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The notion focus affinity refers to the likelihood that a grammatical role (e.g., subject, object) is the narrow focus of a sentence. There is evidence that such differences exist at the level of distributional data. For example, subjects are less often focal and more often topical as compared to direct objects. However, it is not obvious whether focus affinity is genuinely related to grammatical roles. Focus affinity could be an epiphenomenon of various other linguistic and pragmatic processes or their interactions (e.g., direct objects are more often indefinite, less often animate, more often new than subjects). In our controlled experimental study, we investigate the focus affinity of three adjunct types (instruments, locatives, depictive secondary predicates) in Spanish and provide evidence that these grammatical roles indeed differ with respect to focus affinity. Depictives show the highest degree of focus affinity, followed by instruments and finally locatives. These effects are robust and stable even if we account for a number of possible alternative explanations. Thus, we suggest that focus affinity is a property sufficiently closely associated with grammatical roles to justify more attention both in theoretical linguistic and psycholinguistic literature.

Dementia with Lewy bodies (DLB) is epitomized by the pathognomonic manifestation of α-synuclein-laden Lewy bodies within selectively vulnerable neurons in the brain. By virtue of prion-like inheritance, the α-synuclein protein inexorably undergoes extensive conformational metamorphoses and culminate in the form of fibrillar polymorphs, instigating calamitous damage to the brain’s neuropsychological networks. This epiphenomenon is nebulous, however, by lingering uncertainty over the quasi “pathogenic” behavior of α-synuclein conformers in DLB pathobiology. Despite numerous attempts, a monolithic “α-synuclein” paradigm that is able to untangle the enigma enshrouding the clinicopathological spectrum of DLB has failed to emanate. In this article, we review conceptual frameworks of α-synuclein dependent cell-autonomous and non-autonomous mechanisms that are likely to facilitate the transneuronal spread of degeneration through the neuraxis. In particular, we describe how the progressive demise of susceptible neurons may evolve from cellular derangements perpetrated by α-synuclein misfolding and aggregation. Where pertinent, we show how these bona fide mechanisms may mutually accentuate α-synuclein-mediated neurodegeneration in the DLB brain.

The article is devoted to the subjective assessment of the Belarusian student youth’s life quality, considered in the context of the implementation of the state youth policy. The concept of life quality is considered within the framework of the subjective approach that attributes to the individual a fundamental role in social life. Measuring of the subjective quality means making use of the index method, designed to reduce social information to a single indicator, regardless of the total number of the object’s indicators. Within the framework of the developed technique for measuring life quality, calculated were individual (particular) indices that describe the characteristics of the student youth’s public consciousness to certain aspects of life quality, as well as the integral index of life quality and aggregate index of the standard of living. The indicators of life quality are as follows: subjective assessment of the material standard of living, subjective assessment of health, accessibility and quality of medical care, subjective assessment of accessibility and quality of education, subjective assessment of accessibility and quality of social infrastructure, subjective assessment of the state of ecological environment, subjective assessment of quality of social environment and satisfaction with quality of life. The given technique enables to diagnose various aspects of the students’ life and identify weaknesses in implementing particular areas of the state youth policy. It was used to measure the quality of life of the Belarus State Economic University students who were the object of the study carried out in two stages – in 2019 and 2020. A comparative analysis of the data showed that the respondents demonstrated a high degree of satisfaction with both objective living conditions and subjective perception of the degree of satisfaction with their needs. The analysis of the general indices of subjective quality of life in retrospective, current and prospective aspects testifies to the respondents’ social optimism since their values do not decrease and in some cases increase. The only exception is the value of the index of subjective assessment of social environment quality: its decrease in 2020 indicates that the respondents fixed a negative impact on their lives and life of the whole society, which was caused by the socio-economic consequences of the COVID-19 pandemic and the political crisis in the country. Although social optimism is weakly expressed, the given epiphenomenon can be explained by the fact that the young people consider all indicators of life quality as virtually equal that is both conditioned by the results of socialisation and logic of a modern society’s development.

Primary progressive apraxia of speech (PPAOS) is a progressive disorder impairing the motor speech act leaving linguistic function unattained. Although apraxia of speech frequently co-occurs with other neurodegenerative conditions, PPAOS defines a clinical syndrome where apraxia of speech is the sole or prominent symptom for much of the disease’s natural history. Mounting evidence is beginning to fully define this disease as the epiphenomenon of 4-repeat (4R) tau pathology although other pathologic signatures have been reported. Indeed, PPAOS patients generally present a parkinsonian syndrome late into their natural history mostly qualifying for either corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP). This is starting to be reflected in diagnostic criteria for PSP, namely, in the PSP speech and language (SL) subcategory; however, this inclusion is not reflected for CBS. Here, we present a single case of a patient with PPAOS and her clinical follow-up lasting 6 years, from the time she sought our attention to her death which occurred 8 years into the disease. PPAOS was the only and prominent symptom for most of the illness with extrapyramidal signs overtly presenting in the last months of its course. Clinical evaluation, imaging, genetic, and cerebrospinal fluid biomarkers all pointed toward an underlying CBD pathology, albeit the eventual anatomopathological confirmation was not performed. Had her clinical course been more suggestive of PSP, she would have qualified for criteria as PSP-SL. Our case therefore suggests the hypothetic need to discuss the broadening of the existing CBS criteria to encompass isolated PPAOS.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19), and has caused more than 80 million infections and 1.7 million deaths worldwide. Although it is primarily a respiratory virus, SARS-CoV-2 also has extra-pulmonary effects. Pancreatic injury and cases of acute pancreatitis (AP) have been recognized and attributed to SARS-CoV-2, but the mechanisms of pancreatic injury are still a subject of debate. There is also controversy on whether SARS-CoV-2 can cause AP or if it is an epiphenomenon. Aim To review and to explore the relationship between SARS-CoV-2 infection and AP, and to provide an overview of the existing literature on possible mechanisms of SARS-CoV-2-induced pancreatic lesion. Methods A systematic review was conducted in accordance with PRISMA guidelines for papers on SARS-CoV-2 infection and AP. A narrative review on possible mechanisms of SARS-CoV-2-induced pancreatic lesion was also performed. Results A literature review revealed a growing body of evidence on SARS-CoV-2-induced pancreatic lesions including the mechanisms of direct virus-mediated injury, systemic inflammatory response and circulating pro-inflammatory interleukins, virus-induced lipotoxicity, and drug-induced injury. A systematic review of the literature revealed 22 cases of AP in COVID-19 patients. However, limitations of the reported cases make it difficult to establish a causal relationship between SARS-CoV-2 infection and AP. All of the studies agreed on special monitoring and surveillance of this subset of patients due to the still unknown clinical progression, therapeutic implications, and prognosis. Conclusion AP should be considered in COVID-19 patients, especially in those exhibiting abdominal pain and systematic, and complete reporting of these cases should be general practice. However, there is still insufficient evidence showing that COVID-19 can cause AP or negatively impact prognosis. Additional studies are needed to clarify the relationship between these two entities and their theragnostic significance.

Coronavirus 2019 disease (COVID-19) is associated with coagulation dysfunction that predisposes patients to an increased risk for both arterial (ATE) and venous thromboembolism (VTE) and consequent poor prognosis; in particular, the incidence of ATE and VTE in critically ill COVID-19 patients can reach 5% and 31%, respectively. The mechanism of thrombosis in COVID-19 patients is complex and still not completely clear. Recent literature suggests a link between the presence of antiphospholipid antibodies (aPLs) and thromboembolism in COVID-19 patients. However, it remains uncertain whether aPLs are an epiphenomenon or are involved in the pathogenesis of the disease.

Aphantasia is the condition of reduced or absent voluntary imagery. So far, behavioural differences between aphantasics and non-aphantasics have hardly been studied as the base rate of those affected is quite low. The aim of the study was to examine if attentional guidance in aphantasics is impaired by their lack of visual imagery. In two visual search tasks, an already established one by Moriya (Attention, Perception, & Psychophysics, 80(5), 1127-1142, 2018) and a newly developed one, we examined whether aphantasics are primed less by their visual imagery than non-aphantasics. The sample in Study 1 consisted of 531 and the sample in Study 2 consisted of 325 age-matched pairs of aphantasics and non-aphantasics. Moriya’s Task was not capable of showing the expected effect, whereas the new developed task was. These results could mainly be attributed to different task characteristics. Therefore, a lack of attentional guidance through visual imagery in aphantasics can be assumed and interpreted as new evidence in the imagery debate, showing that mental images actually influence information processing and are not merely epiphenomena of propositional processing. Supplementary Information The online version contains supplementary material available at 10.3758/s13414-021-02307-z.

The coronavirus disease 2019 (COVID-19) is the largest public health emergency in recent times. A significant number of patients develop a severe form of COVID-19 characterized by coagulopathy, organ failure, and elevated mortality. In addition, an unusually high frequency of antiphospholipid antibodies (aPLs) has been found in patients with COVID-19. These clinical and serological manifestations closely resemble those seen in the antiphospholipid syndrome (APS), especially in its catastrophic form, suggesting a role of aPLs in immune-associated coagulopathy. However, government bodies such as the American Society of Hematology have spoken out against the systematic search for aPLs in patients with COVID-19. In an attempt to bridge the gap on this hot topic, we conducted a comprehensive review of currently available cohort studies and case series systematically evaluating aPLs in COVID-19 patients. In this Perspective, we seek to identify both the frequency and the type of aPLs found in patients with COVID-19, as well as the potential association of these aPLs with vascular thrombosis and other distinctive characteristics of COVID-19. Furthermore, we investigated whether there is evidence that allows us to define the occurrence of aPLs in COVID-19 as an epiphenomenon, as has been observed in other systemic viral infections, or as antibodies against self-antigens bearing hallmarks that suggest a pathogenic role in immune-mediated thrombosis. Defining whether aPLs represent an epiphenomenon or they are actually involved in hemostatic abnormalities of COVID-19 is crucial both for uncovering novel mechanisms of immune-mediated thrombosis and for identifying potential prognostic biomarkers in this devastating disease.

Conduction disorders and arrhythmias remain difficult to treat and are increasingly prevalent owing to the increasing age and body mass of the general population, because both are risk factors for arrhythmia. Many of the underlying conditions that give rise to arrhythmia - including atrial fibrillation and ventricular arrhythmia, which frequently occur in patients with acute myocardial ischaemia or heart failure - can have an inflammatory component. In the past, inflammation was viewed mostly as an epiphenomenon associated with arrhythmia; however, the recently discovered inflammatory and non-canonical functions of cardiac immune cells indicate that leukocytes can be arrhythmogenic either by altering tissue composition or by interacting with cardiomyocytes; for example, by changing their phenotype or perhaps even by directly interfering with conduction. In this Review, we discuss the electrophysiological properties of leukocytes and how these cells relate to conduction in the heart. Given the thematic parallels, we also summarize the interactions between immune cells and neural systems that influence information transfer, extrapolating findings from the field of neuroscience to the heart and defining common themes. We aim to bridge the knowledge gap between electrophysiology and immunology, to promote conceptual connections between these two fields and to explore promising opportunities for future research.

This paper reports a new kind of tone polarity, where the phenomenon is seen in a language with four level tones, Tenyidie (also known as Angami). I show that the polarity is in the features of the tones, i.e. at a subtonal level. The data also provide evidence that tones themselves can be broken down into smaller features. Furthermore, I demonstrate that the polarity pattern observed in the language is an epiphenomenon, a reflex of the Obligatory Contour Principle, not a phonological process in its own right. I show this with the help of a new type of tonal representation. Theoretical discussions of tone polarity have so far been almost entirely restricted to African tone systems, and to languages with just two tones. This paper brings into the discussion a Tibeto-Burman language with four tones.

Beyond being epiphenomenon of shared epidemiological factors, the integration of Osteoporosis (OP) with Cardiovascular Disease (CVD) - termed “calcification paradox” - reflects a continuum of aberrant cardiometabolic status. The present review provides background knowledge on “calcification paradox”, focusing on the endocrine aspect of vasculature orchestrated by the osteoblastic molecular fingerprint of vascular cells, acquired via imbalance among established modulators of mineralization. Osteoprotegerin (OPG), the well-established osteoprotective cytokine, has recently been shown to exert a vessel-modifying role. Prompted by this notion, the present review interrogates OPG as the potential missing link between OP and CVD. However, so far, the confirmation of this hypothesis is hindered by the equivocal role of OPG in CVD, being both proatherosclerotic and antiatherosclerotic. Further research is needed to illuminate whether OPG could be a biomarker of the “calcification paradox”. Moreover, the present review brings into prominence the dual role of statins - cardioprotective and osteoprotective - as a potential illustration of the integration of CVD with OP. Considering that the statins-induced modulation of OPG is central to the statins-driven osteoprotective signalling, statins could be suggested as an illustration of the role of OPG in the bone/vessels crosstalk, if further studies consolidate the contribution of OPG to the cardioprotective role of statins. Another outstanding issue that merits further evaluation is the inconsistency of the osteoprotective role of statins. Further understanding of the varying bone-modifying role of statins, likely attributed to the unique profile of different classes of statins defined by distinct physicochemical characteristics, may yield tangible benefits for treating simultaneously OP and CVD.

The authors describe two approaches to the classification of insomnia - one was presented in earlier works, the other is currently accepted in the medical scientific community. The following three models of the etiopathogenesis of insomnia are considered: a 3-P model that identifies predisposing, precipitating, and perpetuating factors as the key ones in the development and chronicity of insomnia; a hyperarousal model that defines psychological and neurobiological hyperarousal as a factor contributing to the development of insomnia; and a sleep reactivity to stress model, according to which the pronounced premorbid sleep reactivity to stress increases the risk of developing insomnia. Hyperarousal and sleep reactivity to stress are supposed to be autonomous yet equally predisposing factors of insomnia which act reciprocally and can simultaneously contribute to the development of stress-induced insomnia. It is noteworthy that the clinical usefulness of the sleep reactivity to stress model can extend beyond the preliminary assessment of the risk of insomnia development and be used for screening patients in remission who may be at increased risk of recurrence in future and should receive supportive treatment to minimise this risk. At present, it remains unclear whether hyperarousal is the core of the disorder, its cause, risk factor, or epiphenomenon. Further investigations are required to clarify the psychological and biological basis of chronic insomnia and confirm its current theoretical and conceptual models.

This article argues that we have to address the generative potentiality of violence in drawing a rigorous depiction of identity-related violence. Works on identity-related violence often explain the violence as culminating from the perpetrators’ sense of identity. Even though to some extent such an explanation sheds light on the perpetrators’ motivation, it is prone to reducing the actuality of violence to a mere epiphenomenon. In actual circumstances of conflict and purging, the frightening and engrossing horror of violence convincingly imposes the antagonistic discursive boundary of self and other on the involved subject’s senses. As an efficacious embodiment of identity, violence also entails the subjects perpetually performing it in a way that reinforces the facticity of the fictive categories of identity and eventually escalates the violence. This article makes its case through an examination of two incidents of massive violence in Indonesia: the 1966-69 communists purging and the 1999-2002 ethno-religious conflict in Maluku.

This article examines wh-questions with conjunction, i.e. ATB-questions and wh&wh-questions, both of which have been analyzed as elliptical structures in a few different languages. Based on the morphosyntactic and semantic properties of these structures in Greek the article argues against an analysis employing ellipsis. Moreover, it proposes that these complex wh-structures involve multidominance. Specifically, one or more syntactic objects are remerged with Parallel Merge, but they are spelled-out only once, giving rise to discrepancies between meaning and form. According to this approach, ellipsis in wh-questions with coordination can be an epiphenomenon of multidominance. © 2020 The Linguistic Circle of Copenhagen.

Oxidized phospholipids (OxPLs) are known to induce in cultured cells multiple biological effects that are potentially relevant to pathology. However, until recently it was not clear if accumulation of OxPLs plays a causative role in disease or is an epiphenomenon. Recent progress in identification of molecular targets of OxPLs led to development of new in vivo models that clearly demonstrated the importance of these lipid mediators in pathology. This review discusses currently known receptor and non–receptor-dependent mechanisms triggering biological action of OxPLs. Rapidly accumulating evidence suggests that some of these mechanisms represent promising targets for therapy.

Gastrointestinal (GI) symptoms are common in anorexia nervosa (AN), can predate illness onset, complicate renourishment, and persist after recovery. We explore how, through processes of aversive visceral conditioning, early GI pain and discomfort may increase vulnerability to AN in some individuals. Processes include enhanced preoccupation with the gut resulting from aversive visceral memories and disruptions in the typical acquisition of self-attunement when children learn to map and interpret interoceptive sensations and develop adaptive actions. We question whether a fear of weight gain, in some cases, may be an epiphenomenon of the recapitulation of actual or perceived GI symptoms that is especially relevant during puberty, especially in girls. This conceptualization has immediate clinical implications and offers ideas for future research. We propose that GI discomfort associated with renourishment may reignite prior aversive visceral experiences. We encourage development of a formulation that organizes the individual’s current experience of the body with respect to these prior aversive experiences. Our conceptualization underscores the importance of assessment of GI experiences in individuals with AN; the examination of dietary strategies that minimize GI symptoms and enhance renourishment efficacy; and strategies that attempt to alter this aversive visceral conditioning by mapping sensations to meanings and adaptive actions.

The aim of this paper is to argue that there existed relevant interactions between mechanics and geometry during the first half of the nineteenth century, following a path that goes from Gauss to Riemann through Jacobi. By presenting a rich historical context we hope to throw light on the philosophical change of epistemological categories applied by these authors to the fundamental principles of both disciplines (which they came to regard as hypotheses or conventions). We intend to show that presentations of the changing status of the principles of mechanics as a mere epiphenomenon of the emergence of non-Euclidean geometries are inaccurate, that the relations between the two disciplines were richer than what is usually considered in the literature. These claims will be based on historical and philosophical arguments, starting from the fact that disciplinary boundaries at the time were not rigid as we are used today. It is widely known that the main figures we target worked in different areas, which is a first piece of evidence for the plausibility of our main thesis.

The capacity for complex, conscious thought is arguably the human mind's most defining feature. Nevertheless, the efficacy of consciousness has long been debated, with some arguing that consciousness is a feckless epiphenomenon or that its influence on behavior is trivial. We focus specifically on conscious thought, which appears to be a uniquely human capacity, rather than the more basic phenomenal consciousness that humans appear to share with other animals. We argue that the influence of conscious thought on behavior is profound, and that to detect this influence requires observing behavior across multiple events scattered across time. In our view, conscious thought is not the executor of behavior but rather serves as an input into an unconscious executive. Specifically, conscious thought comprises mental simulations that enable the person to imagine and respond to reflections on the past, anticipations about the future, and other nonpresent events. Thus, conscious thought should not be expected in most cases to influence behavior directly and in the current moment. Instead, we argue that conscious thought is for planning for the future, that conscious thought changes automatic responses slowly over time, and that accurate conscious reflections requires observation across multiple events. Therefore, to detect conscious thought's influence requires tests with much broader time spans than is typical in extant research. We argue that an empirical approach that takes such a broad perspective is necessary for understanding fully how conscious thought guides behavior, makes decisions, and otherwise adapts the self to the complexities of human social life.

Background Emerging evidence suggests that dysbiosis, imbalanced gut microbial community, might be a key player in the development of various diseases, including inflammatory arthropathies, such as rheumatoid arthritis, spondyloarthritis (mainly, ankylosing spondylitis and psoriatic arthritis), and osteoarthritis. Yet, the underlying mechanisms and corresponding interactions remain poorly understood. Methods We conducted a critical and extensive literature review to explore the association between dysbiosis and the development of inflammatory arthropathies. We also reviewed the literature to assess the perspectives that ameliorate inflammatory arthropathies by manipulating the microbiota with probiotics, prebiotics or fecal microbiota transplantation. Results Some bacterial species (e.g. Prevotella, Citrobacter rodentium, Collinsella aerofaciens, Segmented filamentous bacteria) participate in the creation of the pro-inflammatory immune status, presumably via epitope mimicry, modification of self-antigens, enhanced cell apoptosis mechanisms, and destruction of tight junction proteins and intestinal barrier integrity, all leading to the development and maintainance of inflammatory arthropathies. Whether dysbiosis is an epiphenomenon or is an active driver of these disorders remains unclear, yet, recent observations clearly suggest that dysbiosis precedes and triggers their development implying a causative relationship between dysbiosis and inflammatory arthropathies. The underlying mechanisms include dysbiosis-mediated changes in the functional activity of the intestinal immune cell subsets, such as innate lymphoid cells, mucosa-associated invariant T cells, invariant natural killer T cells, T-follicular helper and T-regulatory cells. In turn, disturbed functionality of the gut-associated immune system is shown to promote the overgrowth of many bacteria, thus establishing a detrimental vicious circle of actively maintaining arthritis. Conclusions Analysis of the data described in the review supports the notion that a close, dynamic and tightly regulated cross talk between dysbiosis and the gut-associated immune system governs the development of inflammatory arthropathies.

Achalasia is the prototypical obstructive motor disorder diagnosed using HRM, but non-achalasia motor disorders are often identified in symptomatic patients. The clinical relevance of these disorders are assessed using ancillary HRM maneuvers (multiple rapid swallows, rapid drink challenge, solid swallows) that augment the standard supine HRM evaluation by challenging peristaltic function. Finding obstructive motor physiology in non-achalasia motor disorders may raise the option of invasive management akin to achalasia. Certain non-achalasia disorders, particularly hypermotility disorders, may manifest as epiphenomena seen with esophageal hypersensitivity. Symptomatic management is offered for superimposed reflux disease, psychological disorders, functional esophageal disorders, and behavioral disorders.

We propose that preservation of functional integration, estimated from measures of neural synchrony, is a key neurocompensatory mechanism associated with healthy human ageing. To support this proposal, we demonstrate how phase-locking at peak alpha frequency from Magnetoencephalography (MEG) data is invariant over lifespan in a large cohort of human participants, aged 18-88 years. Using empirically derived connection topologies from diffusion tensor imaging (DTI) data, we create an in-silico model of whole-brain alpha dynamics. We show that enhancing inter-areal coupling can cancel the effect of increased axonal transmission delay associated with age-related degeneration of white matter tracts and thus, preserve neural synchrony. Together with analytical solutions for non-biological all-to-all connection scenarios, our model establishes the theoretical principles by which frequency slowing with age, frequently observed in the alpha band in diverse populations, can be viewed as an epiphenomenon of the underlying neurocompensatory mechanisms.

The two target articles address the origins of music in complementary ways. However, both proposals focus on overt musical behaviour, largely ignoring the role of perception and cognition, and they blur the boundaries between the potential origins of language and music. To resolve this, an alternative research strategy is proposed that focuses on the core cognitive components of musicality.

Cancer is a major cause of death in patients with non-alcoholic fatty liver disease (NAFLD). Obesity is a risk factor for cancers; however, the role of NAFLD in this association is unknown. We investigated the effect of NAFLD versus obesity on incident cancers.We identified all incident cases of NAFLD in a US population between 1997-2016. Individuals with NAFLD were matched by age and sex to referent individuals from the same population (1:3) on the index diagnosis date. We ascertained the incidence of cancer after index date until death, loss to follow-up or study end. NAFLD and cancer were defined using a code-based algorithm with high validity and tested by medical record review. The association between NAFLD or obesity and cancer risk was examined using Poisson regression.A total of 4,722 individuals with NAFLD (median age 54, 46% male) and 14,441 age- and sex-matched referent individuals were followed for a median of 8 (range 1-21) years, during which 2,224 incident cancers occurred. NAFLD was associated with 90% higher risk of malignancy: incidence rate ratio (IRR) = 1.9 (95% CI 1.3-2.7). The highest risk increase was noted in liver cancer, IRR = 2.8 (95% CI 1.6-5.1), followed by uterine IRR = 2.3 (95% CI 1.4-4.1), stomach IRR = 2.3 (95% CI 1.3-4.1), pancreas IRR = 2.0 (95% CI 1.2-3.3) and colon cancer IRR = 1.8 (95% CI 1.1-2.8). In reference to non-obese controls, NAFLD was associated with a higher risk of incident cancers (IRR = 2.0, 95% CI 1.5-2.9), while obesity alone was not (IRR = 1.0, 95% CI 0.8-1.4).NAFLD was associated with increased cancer risk, particularity of gastrointestinal types. In the absence of NAFLD, the association between obesity and cancer risk is small, suggesting that NAFLD may be a mediator of the obesity-cancer association.We studied the incidence of malignancies in a community cohort of adults with non-alcoholic fatty liver disease (NAFLD) in reference to age- and sex-matched adults without NAFLD. After 21 years of longitudinal follow-up, NAFLD was associated with a nearly 2-fold increase in the risk of developing cancers, predominantly of the liver, gastrointestinal tract and uterus. The association with increased cancer risk was stronger in NAFLD than obesity.

2AbstractPerception is known to cycle through periods of enhanced and reduced sensitivity to external information. Here, we asked whether such infra-slow oscillations arise as a noise-related epiphenomenon of limited processing capacity or, alternatively, represent a structured mechanism of perceptual inference. Using two large-scale datasets, we found that humans and mice waver between alternating intervals of externally- and internally-oriented modes of sensory analysis. During external mode, perception was more sensitive to external sensory information, whereas internal mode was characterized by enhanced biases toward perceptual history. Computational modeling indicated that dynamic changes in mode are enabled by two interlinked factors: (i), the integration of subsequent inputs over time and, (ii), infra-slow anti-phase oscillations in the perceptual impact of external sensory information versus internal predictions that are provided by perceptual history. Simulated data suggested that between-mode fluctuations may benefit perception by generating unambiguous error signals that enable robust learning and metacognition in volatile environments.3One sentence summaryHumans and mice fluctuate between external and internal modes of sensory processing.

The commonsense view is that a lucid dream starts when the dreamer realizes that they are currently dreaming. The notion of realization, however, has been accepted at face value, with little consideration of whether the dreamer realizes that they are dreaming in the sense of actual reasoning, or if it is a mere epiphenomenon of lucid dream initiation. This article offers a solution to this problem by, first, arguing that the transition to lucidity can occur as a result of successful reasoning, and second, building a model of this reasoning in terms of probabilistic reasoning. The established Bayesian model explains realization in lucid dreams taking under consideration two factors: the beliefs that the dreamer holds on what is generally probable and improbable, and the dreamer’s admissibility of being in a dream. Defended against important objections, the model offers an explanation of lucid dream initiation, relevant for future research on dreaming.

Tumor metabolism supports the energetic and biosynthetic needs of rapidly proliferating cancer cells and modifies intra- and intercellular signaling to enhance cancer cell invasion, metastasis, and immune evasion. Prostate cancer exhibits unique metabolism with high rates of de novo fatty acid synthesis driven by activation of the androgen receptor (AR). Increasing evidence suggests that activation of this pathway is functionally important to promote prostate cancer aggressiveness. However, the mechanisms by which fatty acid synthesis are beneficial to prostate cancer have not been well defined. In this review, we summarize evidence indicating that fatty acid synthesis drives progression of prostate cancer. We also explore explanations for this phenomenon and discuss future directions for targeting this pathway for patient benefit.

BACKGROUND: The Parkinson’s Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson’s disease, healthy controls, and carriers of the most common Parkinson’s disease-related genetic mutations, which aims to define biomarkers of Parkinson’s disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson’s disease that correlate with reduced DAT binding. METHODS: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual’s age. We used t tests, χ(2) tests, and Fisher’s exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number . FINDINGS: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

Background The determinants of restless legs syndrome (RLS) occurring in co-morbid association with Parkinson’s disease (PD) are currently unknown. Methods We performed a skin biopsy in proximal and distal sites of lower limbs in four PD patients, in which RLS had emerged in the pre-motor phase. Results A reduced somato-sensory intraepidermal nerve fiber (IENF) density mainly in the proximal sites, indicative of non-length-dependent small fiber pathology (SFP), was found in all patients, in absence of electroneurographic signs of large fiber neuropathy. Discussion The lack of known secondary causes of SFP is consistent with a process intrinsic to PD and, likewise, the absence of known disease conditions associated to RLS, would support the view of a link between the latter disorder and the distal axonopathy. The non-length-dependent pattern of SFP suggest an involvement of the somato-sensory dorsal root ganglia small neurons, consistent with a somato-sensory neuronopathy, which characterizes the RLS in these patients. Conclusion If these findings will be confirmed in a larger cohort of patients, the RLS co-morbid with PD should be regarded as an heterogeneous condition, since the one emerging in the pre-motor phase might represent a prodromal feature of the neurodegenerative disease as an epiphenomenon of somato-sensory SFP. In contrast, for the RLS developing in clinically manifest PD, a possible association with the impairment of the DAergic diencephalo-spinal pathway and the induction by chronic DAergic treatment has been hypothesized.

Aims Classifications of occluding vasculopathies (except vasculitis [1]) may exhibit some difficulties. Firstly, classifications may follow different principles, e.g. clinicopathologic findings, etiology or pathogenesis. Secondly, authors may not distinguish between vasculitis and occluding vasculopathies. Thirdly, occluding vasculopathies are systemic diseases. Organ-specific variations make morphologic findings difficult to compare. Moreover, subtle changes are recognized in the skin, but may be invisible in other organs. Our aim was to use the skin and subcutis as a tool and clinicopathological correlation as the basic process for classification. Methods and results We first differentiate in the skin between small and medium vessel occluding vasculopathies. Here we focus on medium vessel-occluding vasculopathies. In the second step we differentiate the vessel subtypes. In the final step, we differentiate according to the time point of the coagulation/reorganization process and the involved inflammatory cells/stromal features. By applying the same procedure to the various entities and visualizing the findings in the style of bar codes, the overlaps and differences in the clinical picture as well as the histopathology become more apparent. Conclusions Occluding vasculopathies are often not separate entities, but reaction patterns and epiphenomena. Distinguishing them from vasculitides is crucial because of the differences in pathogenesis, therapeutic approach and prognosis.

Background Premature ventricular complexes (PVCs) are the most common form of ventricular arrhythmia in the general population. While in most cases PVCs represent a primitive phenomenon with benign behavior, in a non-negligible proportion of subjects frequent PVCs may be epiphenomenon of underlying occult heart diseases, requiring special medical attention since they have been resulted linked to increased total and cardiac mortality. Nevertheless, PVCs themselves, when incessantly frequent, may be responsible for left ventricular dysfunction in otherwise normal heart. Aim of this narrative review is to update current knowledge on the general approach to patients with frequent PVCs on the basis of available data, with a special focus on the value of imaging. Hypothesis Routine diagnostic work-up not infrequently miss subtle concealed arrhythmic substrate, leading to erroneously refer to such arrhythmias as to "idiopathic". Methods Literature search of PVCs articles was conducted in PubMed and Scopus electronic database. Results Conflicting data arise from literature about the true clinical significance of idiopathic PVCs. There is growing body of data providing evidence that more advanced non-invasive imaging modalities, such as cardiac magnetic resonance, have an incremental diagnostic and prognostic value. On the other hand, in some cases the prognostic significance of isolated subtle myocardial structural abnormalities in patients with PVCs, still remains area of uncertainty. Conclusion In selected subjects with PVCs and high-risk features for concealed arrhythmic substrate, traditional assessment to rule out the presence of heart disease, including surface ECG and transthoracic echocardiography, should be implemented with more advanced cardiovascular imaging modalities.

The neurovascular unit, consisting of neurons, astrocytes, and vascular cells, has become the focus of much discussion in the last two decades and emerging literature now suggests an association between neurovascular dysfunction and neurological disorders. In this review, we synthesize the known and suspected contributions of astrocytes to neurovascular dysfunction in disease. Throughout the brain, astrocytes are centrally positioned to dynamically mediate interactions between neurons and the cerebral vasculature, and play key roles in blood-brain barrier maintenance and neurovascular coupling. It is increasingly apparent that the changes in astrocytes in response to a variety of insults to brain tissue – commonly referred to as “reactive astrogliosis” – are not just an epiphenomenon restricted to morphological alterations, but comprise functional changes in astrocytes that also contribute to the phenotype of neurological diseases with both beneficial and detrimental effects. In the context of the neurovascular unit, astrocyte dysfunction accompanies, and may contribute to, blood-brain barrier impairment and neurovascular dysregulation, highlighting the need to determine the exact nature of the relationship between astrocyte dysfunction and neurovascular impairments. Targeting astrocytes may represent a new strategy in combinatorial therapeutics for preventing the mismatch of energy supply and demand that often accompanies neurological disorders.