Different primary liver tumors and subclones within each tumor display striking molecular and biological variations. Consequently, tumor molecular heterogeneity contributes to drug resistance and tumor relapse following therapy, which poses a substantial obstruction to improving outcomes of patients with liver cancer. There is an urgent need to the compositional and functional understanding of tumor heterogeneity. In this review, we summarize genomic and non-genomic diversities, which include stemness and microenvironmental causes of the functional heterogeneity of the primary liver cancer ecosystem. We discuss the importance and intricacy of intratumor heterogeneity in the context of cancer cell evolution. We also discuss methodologies applicable to determine intratumor heterogeneity and highlight the best-fit patient-derived  According to the Darwinian evolution selection, a PLC lesion evolves from a single malignant cell into a functionally heterogenous tumor mass with a hierarchically organized tumor cell community, promoting its survival and fitness in response to the various microenvironments.11Tumor heterogeneity consists of intertumor (tumor by tumor) and intratumor (within a tumor) heterogeneity. Intertumor heterogeneity refers to PLCs from different patients whose altered genotype and phenotype are induced by diverse etiological and environmental factors.18 This approach has been successfully applied to the management of chronic myeloid leukemia (CML) and breast cancer.21 For example, most of CMLs are driven by a fused BCR-ABL oncoprotein, a constitutively activated tyrosine kinase. Ninety-eight percent of BCR-ABL CML responds favorably to the initial treatment of tyrosine kinase inhibitors (TKIs). While BCR-ABL-based subclassification and associated target therapy remain the standard care for CML patients, there is growing evidence showing that a minority of mutational subclones within CML are highly resistant to tyrosine kinase inhibitors,24 suggesting that subclassification based on intertumor heterogeneity may not capture the full tumor spectrum. Thus, we need to integrate molecular features of both intertumor and intratumor heterogeneity with functional heterogeneity to improve patient subclassification and response to therapy.The most current understanding of PLC heterogeneity is limited to intertumor heterogeneity, mostly focused on molecular subclassification based on genomic profiling. Accordingly, molecular subclassification has identified different patient subtypes according to their genomic profiles with targeted therapy choice. Notably, subclass-related oncogene addiction loops have been identified based on genomic profiling of various tumor subtypes.10 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), each of which is treated differently, according to their clinical guidelines. Currently, no biomarker-guided targeted therapy is available for HCC or ICC. However, emerging studies aim to HCC or ICC molecular subclassification associated with subtype-related target therapy.29 Studies such as whole-genome sequencing (WGS) of HCC reveal frequent mutations in various tumor suppressor genes and oncogenes, including telomerase reverse transcriptase promoter mutations (54–60%), catenin beta 1 (CTNNB1) mutations (11–37%), tumor protein P53 (TP53) mutations (12–48%) and AT-rich interactive domain-containing protein 1A (ARID1A) mutations (4–17%).33 However, mutation-specific subtypes are not evident. In contrast, transcriptome-based studies have revealed stable molecular subtypes of HCC and ICC. For example, HCC can be divided into several molecular subtypes based on stemness gene expression patterns.35 Similarly, ICC have been categorized to two major subclasses linked to patient outcomes, that is, proliferation subtype and inflammation subtype.37 While subclassification based on intertumor heterogeneity is stable among different data sets, improved PLC treatment remains to be seen. Furthermore, much less is known about intratumor molecular heterogeneity of HCC or ICC. It is unclear whether the degree of intratumor heterogeneity is associated with specific tumor types and patient outcomes. Thus, understanding the link between intertumor and intratumor heterogeneity may help improve PLC subclassification and treatment stratification.PLC consists of two major histological types,42 Here we propose a concept of intratumor ‘functional’ heterogeneity that describes the abilities of cancer cells to undergo cellular proliferation, adaption and drug resistance within a defined microenvironment linked to a specific etiology. We argue that the compositional heterogeneity helps to understand functional heterogeneity, which is key to understanding PLC heterogeneity , an aerobic glycolysis process enzyme gene, has been demonstrated to be associated with poor survival, compared with the hypomethylation of HK2 promoter.54 As these studies demonstrate the importance of intertumor heterogeneity in PLCs, more functional studies are required to further understand the association between intratumor non-genomic heterogeneity and its related functions.The dysregulation of the epigenome is one mechanism that contributes to intratumor subclonal variations. Non-genomic intratumor heterogeneity, including histone modifications, DNA hypo- or hyper- methylation, non-coding RNAs, and transcriptional regulators, contribute intratumor heterogeneity by regulating the spatial chromatin organization and altering the transcriptome. Interestingly, aberrant DNA methylation patterns in PLCs are associated with chronic viral hepatitis infections.55 CSCs acquire stem-like characteristics (or stemness) similar to normal stem/progenitor cells, which have been demonstrated to promote liver cancer progression, relapse and intratumor heterogeneity.57 Accordingly, Fan’s group recently showed that spatial heterogeneity of CD13+ CSCs is associated with long non-coding RNAs (lncRNAs), including lnc-β-Catm, lncTCF7 and lncBRM, which have been demonstrated to promote the PLC organoid formation.60 Although the spatial CSCs heterogeneity has been demonstrated, the functional diverse distribution of CSCs remains unclear.Cancer stem cells (CSCs) have been demonstrated to contribute to tumor heterogeneity.62 Notably, the peritumor microenvironment, from the seed and soil concept, can foster tumor development by reprograming the stromal with the aid of cancer-associated fibroblasts.64In vivo studies have demonstrated that tumor cells benefit from the microenvironment, which contributes to promoting cellular diversity by supporting the tumor vasculature and reprogramming immune cell.62 Interestingly, tumor-infiltrating lymphocytes can be recruited by HCC cells without secreting the tumor-toxic cytokine interferon gamma (IFN-γ).66 These studies suggest that PLC cells could recruit non-toxic infiltrating lymphocytes to promote intratumor heterogeneity and evade from the immune system. HCC studies show that diverse microenvironments are composed of immuno-regulating cytokines, growth factors, immunosuppressors and heterogenous and naturalized stromal cell types. These diverse microenvironments functionally suppress the immune system, by diminishing natural killer cells (NK cells) or enhancing the immunosuppressive regulatory T cells (Treg cells).79Genomic and non-genomic heterogeneity and the presence of stemness from CSCs have provided some degrees of understanding of PLC. Importantly, microenvironment heterogeneity, which can directly interact with tumor cells and influence therapeutic response, has been considered as a novel hallmark of cancer.11 proposed that most tumors arise from a single cell which gains genetic instability within the original clone with sequential selection of branching subclones evolving over time. Notably, recent studies from WGS of different lesions of a tumor mass have extended this model, further suggesting that a tumor cell community is hierarchically organized through a branching or paralleling evolution.81 It has been shown that PLC has the propensity to develop multiple subclones, resulting in extended intratumor heterogeneity.49 A systematic analysis of PLC intratumor heterogeneity came from a study by Xue et al.,42 in which the authors performed somatic mutations and copy number variations (CNVs) using a low-depth whole genome and exome sequencing in 43 tumor lesions derived from 10 HBV-positive HCC cases and found evidence of branched evolution linked to HCC. This comprehensive study provides evidence of branched evolution linked to HCC and demonstrate that while tumors from each patient have different clonal hierarchies, satellite nodules share more than 90% of somatic mutations with their primary tumors. Intriguingly, in a patient with multicentric tumors, six lesions show parallel evolution patterns that can be divided into two major subclones, each with its own unique genomic characteristics. In contrast, PLCs with histologically mixed HCC and ICC, satellite nodules shared more than 100 somatic mutations, indicating that subsequent diverse subclones are evident through the genetic evolution of tumor nodules within each PLC. In another study, Ling et al.41 have analyzed 286 tumor regions from one HCC sample using whole-exome sequencing and genotyping and discovered the evidence of high genetic diversity within a single tumor, indicative of non-Darwinian cell evolution prevalence.41 These results suggest that the extent of intratumor heterogeneity varies considerably among patients with HCC.The process of tumor initiation has not been fully understood, as not much is known about the cellular origin of a tumor mass. In 1976, Nowell80 In addition, longitudinal sampling from each patient including prior and post treatment can be implemented.44 This approach improves our understanding of the PLC evolution during tumor progression. Notably, some has suggested that the use of imaging techniques is sufficient for PLC diagnosis. Given the extent of genomic and biological heterogeneity associated with PLC, such a view is shortsighted.82 Therefore, a comprehensive and systematic analysis of multiple biopsies is recommended to uncover the PLC functional heterogeneity that drives tumor evolution.To address the extent of PLC heterogeneity, multiple biopsies from a single tumor is required. This can be accomplished by collecting multiple biopsies from different geographical regions within a tumor or patient. Such analyses will reveal tumor cell hierarchies at the genomic and non-genomic level, including the presence of CSCs and the diversities within the tumor microenvironment at a given time .80 In adSeveral studies in recent years have begun to explore methodologies to study intratumor heterogeneity. Here we outline some of the current methodologies that have been successfully used to characterize intratumor heterogeneity .80 Mutational intratumor heterogeneity was observed for multiple tumor suppressor genes and further analysis of multiple regions of PLCs provide evidence of the trunk and branch mutational profile.42 Moreover, Zhang’s group studied HCC heterogeneity using allelic frequency profiles of frequently mutated genes across genomes and exomes based on deep sequencing of two separate biopsies from each tumor.83 Among 42 HCC cases analyzed, they found evidence of diverse modes of genomic alteration in HCC. These studies suggest that given the extent of intratumor mutational heterogeneity, multiple sampling of only a few regions to determine driver mutations may not necessarily be adequate to capture the true mutational landscape of a tumor type.Morphological intratumor heterogeneity has long been observed by pathologists. However, intratumor molecular heterogeneity has only been appreciated in recent years due to WGS technologies. The first study to address intratumor molecular heterogeneity was based on multiregional sequencing of renal carcinomas and associated metastatic sites.84 Single-cell analysis may provide the level of sensitivity and specificity to study tumor cell diversity in a tumor cell ecosystem.87 One latest technological advance includes the development of scTrio-seq, a single cell triple omics method developed by Hou et al.51 to simultaneously analyze genome (CNVs), DNA methylome and transcriptome in a single cell. While single-cell technology is useful to study tumor cell diversity in each tumor cell ecosystem, it lacks information about topological space within a tumor cell community. New approaches such as single-cell gene expression profiling with multiplexed error-robust fluorescence in situ hybridization may help resolving this issue.89 In addition, while single-cell RNA transcriptome has provided sufficient resolution to distinguish single cells, whole genome or exosome sequencing technologies are not sufficient to provide a comprehensive view of global genomic landscape of a tumor at the single-cell level. Therefore, identifying cancer driver genes linked to single tumor cells is a challenge.The recent development of single-cell genome sequencing technologies has generated many new insights into complex biological systems including human cancer.90 However, not all CTCs are tumorigenic, suggesting that these cells are heterogeneous.93 Molecular analysis of CTCs may provide information on tumor cell heterogeneity. A deep understanding of CTC heterogeneity may facilitate our ability to identify key molecular targets to improve cancer therapy. Interestingly, Miyamoto et al.94 demonstrated considerable heterogeneity among CTCs by analyzing 77 intact CTCs from 13 prostate cancer patients by single-cell RNA sequencing. As CTCs are rare, therefore methods that can accurately detect and isolate them for downstream analysis are crucial. In a study by Lohr et al.,95 the authors developed a microscope-based technology to detect and isolate CTCs from multiple myeloma (MM) patients for single-cell RNA-sequencing analysis. They found that CTCs provide the same genetic information as bone marrow multiple myeloma cells, providing a more clear overview of the tumor itself than bone marrow biopsies thus enabling the classification of MM to improve precision medicine.95 In addition, Kalinich et al.96 developed a high-throughput microfluidic CTC-iChip, which can be used to enrich HCC CTC while excluding hematopoietic cells from the blood. It will be interesting in determining if these methods allow assessment of CTC heterogeneity. Moreover, whether these methods can be incorporated into clinical practice, especially PLC management, remains to be determined.Circulating tumor cells (CTCs), found in blood and originated from aggressive subclones of the primary tumor, are responsible for metastasis and tumor relapse. A meta-analysis of HCC CTC studies revealed that CTCs are positively correlated with poor prognosis.In situ methods are desirable techniques for understanding PLC heterogeneity because it can address the spatial organization of a tumor cell community. This method has been used to detect DNA and RNA using formalin-fixed paraffin-embedded tissue microarrays in a high-throughput manner.98 With the use of high-resolution microscopy, CNVs, genetic mutation profile and RNA quantification can be profiled at the single-cell level. This is evident in a study by Kimura et al.99 who demonstrated the presence of molecular heterogeneity by in situ hybridization with a chromosome 17-specific DNA probe. The authors found that distinct subclones in 2/25 HCC samples with chromosome 17 copy number alterations and ploidy patterns.99 Others have also determined topological features of intratumor subclones by in situ approaches.44 While the current in situ hybridization method still has a poor resolution as only a few molecular features can be assessed at one time. More sensitive methods with higher densities of DNA/RNA probes are being developed to help further our understanding of spatial organization of a tumor subclone.89 Additional mathematical models such as the Shannon diversity index method are being explored to precisely measure the degree of intratumor heterogeneity in a tumor cell ecosystem. New models to incorporate spatial organization with Shannon diversity index should be exploited to measure the true dynamic of a tumor cell community.101 Among various available models, patient-derived tumor xenografts (PDTXs) and matched patient-derived tumor cells (PDTCs) have been the preferable choices. Accordingly, Bruna et al.102 have generated a living biobank of human breast cancers in order to adequately capture the inter- and intratumor heterogeneity in pre-clinical models. Remarkably, the intratumor genomic clonal architecture of the originating tumors is largely preserved in PDTXs and matched PDTCs.102 Using this resource coupled with a high-throughput response and resistance screens, they have successfully assessed drug responses in these models.102 In addition, in vivo PDTX can recapture up to 82.5% of ex vivo PDTCs in terms of the drug response. These results suggest that both PDTC and PDTX represent a powerful resource for pre-clinical pharmacogenomic studies. Most recently, Gao et al.103 also observed considerable intratumor heterogeneity and branched evolution in HCC samples that correspond to existing pharmacologic agents using PDTCs. These studies indicate that PDTX and PDTC coupled with the use of their genomic information are useful platforms for pharmacologic assessments linked to intratumor heterogeneity. Thus, improving assessment of the complexity of PLC intratumor heterogeneity will provide a better understanding of functional heterogeneity, which may be linked to therapeutic responses.Experimental models are very useful tools to explore molecular mechanisms that drive tumorigenesis, and ideally used to study intratumor heterogeneity. Appropriate models that mimic human diseases are necessary to provide the clinical relevance.104 Third, given the importance of the molecular and phenotypical intratumor heterogeneity of PLCs, the access to a living biobank of PLCs will help build the much-needed database to further understand features of intratumor heterogeneity. Furthermore, a drug response database from high throughput single drug and drug–drug combination screen using in vivo PDTX and in vitro PDTC models will prove effective for developing targeted therapies (105 With the development of better molecular technologies, we may be able to ultimately find solutions to improve outcomes of patients who suffer from this dreadful disease once for all.Our understanding of PLC heterogeneity has been improved in recent years, but many challenges are still ahead such as a precision measurement to recapture and preserve the diversity of a tumor cell community linked to patient outcomes including treatment response. The PLC ecosystem is dynamically changing during therapy as resistant clones may be selected and expanded throughout tumor evolution. To improve HCC therapies, understanding the impact of tumor heterogeneity must be appreciated. First, we need to understand the diversity of a given tumor cell community and to learn their collective behaviors. By measuring the phylogenetic relationship among different cells and using the Shannon diversity index through subclone bulk or single-cell sequencing , we may herapies . TogetheSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Energy homeostasis of mammals is maintained by balancing energy expenditure within the body and energy intake through feeding. Several lines of evidence indicate that brown adipose tissue (BAT), a sympathetically activated thermogenic organ, turns excess energy into heat to maintain the energy balance in rodents and humans, in addition to its thermoregulatory role for the defense of body core temperature in cold environments. Elucidating the central circuit mechanism controlling BAT thermogenesis dependent on nutritional conditions and food availability in relation to energy homeostasis is essential to understand the etiology of symptoms caused by energy imbalance, such as obesity. The central thermogenic command outflow to BAT descends through an excitatory neural pathway mediated by hypothalamic, medullary and spinal sites. This sympathoexcitatory thermogenic drive is controlled by tonic GABAergic inhibitory signaling from the thermoregulatory center in the preoptic area, whose tone is altered by body core and cutaneous thermosensory inputs. This circuit controlling BAT thermogenesis for cold defense also functions for the development of fever and psychological stress-induced hyperthermia, indicating its important role in the defense from a variety of environmental stressors. When food is unavailable, hunger-driven neural signaling from the hypothalamus activates GABAergic neurons in the medullary reticular formation, which then block the sympathoexcitatory thermogenic outflow to BAT to reduce energy expenditure and simultaneously command the masticatory motor system to promote food intake—effectively commanding responses to survive starvation. This article reviews the central mechanism controlling BAT thermogenesis in relation to the regulation of energy and thermal homeostasis dependent on food availability. Mammals including humans maintain energy homeostasis by balancing energy intake and expenditure. A major physiological activity that expends energy within the body of these homeothermic animals is adaptive heat production (thermogenesis), which is particularly essential to maintain body core temperature under subthermoneutral environmental temperature. Adaptive thermogenesis in brown adipose tissue (BAT) is well known as a major sympathetic response for cold defense in rodents . BAT theUnder strong hunger, on the other hand, adaptive thermogenesis in BAT is suppressed to save energy even in cold environments, often resulting in hypothermia , 107. ThElucidating the central circuit mechanisms that control energy expenditure (thermogenesis) and food intake for energy homeostasis is important in understanding the etiology of obesity as well as the fundamental mechanism of survival responses to hunger and starvation. In this review article, we describe the current understandings of the basic central circuit mechanisms controlling BAT thermogenesis for cold defense, fever and psychological stress-induced hyperthermia, and then, of the central regulation of BAT thermogenesis and energy homeostasis dependent on food availability, with a special focus on a recently identified circuit that commands responses to hunger and starvation.3-adrenoceptors on their surface [3-adrenoceptor-mediated intracellular signaling results in heat production by uncoupling protein 1 (UCP1) in mitochondria [Physiological responses for the autonomous regulation of body core temperature in mammals include heat production within the body and heat loss from the body surface, both of which are controlled by central neural circuits . One of  surface . The actchondria . Indicatchondria . Despitechondria .3-Adrenoceptors are expressed primarily in BAT [3-adrenoceptor agonist in rats of high-fat diet-induced obesity increases body core temperature, energy expenditure and UCP1 content in BAT, and reduces the weights of white adipose tissue depots without altering food intake, ameliorating the obesity [3-Adrenoceptor-deficient mice show a mild obesity phenotype with modestly increased fat stores [3-adrenoceptor-mediated thermogenesis in BAT to prevent obesity and also suggest the involvement of other adrenoceptor subtypes in BAT thermogenesis for energy homeostasis.βy in BAT , and chr obesity . β3-Adret stores , and mict stores . These fPhysiological significance of BAT thermogenesis in adult humans has been demonstrated by studies using positron-emission tomographic and computed tomographic (PET/CT) scanning. This imaging technique can visualize body cooling-induced accumulation of fluorodeoxyglucose (FDG), a glucose analog, in supraclavicular and paraspinal regions, which harbor fat depots rich in adipocytes expressing UCP1, a marker of brown adipocytes , 96, 97.A receptor agonist widely used as a neuronal inhibitor, completely blocks the induction of BAT thermogenesis by cold exposure, central injection of a pyrogenic mediator, and psychological stress [Figure l stress , 60, 64.l stress , 52, 73 l stress   of VGLUT3-expressing neurons in the rMR contains serotonin and likely co-releases glutamate and serotonin from their axon terminals in the spinal IML , 65, 88.BAT sympathetic premotor neurons in the rMR receive glutamatergic (VGLUT2-positive) excitatory projections from the dorsomedial hypothalamus (DMH) consisting of the dorsomedial hypothalamic nucleus and dorsal hypothalamic area . DMH neuA receptors in the DMH or transection of descending outputs from the POA elicits robust BAT thermogenesis [The DMH-rMR thermogenic pathway is likely under a tonic GABAergic control by the preoptic area (POA), in which the thermoregulatory center is located. Blockade of GABAogenesis , 77, 106ogenesis , 54  on neurons in the POA. PGE2, which is biosynthesized in brain endothelial cells in response to immune signaling stimulated by infection [i [2 on POA neurons through EP3 receptors likely inhibits their firing activity. EP3 receptor-expressing POA neurons are predominantly GABAergic and project to the DMH and rMR [2 on EP3 receptor-expressing POA neurons to inhibit their tonic activity leads to disinhibition of the DMH and rMR neurons, resulting in stimulated sympathetic outflows to thermoregulatory effectors including BAT to develop fever [The POA is also known as the febrile center, which commands febrile responses including BAT thermogenesis and cutaneous vasoconstriction to increase body temperature during infection or systemic inflammation. Febrile command signaling from the POA is triggered by an action of prostaglandin Enfection , 99, 100nfection , 56 to tnfection . Becausection [i , the act and rMR , 67, and and rMR . These fop fever , 58, 67.The subpopulations of EP3 receptor-expressing POA neurons projecting to the DMH and to the rMR are distinct . CoolingThere are multiple mechanisms for the brain to sense hunger. A well-known humoral mechanism to transmit the information of hunger to the brain is the ghrelin-neuropeptide Y (NPY) pathway. In fasted animals, the stomach releases ghrelin, which is delivered to the hypothalamic arcuate nucleus in the brain through the circulation . GhrelinA receptor antagonist into the rMR evokes BAT thermogenesis [A receptors in the rMR [A recent study demonstrated that the hypothalamic NPY-triggered hunger signaling provides an inhibitory input to BAT sympathetic premotor neurons in the rMR  Fig. 3)3). Consiogenesis   and parvicellular (PCRt) reticular nuclei of the medulla oblongata  Fig. 4)4). Neura the POA , indicat the rMR , consist the rMR  5). FurthIntriguingly, stimulation of IRt/PCRt neurons in rats, which inhibits BAT thermogenesis, also elicits mastication even under anesthesia and increases food intake in free-moving animals, often accompanied by increased saliva secretion  Fig. 7)7). FurthThe IRt/PCRt is considered one of the premotor regions that contain the central pattern generator for the rhythmic masticatory muscle movements . AlthougA receptor antagonist or excitation of PVH neurons with a nanoinjection of NMDA inhibits BAT thermogenesis [A receptors in the rMR, indicating BAT sympathoinhibition through GABAergic inhibition of premotor neurons in the rMR [The hypothalamic mechanisms by which the brain senses hunger and satiety have been intensively studied. As mentioned above, the ghrelin-NPY signaling pathway is known as one of hunger signaling mechanisms. However, whether the action of NPY on PVH neurons is stimulatory or inhibitory is controversial . Electroogenesis . Similar the rMR . All theA receptors in the PVH [However, NPY can also exert an inhibitory effect on the activity of PVH neurons expressing melanocortin-4 receptors (MC4Rs) through its postsynaptic action . Optogen the PVH , suggestThe pathway through which the NPY-triggered hunger signals are transmitted from the PVH to the IRt/PCRt has yet to be determined. The existence of few direct projections from the PVH to the IRt/PCRt  suggestsThe NTS also receives information on nutritional conditions from visceral organs through the vagus nerve. Increased glucokinase expression in the mouse liver, which is induced by high-fat feeding, leads to decreases in BAT thermogenesis and energy expenditure through the liver–brain vagal afferent , suggestAnother pathway that can be hypothesized to transmit the hypothalamomedullary signaling to the IRt/PCRt is an LPB-mediated pathway. The LPB receives projections from the PVH  and provIn addition to the postsynaptic inhibitory action of NPY on MC4R-expressing PVH neurons , NPY-conStudies over the past two decades have made remarkable progress in understanding the central neural circuit mechanisms for body temperature regulation, particularly the control of adaptive thermogenesis in BAT. In the central circuit mechanism controlling BAT thermogenesis, the DMH-rMR-spinal sympathoexcitatory pathway is controlled by tonic GABAergic transmission from the POA, whose activity is altered by body core and cutaneous thermosensory signals. This neural circuit for cold defense also functions to drive BAT thermogenic responses to infection and psychological stress. Therefore, this central circuit mechanism is important not only for thermal homeostasis, but also for the defense of life from various environmental stressors.Central regulation of BAT thermogenesis dependent on nutritional conditions and food availability is critical for energy homeostasis. Recent studies have revealed that during hunger, a GABAergic group of neurons in the IRt/PCRt of the medulla oblongata takes the control of the two independent (sympathetic and somatic) motor systems to simultaneously command the inhibition of adaptive BAT thermogenesis (energy saving) and the promotion of food intake (energy intake) to survive starvation. The NPY-triggered hunger signaling from the PVH to the IRt/PCRt may be mediated by the NTS, whereas melanocortin-triggered satiety signaling from MC4R-expressing PVH neurons activates LPB neurons, which might inhibit IRt/PCRt neurons to reduce food intake. More physiological investigations are required to determine the mechanisms of the hypothalamomedullary hunger and satiety signal transmission. In addition to the aforementioned humoral and neural  transmission of hunger and satiety signals from the periphery to the brain, central sensing of fatty acids and glucose levels , 75 also


Intensive care units (ICU) physicians are experiencing a rapidly expanding collection of vast amounts of data from routine practice, patients’ monitoring as well as from diagnostic or prognostic tests. However, although these data could influence their clinical decisions and management, the validity and relevance of data processing methods, in particular in case of complex data sets , one of the world’s largest biological data repositories, is currently storing: ~ 5 petabytes , and the potential use of brain MRI grey matter morphometry to predict patients’ one-year neurological outcome. The authors  studied Complex statistical analyses designed to deal with large data sets might appear as magic bullets rendering cumbersome randomized trials dispensable  computational issues should be adequately addressed probably by means of cloud storage and cloud computing facilities , (2) impConsidering the complexity of ICU setting, we have illustrated how data-driven approaches, through closed-loop systems integrating multimodal data, hold the promise to provide individually tailored and real-time patient care based on the large amount of information currently at our disposal. Regarding translational research, data-driven and hypothesis-driven approaches appear not to be mutually exclusive, but largely complementary and reciprocally challenging. Understanding the opportunities and pitfalls of implementing big data in the ICU setting and considering the subsequent technical, ethical and societal changes are key issues for the upcoming years, paving the way for critical diagnostic and therapeutic innovations.Additional file 1: Figure S1. Analytical methods for biomedical research. Compared to rational hypothesis-driven research methods (upper panel), data-driven analysis (lower panel) does not imply reductions neither of the number of hypothesis that could be studied , nor of the obtained data that is used to extract relevant information. Additionally, hypothesis-driven methods are built on optimised models derived from artificial intelligence domains, which can learn and evolve without explicit programming, and validate the created model using data from multiple and independent data sets .Additional file 2: Table S1 Conventional terms used to describe data size. Scale is based on powers of 1000.Additional file 3: Table S2 Opportunities and difficulties related to data-driven analysis.


This study examined patterns of neologistic and perseverative errors during word repetition in fluent Jargon aphasia. The principal hypotheses accounting for Jargon production indicate that poor activation of a target stimulus leads to weakly activated target phoneme segments, which are outcompeted at the phonological encoding level. Voxel-lesion symptom mapping studies of word repetition errors suggest a breakdown in the translation from auditory-phonological analysis to motor activation. Behavioral analyses of repetition data were used to analyse the target relatedness  of neologistic errors and patterns of perseveration in 25 individuals with Jargon aphasia. Lesion-symptom analyses explored the relationship between neurological damage and jargon repetition in a group of 38 aphasia participants. Behavioral results showed that neologisms produced by 23 jargon individuals contained greater degrees of target lexico-phonological information than predicted by chance and that neologistic and perseverative production were closely associated. A significant relationship between jargon production and lesions to temporoparietal regions was identified. Region of interest regression analyses suggested that damage to the posterior superior temporal gyrus and superior temporal sulcus in combination was best predictive of a Jargon aphasia profile. Taken together, these results suggest that poor phonological encoding, secondary to impairment in sensory-motor integration, alongside impairments in self-monitoring result in jargon repetition. Insights for clinical management and future directions are discussed. Neologistic Jargon aphasia is an acquired language disorder characterized by severely distorted speech output. Production in Jargon aphasia is fluent but underspecified and contains numerous non-word errors, rendering it hard to comprehend. Prognosis in Jargon aphasia is poor, with reports of declining vocabulary size and mixed therapeutic outcomes , typically referred to as phonological paraphasias, to severe distortions which bear little resemblance to target phonology , typically referred to as neologisms. Perseverative errors, the repeated intrusion of phoneme strings or syllabic patterns, have been noted to occur alongside neologistic production in Jargon aphasia , mean age 69.7 years , mean time post onset 35 months , see Table We report data from 46 individuals with aphasia ; to enable automated data extraction via Microsoft excel and MATLAB. Responses were categorized following criteria used by Moses et al. . Non-lexFour different analyses were undertaken to explore behavioral patterns in jargon production. Phonological accuracy of non-words was explored, using the Phonological Overlap Index measure  distribution of both non-word error types (paraphasias and neologisms) was examined using the one sample Kolmogorov-Smirnov (KS) test of normality, in order to examine whether distributions adhered to a normal curve and conformed to the single source hypothesis.The IPP measure, adapted from Cohen and Dehaene , calculaTo interpret the prevalence of perseveration within the Jargon aphasia group, observed IPP values were compared against a chance rate. In the current study, all responses from all participants were randomly reassigned to a new target to create a null distribution and 40 trials were randomly selected to undergo IPP analysis. This process was repeated 1,000 times. The observed IPP score was compared against each resampled IPP score to derive a level of significance.For individuals who presented with fluent Jargon aphasia, the number of perseverative non-word errors was calculated using criteria from Martin and Dell . A non-wp < 0.05 and <200 voxels were identified and the percentage lesion overlap with each cluster was extracted in each participant. ROI data were used to identify the consistency of lesion-behavior associations and the strongest predictors of jargon repetition.All participants with an available clinical or 3T T1wimage were included in an exploratory VLSM analysis implemented in the vlsm2 matlab toolbox . Participants who presented with fluent speech and produced 5 or more neologistic errors during repetition were considered to present with neologistic Jargon aphasia; 25 participants met these criteria.All but 4 individuals  displayed a repetition impairment  independent of the number of samples extracted from each null distribution (see Section Methods). The mean POI of neologisms produced by 23 Jargon individuals was greater than the chance prediction (p ≥ 0.067). Non-word POI distributions exhibited by individuals 41, 30, 22, 12, and 44, violated the normal distribution  produced by 20 neologistic individuals adhered to a normal distribution (n = 25). The perseveration probability scores observed across lags 1–10 were averaged to derive a single IPP (perseveration) score. Individual IPP scores were compared against the null chance distributions. Thirteen individuals  produced perseveration at significantly greater rates than the chance prediction .Non-word errors were coded as a perseveration if an intruded phoneme was present in the previous response. Remaining non-words were coded as non-perseverative errors. A correlation analysis revealed a significant positive relationship between rates of perseverative and non-perseverative non-words  in the wider aphasia group displayed a degree of repetition impairment; however, these impairments were only considered Jargon in 25 participants. As well as the significant relationship between perseverative and non-perseverative errors, Pearson correlation analyses displayed strong to medium relationships between overall repetition accuracy, number of neologistic errors, number of paraphasic errors and total number of intruded phonemes, see Table p = 0.01,  = 2.0, p = 0.049], and a borderline significant difference in cluster 4, STG gray matter ,  = 2.05, adjusted R2 = 0.253, p = 0.063]. Time post onset was a significant predictor  indicating that the greater time post onset the less jargon production. Lesions in isolated clusters did not significantly contribute to the model, however the interaction between cluster 2 (STS GM) and cluster 4 (STG GM) was a significant predictor  indicating that jargon was more severe when lesions affected both the STS and STG.A regression analysis was performed to investigate whether a combination of lesions was most predictive of jargon production. The centered percentage lesion overlap of each ROI and the two-way interaction between ROIs were added as predictor variables alongside age, time post onset at testing and total lesion volume into a linear regression; jargon score was the dependent variable. Interaction terms were calculated by multiplying percentage of lesion in each cluster e.g., percentage overlap in cluster 1 × percentage overlap in cluster 2. Predictors in the model displayed sufficient collinearity tolerance; the minimum tolerance value outside interaction predictors was 0.2. The regression returned a borderline significant model [The aim of the current study was to explore, side by side, the behavioral and neurological patterns associated with repetition deficits in Jargon aphasia. Behavioral analyses identified the target relatedness of phonological distortions, and explored the effect of phoneme perseveration in Jargon repetition. Correlation analyses exposed the relationship between perseverative and non-perseverative errors. Lesion analyses were used to identify neurological regions and patterns of damage associated with jargon repetition. Results support the hypothesis that weak activation of target phonology results in neologistic production. Individuals with increasingly severe production deficits showed greater degrees of perseveration, and there was a clear association between the occurrence of perseverative and non-perseverative non-words, suggesting that both error types arise from a common mechanism. Lesion analyses converge with this interpretation and, additionally, implicate a contribution of impairments in analysis, and maintenance of auditory information to jargon repetition.Psycholinguistic models account for non-word errors in Jargon aphasia through a breakdown in phonological encoding, whereby activation is not effectively transferred from the lexical to the phonological level  analyses were used to explore the relationship between lesion distribution and a sensitive measure of jargon repetition. Results parallel those obtained in previous VLSM studies and revealed a significant relationship between jargon production and lesion in the posterior temporoparietal region. Four significant clusters were identified in the gray matter of the pSTG, SMG, and superior temporal sulcus (pSTS) and the white matter at the border of the superior temporal and inferior parietal lobes. These regions are commonly observed to activate during functional imaging studies of speech production and repetition, although the precise roles remain under discussion. The pSTG region identified included area Spt at the border between the temporal and parietal lobe. Area Spt is proposed to be a hub region supporting the translation of auditory into motor information . However, over 1/3 of the group displayed high lesion overlap in the STG or STS but not in the other region, therefore this pattern is not fully accounted for by a lesion to a single region.ROI analyses were used to explore whether combinations of lesions across the posterior temporal-parietal region were predictive of jargon repetition. Regression analysis found that combined lesions to the STG and STS region were associated with jargon production. This indicates that jargon is more likely to occur when impairments in phonological encoding and self-monitoring occur in combination. The STG and STS clusters were proximal and consequently there was a medium correlation between percentage lesion overlap in these clusters across the group  and sub-lexical . To fully utilize and maximize activation via lexical and sub lexical avenues, clinical tasks should include stimuli in multiple modalities, administering a written and verbal model of the stimuli and imagery where possible. Phonological awareness training could be adapted to include post phonological processing tasks—an area of comparative strength in this patient population , and a Stroke Association Senior Research Training Fellowship awarded to HR (TSA SRTF 2012/2).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.


This was, however, not the case. Instead, both unconsciously and consciously encoded memories influenced decisions: identical unconscious and conscious memories exerted the strongest bias on income decisions, while both incongruous and congruous  subliminally and supraliminally formed memories canceled each other out leaving no bias on decisions. Importantly, the increased decision bias following the formation of identical unconscious and conscious memories and the reduced decision bias following to the formation of non-identical memories were determined relative to a control condition, where conscious memory formation alone could influence decisions. In view of the much weaker representational strength of subliminally vs. supraliminally formed memories, their long-lasting impact on decision-making is noteworthy.Common wisdom and scientific evidence suggest that good decisions require conscious deliberation. But growing evidence demonstrates that not only conscious but also unconscious thoughts influence decision-making. Here, we hypothesize that both consciously and unconsciously acquired memories guide decisions. Our experiment measured the influence of subliminally and supraliminally presented information on delayed (30–40 min) decision-making. Participants were presented with subliminal pairs of faces and written occupations for unconscious encoding. Following a delay of 20 min, participants consciously (re-)encoded the same faces now presented supraliminally along with either the same written occupations, occupations congruous to the subliminally presented occupations (same wage-category), or incongruous occupations (opposite wage-category). To measure decision-making, participants viewed the same faces again (with occupations absent) and decided on the putative income of each person: low, low-average, high-average, or high. Participants were encouraged to decide spontaneously and intuitively. Hence, the decision task was an implicit or indirect test of relational memory. If conscious thought alone guided decisions (= H Decision-making is the cognitive process of collectively integrating relevant knowledge to determine the optimal option among several possibilities. Decision-making is considered to depend on conscious deliberation Simon,  because Prominent evidence for unconscious influences on decision processes is provided by priming studies, in which subliminal stimuli are presented as primes to alter the conscious processing of subsequently presented target stimuli  for unconscious encoding. Following a resting period of 20 min duration, participants consciously (re-) encoded the same faces presented supraliminally along with either the same written occupations, occupations congruous to the subliminally presented occupations (same wage-category), or incongruous occupations (opposite wage-category). Faces unconsciously encoded with consonant strings (control condition) were presented along with new occupations. Five minutes following the conscious acquisition of face-occupation associations, we assessed the influence of unconsciously and consciously formed memories on decision-making. Participants were presented with the same faces (no occupations) and were instructed to rate each person's putative income on a four-point scale: low, low-average, high-average, or high income. Importantly, participants were encouraged to respond spontaneously and intuitively when deciding about the income of a person. The decision-making task thus constituted an indirect (implicit) test of memory for subliminally (unconsciously) and supraliminally (consciously) presented face-occupation pairs. If conscious thought alone guided income decisions, supraliminal information should determine decision outcomes independently of its congruency with subliminal information. We hypothesized, however, that subliminally formed memories would interact with consciously formed memories to exert an influence on decision-making. To test this hypothesis, we measured the bias that consciously encoded face-occupation pairs exerted on income decisions and examined how this bias was modulated by subliminally presented occupations that were identical, congruous, or incongruous to the supraliminally presented occupations. We expected the decision bias provoked by supraliminal occupations to be increased, reduced, or unchanged depending on whether the same/congruous occupations, incongruous occupations, or no occupations (control condition) had been presented subliminally. Faces that were supraliminally shown as high-earning “manager” or low-earning “postman” should thus yield higher or lower income ratings, respectively, if they were subliminally encoded with the same or a congruous occupation instead of an occupation of the opposite wage-category  and faces paired with consonant strings (control condition) for unconscious relational encoding. Participants were ignorant of subliminal presentations. They performed an attention task that directed their focal attention to the screen center while subliminal faces and occupations were presented around the screen center  and then were instructed about the decision task (~3 min). To measure the common influence of unconsciously and consciously encoded information on decision-making, participants were again presented with all faces to decide on the income of each person . They were encouraged to respond spontaneously and intuitively and to listen to their gut feeling when deciding on the income. Following each income decision, participants were also asked to remember the actual occupation of the person.Once the decision task and recall test were completed, participants were questioned about the strategies they had used to rate the income of the depicted persons (open-ended question). This interview should reveal the actually employed strategies in the income rating task. Next, participants were queried on their expectancy and subjective awareness of masked stimuli during the experiment. This inquiry was succeeded by objective awareness tests in which masked stimulus presentations were immediately followed by forced-choice questions to test explicit stimulus visibility.The sequence of tasks and delay periods was designed to provide optimal conditions for studying the joint impact of unconsciously and consciously formed long-term memories on decision-making. The delay periods that followed the two encoding runs allowed us to demonstrate that both unconscious and conscious influences on decision-making depended on long-term memory. The duration of delays was chosen such that ~30 min passed between unconscious encoding and the decision task. This experiment replicates and extends a previous experiment . Participants were assigned to 3 groups that corresponded to the three experimental conditions “identical,” “congruous,” “incongruous”: identical N = 32 , congruous N = 29 , and incongruous N = 28 . Experimenters were aware of the group assignment. We used a cover story (“we study attention and person perception”) to keep participants naïve regarding subliminal presentations and the study rationale. This was necessary to render participants susceptible to subliminal information  or vertical (FV) line segment instead of a complete fixation cross (F+). Each trial of the attention task took 1 s and started with a fixation screen  that was followed by four visual noise masks (M) and two subliminal presentations (S) constituting the sequence F+/H/V–M–S–M–M–S–M. Fixation screens were presented for 233 ms, subliminal stimuli for 17 ms, and masks for 183 ms. Each face-occupation pair was presented 12 times in sequence during six adjacent attention trials spanning 6 s. During this time, one in six fixation screens featured a target (FH or FV) that participants had to respond to . Each participant encoded 40 subliminal faces, whereof 10 faces were combined with a low-wage occupation, another 10 faces with a high-wage occupation and the remaining 20 faces with a non-sense consonant string. Unconscious encoding took 4 min.We used an established forward and backward masking paradigm  relaxed fully and half were required to perform an undemanding acoustic vigilance task, namely to hit a button when hearing a tone played at random intervals of 15–25 s. This manipulation served the aim of finding out whether a deeper relaxation (no task vs. a vigilance task) would benefit memory consolidation. Self-reports in the no-task condition and the number of missed target tones in the vigilance task condition revealed that participants of both groups were equally inclined to fall asleep, suggesting that both conditions were very relaxing. The factor resting condition (no task/vigilance task) was therefore excluded from analyses but the pattern of findings remains the same if it is included.Following rest, participants were presented with supraliminal displays of the same 40 faces that had been flashed subliminally Figure . DependiWe assessed the influence of unconsciously and consciously acquired face-occupation pairs on income ratings regarding these same persons Figure . The preFollowing the experiment, participants were asked whether they had used a specific strategy to decide on the income (open-ended question). This interview should reveal the actually employed strategies in the income rating task.At the end of the experiment, we determined subjective awareness of subliminal stimuli. Participants were asked about any potential awareness of the study purpose and the presence of subliminal stimuli with a series of increasingly specific questions. Finally, we measured awareness of subliminal faces and subliminal occupation words using two objective forced-choice awareness tests  in which participants estimated the income each occupation would yield on a 5-point scale ranging from −2 (low) to +2 (high). The estimated income of high-wage occupations ranged from 0.17 to 1.60  with a mean of 0.88 (SD = 0.07). The income of low-wage occupations ranged from −0.42 to −1.61 with a mean of −0.92 (SD = 0.05). Assuming that average income ratings on a 5-point scale are normally distributed, we estimated that high-wage occupation words reflected the upper 41% and low-wage occupations the lower 34% of all possible wages. The total of 80 occupation words were assigned to 4 lists of 10 high-wage and 10 low-wage occupations, of which two lists contained congruous occupations required for the congruous condition in the experiment (A and A′ and B and B′). In the incongruous condition, high- and low-wage occupations were swapped between faces from subliminal to supraliminal encoding to induce semantic conflict. A and B lists were used in the experiment and awareness tests, respectively, in a counterbalanced fashion. Words in the four lists were matched regarding mean logarithmic word frequency  and character count. The 20 consonant strings required for the subliminal presentations in the control condition were built by randomly assembling the consonants contained in the selected occupation words. Consonant strings corresponded to occupation words regarding their character count. Supplementary Table We came up with 40 pairs of semantically congruous occupations—such as “director” and “manager” or “postman” and “messenger.” Twenty pairs corresponded to common high-wage occupations  and 20 pairs to common low-wage occupations . The typical wage of occupations was assessed in a pilot study (http://www.neurobs.com) on a standard Dell Notebook running Windows XP. A Digital Light Processing (DLP) projector BenQ SP831 projected the face-occupation pairs (occupation written below face) onto a screen in front of participants in a visual angle of 15° width with a resolution of 1,024 × 768 at a refresh rate of 60 Hz.Stimuli were presented using the software Presentation®  and High-/low-wage  and the between-subjects factor Congruency .The dependent variable in the decision task was the subjects' mean income rating  for the 10 faces of each of the four within-subject conditions, i.e., for faces consciously encoded with high- vs. low-wage occupations and unconsciously encoded with occupations vs. consonant strings. The dependent variable in the cued recall test was the percentage of correctly recalled occupations for each condition. Each dependent variable was used in a 2 × 2 × 3 repeated measures ANOVA with the two within-subject factors D(89) > 0.09, all p < 0.05], histograms, Q-Q plots, and skewness  and kurtosis  values indicated a normal distribution. We therefore used parametric tests to examine our hypotheses. Note, however, that the observed pattern of results (see Section Decision-Making) was replicated when we standardized the raw income ratings per participant (z-transformation) to obtain mean ratings that satisfied all criteria of normality ]. The pattern of results was also replicated when using non-parametric repeated measures ANOVAs as implemented in the function ezPerm of the R-package “ez”  > 0.21, all p < 0.001]. The low overall recall performance prevented a meaningful analysis and interpretation of the influence of subliminal information on the conscious recall of supraliminal information.We assessed normality of the two dependent variables separately for each of the four within-subject conditions, i.e., for faces consciously encoded with high- vs. low-wage occupations and unconsciously encoded with occupations vs. consonant strings. Although, Kolmogorov–Smirnov tests suggested that mean income ratings deviated from normality . The decision bias was marginal or even reversed following the encoding of congruous  and incongruous occupations , respectively. Although bias in the incongruous group was negative and did not significantly differ from zero, the Bayes factor of 0.44 suggests that the data were only 2:1 in favor of the null hypothesis, indicating merely anecdotal evidence for the absence of any bias. Importantly decision bias was stronger in the identical group compared to the congruous  and incongruous group . In the control condition , decisions were biased toward consciously encoded occupations . The change in decision bias between faces that had been presented subliminally with occupations vs. consonant strings failed to reach significance for each congruency group  = −2.26, p = 0.028, BF = 6.47]. Importantly, the change in decision bias between experimental and control stimuli differed significantly between the identical group and both the congruous and the incongruous groups  when making their income decision. These instructions should allow the penetrance of the influence of available unconscious, implicit knowledge on decision-making. Note however, that income decisions in all trials were immediately followed by a direct test of explicit memory: participants were required to remember the supraliminally presented occupation. This second task might have motivated participants to first try to retrieve the person's occupation and then to rate the income accordingly. This explicit-memory-informed strategy might reduce the impact of subliminally presented face-occupation pairs on decision-making. We therefore tried to determine the strategies that participants had used to form their decisions.Occupation/consonant, High-/low-wage, and Congruency on income decisions remained significant . This suggests that findings were not affected by the subset of participants who employed a memory-based decision strategy.We performed a qualitative analysis of participants' answers to the post-experimentally posed question of what strategy they had used to rate the income. 70.1% of participants reported having focused on aspects of the depicted person . 34.8% of participants explicitly mentioned that they had responded intuitively (note that responses were non-exclusive). Only 12.4% of participants reported that they had tried to remember the associated occupation first only to then deduce the income of the person. The qualitative pattern of results for the decision-making task did not change when these participants were excluded from the analysis: the critical three-way interaction between t(88) = 3.26, p = 0.002]. Hence, decisions were only weakly influenced by supraliminally seen occupations, which suggests that participants decided intuitively. Importantly, accuracy was much higher for faces for which participants succeeded vs. failed to remember the supraliminally presented occupation . Accuracy of income ratings  exceeded chance level only if occupations were remembered . This suggests that participants relied on the wage-category of supraliminally presented occupations only in trials, where encoding and later explicit retrieval were successful. However, the explicit retrieval may have been delayed to the second task, where it was demanded. This would reduce the influence of supraliminally formed memories at that moment to a preconscious effect that influenced intuitive decisions along with any unconscious effect due to subliminal encoding. The fact that decision accuracy was only 75% even when occupations were remembered speaks in favor of this assumption.To determine participants' decision strategy in a more objective way, we calculated their “decision accuracy,” i.e., the percentage of decisions that corresponded to the wage-category of the supraliminal occupation (% of ratings 3 and 4 for high- and 1 and 2 for low-wage occupations). We determined each participant's accuracy averaged across all faces as well as separately for faces for which occupation retrieval succeeded vs. failed. Classification accuracy averaged across all faces was low  but exceeded chance level of 50% , explicit recall performance , age , hit rate on the attention task given during unconscious encoding , awareness of subliminal stimuli (see Section Awareness Test), self-reported decision-making strategy , and decision accuracy (see Section Assessment of Decision-Making Strategy), i.e., the percentage of income decisions that corresponded to the wage-category of supraliminally seen occupations . This further suggests that participant groups were highly comparable.Furthermore, none of the following variables differed significantly between t(86) = 0.136, p = 0.892; occupation awareness test: mean accuracy = 49.11%, 95% CI , t(88) = −0.844, p = 0.401]. Note that non-significance does not necessarily mean that participants were truly unaware . It is possible that our tests were not sensitive enough to distinguish between the null and alternative hypothesis  = 0.993, p = 0.375, F = 0.092, p = 0.912, The inquiry into subjective awareness revealed that no participant had suspected subliminal stimuli or noticed faces, words, or fragments thereof between masks. The objective awareness tests corroborated this result. Performance on the objective face and occupation awareness test did not significantly deviate from the chance level of 50% ,  Dienes, . To asseDecision-making was influenced by both subliminally and supraliminally displayed combinations of faces and written occupations. Income decisions were biased toward the wage category of supraliminally presented occupations, and this bias was either increased or reduced by subliminal encoding, depending on whether subliminal and supraliminal occupations were identical or not. Identical subliminal and supraliminal occupations added up, yielding the strongest observed bias on income decisions, whereas non-identical  occupations canceled each other out, leaving no clearly discernible or even a numerically inverted decision bias  reduced the supraliminal influence on decisions. This might suggest that subliminal stimulation merely enhanced the perceptual fluency of distinct faces and word forms without leaving a relational memory trace. According to this perspective, an enhanced word and face fluency would facilitate the subsequent conscious encoding and retrieval of identical faces and words which would boost the supraliminal influence on income decisions. Changes in perceptual fluency due to subliminal stimulation might also account for the finding that the supraliminal influence on decision-making was impaired following subliminal presentation of faces paired with non-identical (congruous and incongruous) occupation words compared to consonant strings (control). If meaningful subliminal words undergo more cognitive processing than non-words, words might reduce the resources available for the processing of subliminal faces. Hence, subliminal faces might be better processed in the control than the experimental condition, which would facilitate encoding and retrieval of supraliminal faces and would enhance the supraliminal influence on income decisions. This scenario of perceptual priming thus accounts for both subliminal effects—the enhanced decision bias for identical face-occupation pairs and the reduced decision bias for non-identical pairs. This parsimonious interpretation of results contradicts, however, the well-established fact that one-trial subliminal priming is short-lived and limited to the prime-adjacent target  also helped participants distinguishing between supraliminally displayed correct and incorrect translations of the same foreign words , i.e., they still reflected different professional activities and were associated with different incomes (see Supplementary Table If unconscious relational learning rather than priming is assumed to account for our results, the question about the mechanism of subliminal influences on decision-making arises. Did subliminally and supraliminally formed memories exert independent effects on decision-making? Did subliminally formed memories modulate the subsequent encoding of supraliminal information? Were subliminally and supraliminally formed memories integrated into one single memory representation or two separate but semantically overlapping memory representations? The current experimental design and the present data cannot distinguish between these mechanisms. To unravel the precise nature of interactions between overlapping unconscious and conscious relational memories, sophisticated neuroimaging techniques in combination with multivariate pattern classifier analyses will be required (Chadwick et al., The scope of our findings may be limited by several aspects of the experimental design. First, the main factor of interest—congruency between subliminal and supraliminal information—was varied between rather than within subjects. This opens up for the possibility that individual differences in an unknown variable (e.g., the ability to recognize faces; Wilhelm et al., Our findings confirm the view that unconsciously processed information can be rapidly encoded into long-term memory (Gaillard et al., SR and KH developed the study concept and designed the experiment. SR collected and analyzed the data. KH and SR contributed to the final analyses and the interpretation of the data. BH wrote a first draft of the manuscript, KH and SR wrote the final report. All authors approved the final version of the manuscript for submission.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. The reviewer GH and handling Editor declared their shared affiliation.


Inverted Takotsubo cardiomyopathy, a less common variant in the spectrum of stress-induced cardiomyopathy, is increasingly being reported. This report describes an acute psychiatric illness leading to the onset of this syndrome. The patient presented here developed cardiogenic shock but successfully recovered with the use of a percutaneous left ventricular assist device. Stress-induced cardiomyopathy (SIC) has been characterized as a syndrome of transient left ventricular (LV) systolic dysfunction that occurs in the absence of obstructive coronary artery disease and that is provoked by physical or emotional distress. The less common SIC variant of inverted Takotsubo cardiomyopathy (ITC) with its unique contractile pattern of basal and mid-LV wall akinesis but normal apical movement is increasingly becoming recognized. While its clinical presentation is typically nonthreatening, requiring only supportive care, there are rare instances of ITC presenting catastrophically with cardiogenic shock. Such a unique case and its successful treatment are described herein.A 51-year-old female, who is originally from Italy, presented to the Emergency Room (ER) 24 hours after landing in the United States with increasing psychosis. Her history was only remarkable for paranoid schizophrenia, but she was highly functional at baseline. As per her family, she was hearing command hallucinations which did not improve with her usual antipsychotic medications, aripiprazole and haloperidol. Her haloperidol dosing was actually being tapered over the previous 4 months. She had no history of drug or alcohol use.In addition to increasing psychomotor agitation, her only other complaints were profound weakness and dyspnea. Her initial vital signs revealed a systolic blood pressure of 70 mmHg, a heart rate of 118 beats per minute, and oxygen saturations via pulse oximetry of 78% on room air. The chest X-ray revealed bilateral infiltrates concerning for congestive heart failure. She ultimately progressed to requiring mechanical ventilatory support and within the first few hours in the ER was necessitating escalating doses of 3 vasopressors. Her electrocardiogram showed precordial ST segment depressions , and theThe decision was made to proceed with left ventricular assist device (LVAD) support using an Impella 2.5 LP  device. Over the ensuing 24 hours following Impella LVAD placement, phenylephrine, norepinephrine, and vasopressin were all tapered off. Her hemodynamic indices showed steady improvement , and theInverted Takotsubo cardiomyopathy has been described as one of the 4 patterns of SIC, with the most predominant being the classical Takotsubo cardiomyopathy (CTC) with its characteristic LV apical-ballooning. With ITC, the pattern of contractile dysfunction is different from CTC and localized to the basal and mid-LV wall segments but the apical wall shows preserved contractility. Two case series, totaling 163 patients, have compared clinical features of ITC to CTC showing the former cohort as being comprised of younger individuals and universally having an identifiable stress trigger . InteresWe present here an original case of ITC complicated by cardiogenic shock that was precipitated by worsening psychosis in an individual with schizophrenia who was suboptimally treated with antipsychotic medications. While the patient herein fell within the age group and gender predilection expected for the typical ITC subject, she also demonstrated unusual features. For one, mental illness exacerbation, as an emotional source of stress, is a unique addition to the list of primarily physical stressors that have been described to bring forth ITC, such as neurologic insult and post-surgical/procedural state , 4. EmotWhile the specific pattern of SIC does not appear to carry prognostic implications, the in-hospital mortality for SIC is high at 8.7% based upon the largest case series of 208 patients . In mult


Activation of the renin-angiotensin system is a key adaptive response to hypovolemia aiming at maintaining mean arterial pressure, cardiac output, and organ perfusion. Angiotensin converting enzyme inhibitor (ACEI) therapy, widely prescribed to treat chronic hypertension, chronic heart disease, or diabetic nephropathy, blunts this adaptive mechanism . These tp < 0.001). Second, we showed that survival in the control and ACEI groups treated with icatibant was significantly higher  than in the ACEI group (36.4%) (p < 0.01). Of note, poor outcome was mostly observed in ACEI-treated mice while control untreated mice had good outcomes. Figure First, we confirmed our previous results regarding the beneficial effect of icatibant to prevent the deleterious hemodynamic consequences of ACEIs in shocked mice. In fact, the mean arterial blood pressures during shock in the ACEI group were significantly lower compared to the control and ACEI group treated with icatibant (25  mmHg vs 38  mmHg and 36  mmHg, respectively; The results of this proof-of-concept study suggest that very early administration of icatibant may limit the consequences of hemorrhagic shock in patients treated with ACEIs before resuscitation could be initiated. Further research is needed with respect to dose and timing of icatibant administration and comparison with conventional vasopressors.


Optical coherence tomography (OCT) has emerged as a powerful intravascular imaging modality in recent years. The introduction of frequency-domain OCT has simplified the procedure and enabled its safe utilisation in different clinical settings including acute coronary syndromes, where it can determine the mechanism of plaque disruption, thrombus burden, and guide percutaneous coronary intervention. In patients presenting with stent failure (stent thrombosis and instent restenosis), OCT can also be very useful in determining the underlying mechanism and guiding therapy thereafter. This article aims to review the role of OCT in acute coronary syndromes as well as its potential clinical applications. NIRS currently remains an investigational tool with very limited use in daily clinical practice, while IVPA catheters that can be used safely in-vivo are still under development.21 On the other hand, both NIRS and IVPA offer superb detection of lipid type and plaque composition, with IVPA being capable of identifying active macrophages and determining matrix metalloproteinase activity. However, NIRS lacks depth resolution and is unable to define the exact location or amount of the lipid pool, and IVPA has very limited ability to define the anatomical details of the arterial wall. This has led to the current perception of both modalities as hybrid technologies that require superimposition on IVUS images.19,20Compared to coronary angiography, IVUS and CAS have higher spatial resolution (150–200 µm and 50 µm respectively). However, at this resolution, characterization of plaque morphology and fibrous cap integrity remains challenging.in-vivo characterization of coronary plaques and the mechanism of their disruption.Introduction of OCT as a novel technique for intravascular imaging is frequently considered the real beginning for accurate 22–24 Light in OCT systems comes from ultra-short pulsed lasers capable of emitting a wide range of wavelengths over ∼100 nm. The emitted light beam is then broken into two arms: one goes to the item of interest, and a reference arm going to a semi-reflective mirror. During processing, combination of reflected light from both beams gives an interference pattern if light has travelled similar optical distance. Reflectivity profile of the item of interest can be made by scanning the mirror of the reference light beam, where structures reflecting more light create more interference and so forth, while light outside the short coherence length will not cause interference. The obtained reflectivity profile (the A-scan) gives details about location and spatial dimensions of the structure(s) of interest. Subsequently, a series of those acquired A-scans are laterally combined to obtain a cross-sectional tomograph (the B-scan).24–27 This is the main principle behind the time-domain (TD) OCT . It employs near infra-red light rays and depends on interferometric principles.in-vivo measurement of the thickness of fibrous cap is not possible by any other intracoronary imaging modality.31 Compared to IVUS, OCT is significantly superior in its ability to detect luminal and mural thrombi, discriminate between RBC-rich red thrombi (high backscattering and high beam attenuation) and platelet-rich white thrombi (low backscattering and low attenuation)  which enables accurate characterization of the plaque content with the ability to differentiate between fibrous, lipid and calcific plaques . OCT alsnuation) . One of p = 0.021), plaque erosion  and coronary thrombi 31 31 . 10.771725 Activated macrophages are believed to correlate with the degree of inflammation in the plaque cap especially with the release of matrix metallo-proteinases (MMP) that accelerate cap degradation and thus rupture.33–35 In a study to validate OCT detection of macrophages against pathology, OCT was found to be 100% sensitive and specific in identifying macrophages in fibrous caps that had >10% CD68 staining.36Owing to its superb image quality, cumulative knowledge about the OCT features of ruptured plaques and eroded plaques had accumulated over the past few years. Ruptured plaques are typically characterized by a large lipid core that appears as signal-poor regions with poorly defined borders and rapid signal drop off. The fibrous cap separating the plaque core from the arterial lumen is typically thin. The term “thin cap fibro-atheroma (TCFA)” is used to describe plaques with a fibrous cap that is <65 µm thick and a lipid pool extending through 2 or more quadrants, and is considered the primary substrate for plaque rupture . Macroph24,25,37 Neovascularization is a substrate for intra-plaque hemorrhage (which can cause sudden increase in plaque size), and is strongly associated with local inflammation and plaque vulnerability. ” rather than plaque erosion is preferable.40On the other hand, eroded plaques usually are predominantly fibrous, with minimal lipid content. Compared to ruptured plaques, eroded plaques are typically characterized by relatively thicker fibrous caps. The higher OCT light signal of such fibrotic plaques is usually correlated with the high proteoglycan content. Macrophages and neovascularization are only sparsely detected in eroded plaques. It is important to recognize that the current resolution of OCT is still insufficient to visualize endothelial cells and detect such denudation. For this reason, the term “In-vivo identification of erosion-prone plaques before they get disrupted and cause ACS remains a great challenge. To the best of our knowledge, there are currently no markers that can predict erosion of a stable fibrotic, thick-capped plaque. This means that at least one third of catastrophic acute coronary events are impossible to predict despite the major advances in coronary imaging, which remains an important area for future research.12 In a study involving 72 consecutive anterior AMI patients, MIs induced by plaque rupture were found to cause more myocardial damage and poorer functional recovery compared to those caused by plaque erosions, even after successful primary angioplasty.41 In another study, culprit plaques with ruptured fibrous caps (RFC) were associated with larger infarct size than those with intact fibrous cap (IFC).42Data from small observational studies suggest that culprit plaque morphology could have a strong impact on the clinical outcomes of AMI patients.13 The other 19 patients were treated in the conventional manner . After a follow up period of >2 years, no patients in the lone thrombectomy group and only one patient in the conventional therapy group required repeat revascularization. These interesting results warrant further research into the possible advantages and disadvantages of adopting a treatment strategy that is tailored to the plaque phenotype and severity of residual luminal stenosis.9,13Despite these differences, acute myocardial infarctions are currently treated in a standardized fashion regardless of the underlying mechanism, simply because they all look alike in coronary angiography. The primary treatment objective in patients with STEMI is rapid restoration of TIMI III flow in the culprit vessel; usually (and preferably) achieved with stenting. It is currently unclear whether information about the plaque phenotype can/should alter this strategy. Patients with intact fibrous caps and non-obstructive lesions after thrombus aspiration (or thrombolysis), in particular, represent a distinct group of patients in whom a no-stent strategy may be appealing. This hypothesis was tested in a small study by Prati et al. where – at the discretion of the surgeon – 12 out of 31 patients presenting with acute STEMI and intact fibrous caps with non-obstructive underlying plaques were treated by lone thrombus aspiration, thus sparing patients the added – albeit small – risk of a stent.43From a technical perspective, OCT can be very helpful in planning and optimizing PCI results. Factors such as stent diameter and length, landing zones, lesion characteristics requiring special preparation , stent under-expansion, malapposition, and edge dissection are amongst the parameters that can be readily identified by OCT. In ILUMIEN I study which enrolled 418 patients, pre-stenting OCT imaging modified PCI strategy in 55% of cases. After PCI was completed, further intervention was deemed necessary by the operator after OCT imaging in 25% of cases .p = 0.005). Post-procedure OCT imaging revealed under-expansion in 42%, stent malapposition in 32%, stent edge dissection in 37.5% of cases. OCT use was associated with the use of more contrast, and longer procedural times, but the rates of acute kidney injury and overall procedural complications were identical both groups.44 Whether such optimization translates into better outcomes remains to be tested in larger trials with hard clinical endpoints.In another multicenter study randomizing 240 NSTE-ACS patients to OCT versus angiography-guided intervention, OCT changed procedural strategy in 50% of cases in the OCT group. Post procedural FFR values were significantly higher in the OCT-guided group , isolated uncovered struts, and evaginations related to late positive remodeling .modeling .51–5347,48,54 OCT is able to identify the underlying mechanism in the vast majority of instances, and is therefore a perfect diagnostic tool to guide therapy in such critical situations.55The treatment of patients presenting with stent thrombosis can be substantially different depending on the underlying mechanism; e.g., balloon dilatation with gross underexpansion, stent-in-stent for neoatherosclerosis, or thrombus aspiration followed by prolonged dual antiplatelet therapy (frequently with a 24-48 hour infusion of IV GP IIb/IIIa inhibitors in the acute phase) with isolated uncovered struts.54 Contrary to bare metal stents where the main mechanism for restenosis is neointimal hyperplasia, the predominant mechanism for restenosis with drug eluting stents is accelerated neoatherosclerosis. Stent under-expansion - defined as minimum stent area <70% of reference luminal area - has been shown to be a strong predictor of stent failure (instent restenosis or stent thrombosis).56–59The incidence of instent restenosis has declined substantially with the introduction of drug eluting stents. The rates of angiographic and clinically relevant restenosis with the newer generation drug eluting stents are 12% and 5% respectively.60 Because of its 10x-to-15x higher resolution compared to IVUS, OCT is progressively becoming the modality of choice for this indication.46,55,57The European Society of cardiology guidelines for revascularization has therefore recommended the use of IVUS or OCT in the assessment and management of stent failure as class IIa.OCT has emerged as an exciting and powerful intravascular imaging modality. With the introduction of FD-OCT, image acquisition has become a simple and safe task that can be accomplished within a few minutes. Because of its high resolution, OCT is able to provide immediate in-vivo information about the mechanism of plaque disruption, mode of stent failure, and can guide interventions - particularly in complex anatomies. Incorporating the multitude of information provided by OCT in day-to-day decision making, understanding its impact on clinical outcomes, and determining its cost effectiveness in different scenarios remain to be tested in larger-scale clinical studies.


Traumatic pseudoaneurysms of the middle meningeal artery (MMA) represent less than 1% of all intracranial aneurysms, and occur mostly in association with temporal bone fractures following head trauma. Given the unknown natural history, it is unclear whether they should be treated. We present two cases of MMA pseudoaneurysms discovered during trauma workups. The first patient is a 44-year-old male with severe traumatic brain injury (TBI) following a motor vehicle accident. The patient was found to have two right-sided middle meningeal artery pseudoaneurysms that were treated successfully with Onyx®  embolization. The second patient is a 56-year-old male that sustained a severe TBI and skull fracture following a motorcycle collision. Angiography demonstrated an unruptured right MMA aneurysm, which was also treated successfully with Onyx embolization. MMA pseudoaneurysms occur rarely in the setting of severe traumatic injuries. In select patients, treatment by an experienced neuro-interventionalist can prevent highly morbid future intracranial hemorrhages with minimal risk of complications. Traumatic pseudoaneurysms of the middle meningeal artery (MMA) are rare and potentially serious complications of traumatic brain injuries . DelayedThe first patient is a 44-year-old male, involved in a motor vehicle accident, who sustained a severe traumatic brain injury resulting in an acute subdural hematoma, intraparenchymal and subarachnoid hemorrhages. An emergent decompressive craniotomy was performed at a community hospital and no specific vascular lesions of the MMA were appreciated intra-operatively. Consequently, the patient was referred to our tertiary care center for evaluation of vascular injuries discovered on computed tomography (CT)e angiography. Cerebral angiography revealed two traumatic pseudoaneurysms of the right MMA. The decision was made to treat the MMA aneurysms using endovascular Onyx 18 embolization per standard technique, with excellent results. The second patient is a 56-year-old male that sustained a frontal bone fracture with severe cerebral edema following a motorcycle collision. Field resuscitation and intubation were completed prior to arrival to the emergency department. Initial survey showed a large scalp laceration, periorbital ecchymosis, scattered chest and abdominal abrasions, multiple orthopedic fractures, which required surgical fixation as well as extensive intra-abdominal injuries, which required a laparotomy and repair. An external ventriculostomy drain was placed for cerebrospinal fluid diversion and intracranial pressure monitoring. Critical care management was done for eight days and the patient was extubated. Follow-up CT Angiography showed bilateral carotid artery dissection and various other traumatic vascular lesions that were treated according to standard guidelines. Follow-up angiography performed one year later revealed a right-sided traumatic unruptured middle meningeal artery aneurysm in addition to persistent right-sided internal carotid artery (ICA) dissection with an enlarging pseudoaneurysm. The decision was made to treat both lesions concurrently. The right MMA aneurysm was treated with transcatheter embolization using Onyx 34, with excellent angiographic results. The ICA pseudoaneurysm was treated using overlapping pipeline embolization. Figure Neither patient experienced any intraoperative or immediate postoperative complications. The first patient remained mechanically ventilated in the perioperative period and his respiratory status steadily improved. He was discharged several days later to an acute rehabilitation facility. There was no recurrence of any of the lesions at 10-month follow-up angiography. The second patient tolerated the procedure well and was discharged home the next day in stable condition. Follow-up angiography one year later showed no recurrence of lesions post-embolization.Pseudoaneurysms of the middle meningeal artery are a rare complication of severe traumatic brain injury, where 70-90% of all cases occur in the setting of a temporal bone fracture along the course of the artery. The remainder of the cases occurs in the setting of severe traumatic brain injury independent of fracture sites, or as iatrogenic lesions . True ceIn the past decade, endovascular therapy has emerged as a safe and effective alternative to open surgery. Various endovascular techniques have been successfully used to treat traumatic pseudoaneurysms including coiling, liquid embolization, and stenting , 10. EmbUnruptured traumatic pseudoaneurysms of the middle meningeal artery are rare but potentially devastating lesions associated with severe traumatic brain injury. Although their natural history is largely unknown, treatment of these aneurysms should be considered for the prevention of severe morbidity and mortality associated with their potential rupture. When performed by an experienced neuro-interventionalist, Onyx embolization provides a safe, effective, and durable treatment option for these lesions.


Decision-making on resuming oral anticoagulant (OAC) after intracerebral hemorrhage (ICH) evokes significant debate among clinicians. Such patients have been excluded from randomized clinical trials. This review article provides a comprehensive summary of the evidence on anticoagulation resumption after ICH.OAC resumption does not increase the risk of recurrent ICH and can also reduce the risk of all-cause mortality. OAC cessation exposes patients to a significantly higher risk of thromboembolism, which could be reduced by resumption. The optimal timing of anticoagulation resumption after ICH is still unknown. Both early (< 2 weeks) and late (> 4 weeks) resumption should be reached only after very careful assessment of risks for ICH recurrence and thromboembolism. The introduction of new oral anticoagulants and other interventions, such as left atrial appendage closure, has provided some patients with more alternatives.Given the lack of high-quality evidence to guide clinical decision-making, clinicians must carefully balance the risks of thromboembolism and recurrent ICH in individual patients. We propose a management approach which would facilitate the decision-making process on whether anticoagulation is appropriate, as well as when and how to restart anticoagulation after ICH. Intracerebral hemorrhage (ICH) is associated with a high risk of mortality and stroke, as well as recurrent ICH •. Of notAnticoagulation is supported by Class I guidelines for patients with atrial fibrillation (AF) and high risk of ischemic stroke (IS) and systemic embolism (SE), mechanical prosthetic valves, or those at high risk of deep venous thrombosis (DVT) and pulmonary embolism (PE). Decision-making on resuming anticoagulation after ICH evokes significant debate among clinicians. Such patients have been excluded from randomized clinical trials of stroke prevention in AF. As with decision-making with anticoagulation therapy in any patient, carefully balancing the risks of thromboembolism and bleeding, especially the risk of recurrent ICH, is the primary concern when making this decision in patients who have experienced a recent ICH . The lacAt a simplistic level, we propose three steps to make such a decision Fig. : first, Nevertheless, this approach towards decision-making could also be difficult in clinical practice, because of the lack of risk evaluation tools for complicated clinical conditions, the insufficient evidence from the randomized clinical trials, and the existence of shared risk factors for both thromboembolism and hemorrhage.This review article aims to provide an up-to-date overview regarding the pros and cons of restarting anticoagulation after ICH. We also propose a management approach which would facilitate the decision-making process on whether anticoagulation is appropriate, as well as when and how to restart anticoagulation after ICH.Current guidelines recommended that the decision on restarting OAC should be taken by a multidisciplinary team of stroke physicians, neurologists, cardiologists, neuroradiologists, and neurosurgeons . This den = 267), warfarin resumption was associated with an annual ICH recurrence rate of 2.56% . In. In77]. p < 0.01, respectively) [In patients treated with warfarin, well-controlled international normalized range (INR) was related to less major bleeding and thromboembolism compared with those without OAC (ctively) . Thus, ictively) .Given the observational nature of the studies regarding OAC resumption after ICH, there is uncertainty regarding resumption of OAC therapy and its timing. The limited high-quality evidence regarding this issue leads to limited evidence-based guidelines and inconsistency in clinical practice. There are randomized clinical trials ongoing, which may provide more information in the future . For exa


With an estimated prevalence of 296 to 627 per 100.000 men, male urethral stricture disease imposes a significant burden on the health care system -5. WhileA 25-year meta-analysis of the contemporary EPA urethroplasty literature demonstrates a uniformly high level of success >90%) for EPA of bulbar strictures , superio0% for EPUnfortunately, DVIU remains the most frequently used treatment for anterior urethral stricture, despite its inferior results compared to urethroplasty , 3, 13. Our EPA technique emphasizes complete scar excision, while maintaining the vascular integrity of the spongiosum. Though EPA failure is rare, it is our belief that many failures are caused by inadequate proximal urethral dissection, leading to incomplete resection of diseased tissue. In order to optimize the proximal dissection, we utilize antegrade instrumentation via a suprapubic tract (if present), or retrograde placement of a guidewire, which aides in the identification of the proximal lumen. With control and adequate visualization of the proximal urethral stump, the strictured mucosa and associated spongiofibrosis is completely excised, leaving well-vascularized urethral tissue for a healthy anastomosis. We advocate performing a two-layer ventral anastomosis after urethral transection for precise re-approximation of the robust vasculature of the ventral spongiosum. We avoid additional maneuvers such as corporal splitting whenever possible, as they may further compromise antegrade and retrograde corporal blood flow to the urethra. Instead, we facilitate urethral lengthening by aggressively mobilizing the urethra from its ventral crotal attachments while preserving dorsal perforating vasculature as much as possible. Our results underscore the value of incorporating these various alternative technical measures to avoid urethral ischemia.Adequate urethral length after transection is essential for a tension-free anastomotic repair. Despite traditional recommendations that the EPA technique be limited to strictures 2cm or less long , our expContemporary analysis of urethroplasty in the United States reveals a low post-operative complication rate of 6.6% . CompareThe complication of erectile dysfunction after anterior urethroplasty is a controversial topic with many divergent opinions . OverallExcision and primary anastomotic urethroplasty demonstrates the highest long-term success rate among available techniques for bulbar urethral strictures. The overall complications of EPA are low, and erectile dysfunction, if encountered, generally resolves after six months of recovery. EPA should be considered the gold standard in treatment of bulbar strictures.