remission (CR) and 1 CR with incomplete hematologic recovery (CRi). Conclusions: The safety of siremadlin monotherapy in pts with relapsed AML following prior SCT(s) appears to be consistent with that previously defined in R/R AML. No excessive GvHD was reported and siremadlin could be continued safely at full or reduced dose. Preliminary efficacy data indicate anti-leukemic activity. Despite the limitation of this post-hoc analysis in a small cohort of patients, these results and recently identified IME provide evidence to support further exploration of siremadlin post SCT as a potential maintenance or preemptive treatment in AML pts with high risk of relapse to enhance the allogeneic graft vs leukemia, an important and potent therapy against AML relapse. Figure 1 Figure 1. Disclosures Stein: Blueprint Medicines: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Syndax Pharmaceuticals: Consultancy; Genentech: Consultancy; Gilead Sciences, Inc.: Consultancy; Astellas: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Curti: Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeiser: Incyte, Mallinckrodt, Novartis: Honoraria, Speakers Bureau. Eldjerou: Novartis Pharmaceuticals: Current Employment. Weber: Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Fabre: Novartis: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Scott: Novartis Pharmaceuticals: Current Employment. DeAngelo: Abbvie: Research Funding; Takeda: Consultancy; Servier: Consultancy; Glycomimetrics: Research Funding; Blueprint: Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Amgen: Consultancy; Agios: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy.

The estimand framework included in the addendum to the ICH E9 guideline facilitates discussions to ensure alignment between the key question of interest, the analysis, and interpretation. Therapeutic knowledge and drug mechanism play a crucial role in determining the strategy and defining the estimand for clinical trial designs. Clinical trials in patients with hematological malignancies often present unique challenges for trial design due to complexity of treatment options and existence of potential curative but highly risky procedures, e.g. stem cell transplant or treatment sequence across different phases (induction, consolidation, maintenance). Here, we illustrate how to apply the estimand framework in hematological clinical trials and how the estimand framework can address potential difficulties in trial result interpretation. This paper is a result of a cross-industry collaboration to connect the International Conference on Harmonisation (ICH) E9 addendum concepts to applications. Three randomized phase 3 trials will be used to consider common challenges including intercurrent events in hematologic oncology trials to illustrate different scientific questions and the consequences of the estimand choice for trial design, data collection, analysis, and interpretation. Template language for describing estimand in both study protocols and statistical analysis plans is suggested for statisticians' reference., Comment: 5 tables, 1 figure

BackgroundCognitive behavioral therapy (CBT) is an effective treatment for many patients suffering from major depressive disorder (MDD), but predictors of treatment outcome are lacking, and little is known about its neural mechanisms. We recently identified longitudinal changes in neural correlates of conscious emotion regulation that scaled with clinical responses to CBT for MDD, using a negative autobiographical memory-based task.MethodsWe now examine the neural correlates of emotional reactivity and emotion regulation during viewing of emotionally salient images as predictors of treatment outcome with CBT for MDD, and the relationship between longitudinal change in functional magnetic resonance imaging (fMRI) responses and clinical outcomes. Thirty-two participants with current MDD underwent baseline MRI scanning followed by 14 sessions of CBT. The fMRI task measured emotional reactivity and emotion regulation on separate trials using standardized images from the International Affective Pictures System. Twenty-one participants completed post-treatment scanning. Last observation carried forward was used to estimate clinical outcome for non-completers.ResultsPre-treatment emotional reactivity Blood Oxygen Level-Dependent (BOLD) signal within hippocampus including CA1 predicted worse treatment outcome. In contrast, better treatment outcome was associated with increased down-regulation of BOLD activity during emotion regulation from time 1 to time 2 in precuneus, occipital cortex, and middle frontal gyrus.ConclusionsCBT may modulate the neural circuitry of emotion regulation. The neural correlates of emotional reactivity may be more strongly predictive of CBT outcome. The finding that treatment outcome was predicted by BOLD signal in CA1 may suggest overgeneralized memory as a negative prognostic factor in CBT outcome.

The sluggish kinetics of hydrogen oxidation/evolution reaction (HOR/HER) is one of the major barriers for the breakthrough of alkaline membrane fuel cells. In particular, the effects of different cations on the HOR/HER kinetics are poorly understood to date. In this work, the catalytic HOR/HER activity on polycrystalline platinum (poly-Pt) and high surface area carbon-supported platinum nanoparticles (HSAC-Pt) in various alkaline 0.1 M electrolyte solutions (MOH, M = Li+, Na+ and K+) at different temperatures was studied using rotating disc electrode (RDE) technique. Our results show the increase of the HOR/HER activity for Pt in the order of K+ < Na+ < Li+. The improved kinetics are attributed to the water arrangement controlled by the monovalent cations resulting in non-covalent interactions of the hydrated cations and the adsorbed hydrogen. We assume that these non-covalent interactions cause the superior HOR/HER activity on the Pt surface in presence of LiOH.

In the corrected version of this Data Descriptor, an error was introduced in the spelling of H. Peter Soyer which was incorrectly given as H. Peter Seter. This has now been corrected in both the PDF and HTML versions of the Data Descriptor.

Suicidal behavior and difficulty regulating emotions are hallmarks of Borderline Personality Disorder (BPD). This study examined neural links between emotion regulation and suicide risk in BPD. 60 individuals with BPD (all female, mean age = 28.9 years), 46 of whom had attempted suicide, completed a fMRI task involving recalling aversive personal memories. Distance trials assessed the ability to regulate emotion by recalling memories from a third-person, objective viewpoint. Immerse trials assessed emotional reactivity and involved recalling memories from a first-person perspective. Behaviorally, both groups reported less negative affect on Distance as compared to Immerse trials. Neurally, two sets of findings were obtained. The first reflected differences between attempters and non-attempters. When immersing and distancing, attempters showed elevated recruitment of lateral orbitofrontal cortex, a brain region implicated in using negative cues to guide behavior. When distancing, attempters showed diminished recruitment of the precuneus, a region implicated in memory recall and perspective taking. The second set of findings related to individual differences in regulation success - the degree to which individuals used distancing to reduce negative affect. Here, we observed that attempters who successfully regulated exhibited precuneus recruitment that was more similar to non-attempters. These data provide insight into mechanisms underlying suicide attempts in BPD. Future work may examine if these findings generalize to other diagnoses and also whether prior findings in BPD differ across attempters and non-attempters.

Can taking the perspective of other people modify our own affective responses to stimuli? To address this question, we examined the neurobiological mechanisms supporting the ability to take another person's perspective and thereby emotionally experience the world as they would. We measured participants' neural activity as they attempted to predict the emotional responses of two individuals that differed in terms of their proneness to experience negative affect. Results showed that behavioral and neural signatures of negative affect (amygdala activity and a distributed multivoxel pattern reflecting affective negativity) simulated the presumed affective state of the target person. Furthermore, the anterior medial prefrontal cortex (mPFC)-a region implicated in mental state inference-exhibited a perspective-dependent pattern of connectivity with the amygdala, and the multivoxel pattern of activity within the mPFC differentiated between the two targets. We discuss the implications of these findings for research on perspective-taking and self-regulation.

Background: Many individuals with alcohol-use disorders who had experienced alcohol craving before joining Alcoholics Anonymous (AA) report little or no craving after becoming long-term members. Their use of AA prayers may contribute to this. Neural mechanisms underlying this process have not been delineated. Objective: To define experiential and neural correlates of diminished alcohol craving following AA prayers among members with long-term abstinence. Methods: Twenty AA members with long-term abstinence participated. Self-report measures and functional magnetic resonance imaging of differential neural response to alcohol-craving-inducing images were obtained in three conditions: after reading of AA prayers, after reading irrelevant news, and with passive viewing. Random-effects robust regressions were computed for the main effect (prayer > passive + news) and for estimating the correlations between the main effect and the self-report measures. Results: Compared to the other two conditions, the prayer condition was characterized by: less self-reported craving; increased activation in left-anterior middle frontal gyrus, left superior parietal lobule, bilateral precuneus, and bilateral posterior middle temporal gyrus. Craving following prayer was inversely correlated with activation in brain areas associated with self-referential processing and the default mode network, and with characteristics reflecting AA program involvement. Conclusion: AA members’ prayer was associated with a relative reduction in self-reported craving and with concomitant engagement of neural mechanisms that reflect control of attention and emotion. These findings suggest neural processes underlying the apparent effectiveness of AA prayer.

Recently, Pt-based core-shell nanoparticles (NPs) have emerged as highly active catalyst materials to accelerate the sluggish oxygen reduction reaction (ORR) in acidic media as well as the hydrogen oxidation reaction (HOR) in alkaline. Less attention has been payed to the chemical state of the less noble metal after forming core-shell NPs. Intuitively; a metallic state of the less noble metal inside the particles has been suggested from many research groups. In this talk, we will show a new catalyst concept for Pt-Co nanoparticles by manipulating the surface arrangement and composition induced by the reaction conditions. More precisely, our catalysts exhibit superior Pt surface area-based specific activities (up to 10-fold) and Pt mass-based activities (up to 5-fold) towards the ORR compared to commercial Pt/C at 0.95 VRHE. In addition, we will show the influence of the chemical state and surface enrichment of the cobalt on the HOR activity in alkaline media. Altogether, we will solve the long standing mystery of the chemical state of the cobalt and its distribution for PtxCo1-x nanoparticles and its remarkable effect on the catalytic performance for HOR and ORR.

Patients with acute myeloid leukemia (AML), who are refractory to induction therapy or experience relapse after a first complete remission (CR), have an unfavorable prognosis.[1][1] Epigenetic dysregulation is frequent in AML. In preclinical studies, the pan-deacetylase inhibitor (DACi) panobinostat

Cognitive behavioral therapy (CBT) is effective for a substantial minority of patients suffering from major depressive disorder (MDD), but its mechanism of action at the neural level is not known. As core techniques of CBT seek to enhance emotion regulation, we scanned 31 MDD participants prior to 14 sessions of CBT using functional magnetic resonance imaging (fMRI) and a task in which participants engaged in a voluntary emotion regulation strategy while recalling negative autobiographical memories. Eighteen healthy controls were also scanned. Twenty-three MDD participants completed post-treatment fMRI scanning, and 12 healthy volunteers completed repeat scanning without intervention. Better treatment outcome was associated with longitudinal enhancement of the emotion regulation-dependent BOLD contrast within subgenual anterior cingulate, medial prefrontal cortex, and lingual gyrus. Baseline emotion regulation-dependent BOLD contrast did not predict treatment outcome or differ between MDD and control groups. CBT response may be mediated by enhanced downregulation of neural activity during emotion regulation; brain regions identified overlap with those found using a similar task in a normative sample, and include regions related to self-referential and emotion processing. Future studies should seek to determine specificity of this downregulation to CBT, and evaluate it as a treatment target in MDD.