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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Neurodegeneration is the ultimate manifestation of various neurodegenerative, neurovascular, and neuroinflammatory diseases, brain traumatisms, and aging. However, viewing neurodegeneration as the pathological/clinical epiphenomenon of numerous specific pathogenetic mechanisms has not provided a unitary neurodegenerative model nor a cure. It is emerging that neurodegeneration is related to failure of the glymphatic-lymphatic system(G-Ls) (Nedergaard and Goldman, 2020). This system represents a functionally integrated unit regulating solute trafficking and immune-surveillance in the CNS (Louveau et al., 2018; Nedergaard and Goldman, 2020). The G-Ls sub-serves CSF's flow from the subarachnoid spaces into the perivascular spaces and subsequently into the interstitium, and the aquaporin-4 water channels drive it. The cerebrospinal-interstitial fluid then passes to the venous perivascular and perineural spaces, lastly draining toxic molecules and immune cells from the brain into meninges and deep lymph nodes. If we think of G-Ls dysfunction as the common final pathway to neurodegeneration (Nedergaard and Goldman, 2020), we can no longer consider the heterogeneous clinical cases where neurodegeneration manifests distinctively as diseases per se, but pathologies of G-Ls where noxae and symptoms are centered on a unique physiopathology. We propose a systematic vision of the events leading to the “G-Ls pathology” and, according to the relevant G-Ls dysfunctions, introduce a new categorization of diseases manifesting with neurodegeneration.

Simple Summary Cancer is one of the main causes of death worldwide and early detection is crucial for effective treatment. Scientists have therefore focused on the identification of circulating cancer-specific molecules, so-called markers, that can be detected with non- or less-invasive techniques. One attractive emerging marker is represented by circulating antibodies against molecules that are specific for the tumor cells and not produced by normal cells. Many such auto-antibodies have been discovered, but still not much is known about their significance and role in either promoting or inhibiting tumor growth. The aim of this review is to summarize the current knowledge on auto-antibodies in different cancer types and on their current or possible utilization for effective cancer management. Reference to autoimmune diseases will also be made, as they share with cancer the presence of such auto-antibodies. Abstract Auto-antibodies are classically associated with autoimmune diseases, where they are an integral part of diagnostic panels. However, recent evidence is accumulating on the presence of auto-antibodies against single or selected panels of auto-antigens in many types of cancer. Auto-antibodies might initially represent an epiphenomenon derived from the inflammatory environment induced by the tumor. However, their effect on tumor evolution can be crucial, as is discussed in this paper. It has been demonstrated that some of these auto-antibodies can be used for early detection and cancer staging, as well as for monitoring of cancer regression during treatment and follow up. Interestingly, certain auto-antibodies were found to promote cancer progression and metastasis, while others contribute to the body’s defense against it. Moreover, auto-antibodies are of a polyclonal nature, which means that often several antibodies are involved in the response to a single tumor antigen. Dissection of these antibody specificities is now possible, allowing their identification at the genetic, structural, and epitope levels. In this review, we report the evidence available on the presence of auto-antibodies in the main cancer types and discuss some of the open issues that still need to be addressed by the research community.

A relationship is emerging between SARS-CoV-2 infections and ANCA-associated vasculitis (AAV) because: (i) the pulmonary involvement of COVID-19 may mimic that observed in patients with AAV; (ii) the two diseases may occur together; (iii) COVID-19 may trigger AAV. However, few cases of AAV have been identified so far in COVID-19 patients. To define the frequency of ANCA autoimmunity in patients with SARS-CoV-2 infection, we analyzed the serum ANCAs and the serum PR3 and MPO antigens by immunoassays in 124 adult patients with a diagnosis of SARS-CoV-2 infection (16 were asymptomatic and 108 were hospitalized) and 48 control subjects. The serum ANCAs were significantly higher in the hospitalized patients compared with either the controls or the asymptomatic patients and increased with the progression of the COVID-19 severity. After one week of hospitalization, the values were significantly lower. In contrast, no differences emerged among the controls, asymptomatic and hospitalized patients for the PR3 and MPO serum levels. None of the patients had clinical signs of AAV with the exception of a severe pulmonary involvement. Further studies are necessary to define whether the increase in the serum ANCAs might mask subclinical vasculitis in a percentage of patients with SARS-CoV-2 infection or it is an epiphenomenon of SARS-CoV-2 infection with no clinical manifestations.

Age related macular degeneration (AMD) represent one of the first clinical entities that were correlated with ocular rigidity (OR). Measurements performed with both indirect and direct methodology have created some evidence that could support an etiopathogenic relation between OR and AMD. Our group has contributed to these data with measurements performed in living human eyes using a direct manometric methodology. However, since there is always the possibility that increased scleral rigidity is an epiphenomenon of AMD and not an etiologic factor, future work focusing on imaging, ocular hemodynamic evaluation and non-invasive rigidity recording could help clarify the possible role of sclera and choroidal vasculature in AMD and possibly provide novel means for intervening in pathophysiology of the disease.

Stress-induced hyperglycaemia (SIH) at hospital admission for acute coronary syndrome is associated with poor outcome, especially in patients without known diabetes. Nevertheless, insulin treatment in these subjects was not correlated with the reduction of mortality. This is likely due to the fact that SIH in the context of an acute coronary syndrome, compared to that in known diabetes, represents an epiphenomenon of other pathological conditions, such as adrenergic and renin-angiotensin system over-activity, hyperglucagonaemia, increase of circulating free fatty acids and pancreatic beta-cell dysfunction, which are not completely reversed by insulin therapy and so worsen the prognosis. Thus, SIH may be considered not only as a biomarker of organ damage, but also as an indicator of a more complex therapeutic strategy in these subjects. The aim of this review is to analyse the molecular mechanisms by which SIH may favour a worse prognosis in non-diabetic patients with acute coronary syndrome and identify new therapeutic strategies, in addition to insulin therapy, for a more appropriate treatment and improved outcomes.

A novel Coronavirus strain, named “Severe Acute Respiratory Syndrome Coronavirus 2” (SARS‐CoV‐2) was recently identified as the etiological agent of the COronaVIrus Disease 2019 (COVID‐19). Interestingly, a consistent number of COVID‐19‐associated skin manifestations seem to share a certain degree of vascular damage as common pathogenetic mechanism1. Vascular injury may be due to the direct damage of endothelial cells by the virus or may represents an epiphenomenon of a dysregulated host inflammatory responses triggered by the infection2. Here, we describe an unprecedented case of leukocytoclastic vasculitis presenting with a hemorrhagic bullous eruption in a patient affected by COVID‐19.

A large body of literature reports the higher prevalence of epilepsy in subjects with Autism Spectrum Disorder (ASD) compared to the general population. Similarly, several studies report an increased rate of Subclinical Electroencephalographic Abnormalities (SEAs) in seizure-free patients with ASD rather than healthy controls, although with varying percentages. SEAs include both several epileptiform discharges and different non-epileptiform electroencephalographic abnormalities. They are more frequently associated with lower intellectual functioning, more serious dysfunctional behaviors, and they are often sign of severer forms of autism. However, SEAs clinical implications remain controversial, and they could represent an epiphenomenon of the neurochemical alterations of autism etiology. This paper provides an overview of the major research findings with two main purposes: to better delineate the state-of-the-art about EEG abnormalities in ASD and to find evidence for or against appropriateness of SEAs pharmacological treatment in ASD.

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic–molecular cohorts.

Sleep disturbance is the most prominent symptom in depressive patients and was formerly regarded as a main secondary manifestation of depression. However, many longitudinal studies have identified insomnia as an independent risk factor for the development of emerging or recurrent depression among young, middle‐aged and older adults. This bidirectional association between sleep disturbance and depression has created a new perspective that sleep problems are no longer an epiphenomenon of depression but a predictive prodromal symptom. In this review, we highlight the treatment of sleep disturbance before, during and after depression, which probably plays an important role in improving outcomes and preventing the recurrence of depression. In clinical practice, pharmacological therapies, including hypnotics and antidepressants, and non‐pharmacological therapies are typically applied. A better understanding of the pathophysiological mechanisms between sleep disturbance and depression can help psychiatrists better manage this comorbidity.

In the older population, one of the serious health concerns associated with negative outcomes such as comorbidity, loss of physical autonomy, excessive use of health care resources, and increased mortality is the onset of mood disorder [1]. Late-life depression (LLD) is an umbrella term to define depressed mood in people older than 65 years. It can have a variety of presentations: as recurrent disease stemming from earlier life (early onset depression [EOD]); as new-onset depression (late-onset depression [LOD]); as a mood disorder secondary to a general medical condition; or as mood symptoms secondary to substance or medication use [2]. Mistakenly, LLD is believed as a normal part of aging. For older people, depression could be the epiphenomenon of underlying biological processes (vascular changes, metabolic disturbances and neurodegenerative diseases); conversely, it could be the leading cause of cognitive impairment [3].

Previous work has found gender differences in restricted and repetitive behaviors and interests (RRBI) for autism spectrum disorder (ASD). Compared to girls, affected boys have increased stereotyped and restricted behaviors; however much less is known about gender differences in other areas of RRBI. This study aims to identify whether specific RRBI (i.e., stereotyped, self-injurious, compulsive, insistence on sameness, ritualistic, and restricted), as measured by item-level data on the Repetitive Behavior Scale-Revised (RBS-R), can distinguish girls from boys with ASD. Participants included 615 individuals with ASD (507 boys; 82.4%), ages 3-18 years of age (M = 10.26, SD = 4.20), who agreed to share data with the National Database for Autism Research (NDAR). Multivariate analysis of variance and discriminant function analysis (DFA) were used to determine whether item-level RBS-R data could correctly classify cases by gender. DFA results suggest that RBS-R items significantly differentiate gender. Strongly differentiating RBS-R items had greater success in correctly classifying affected boys (67.90%) than girls (61.00%). Items that best-discriminated gender were heightened stereotyped behaviors and restricted interests items in boys and compulsive, sameness, restricted, and self-injurious behavior items in girls. This study is the first to find that girls with ASD may have increased compulsive, sameness, and restricted RRBI compared to boys. Additionally, findings support heightened self-injurious behaviors in affected girls. Future research should disentangle whether elevated rates of RRBI in girls are central to the presentation of ASD in girls or an epiphenomenon of the high rates of co-occurring disorders (e.g., anxiety) noted in girls. Autism Res 2019, 12: 274-283 © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study is the first to examine a comprehensive measure of repetitive behavior in children with autism, with findings of increased compulsive, insistence on sameness, and self-injurious behavior characterizing girls and increased stereotyped and restricted behavior characterizing boys. Future research should determine whether these elevated behaviors in girls are directly part of the autism presentation in girls or symptoms of co-occurring psychopathology. It is important for autism diagnostic measures to best capture the types of repetitive behavior girls may demonstrate.

Chronic kidney disease (CKD) has become a global public health problem because of its high prevalence and the accompanying increase in the risk of end-stage renal disease, cardiovascular disease, and premature death. The role of uric acid (UA) in the pathogenesis and progression of CKD remains controversial. Although many evidence-based studies have suggested that UA itself may harm patients with CKD by increasing inflammation and CKD progression, the issue is still a matter of discussions. In this review we try to clarify what is hyperuricemia – cause of CKD, compensation, coincidence, consequence of CKD or it is only an epiphenomenon, and to evaluate current evidence of different types of targeted hypouricemic therapy effectiveness. So, to treat or not to treat?

Background/Aims: Cherry angiomas (CAs) are one of the most common vascular manifestations of the skin. By and large, these benign lesions often only represent an aesthetic problem. In the literature, few authors have focused on the pathogenesis of these lesions, and some risk factors have been identified, such as the presence of cutaneous and nonskin neoplasias. In this study, the correlation between the distribution of CAs and breast cancer was investigated. Methods: We carried out a study whereby 50 women with unilateral breast cancer and the presence of CAs on the anterior thoracic wall were evaluated, with a particular focus on the difference in the number of CAs between the two haemithoraces. The data was elaborated using the Wilcoxon signed-rank test in order to evaluate whether there was a statistical significance in the distribution of CAs. Results: In 31 patients we found that the number of CAs was greater on the cancerous breast than on the contralateral one (p value

The relationship between high-density lipoproteins (HDLs), HDL-cholesterol (HDLC) and cancer incidence and mortality is controversial. Although most studies conducted so far, including well-designed prospective studies and meta-analyses, have revealed a significant inverse association between HDL-C levels and cancer risk, several confounding factors and opposite results showing either a direct or an inverse association between HDL-C levels and cancer mortality have hindered the possibility to derive definitive conclusions. Moreover, different lines of research also pointed out that this association might actually reflect an inverse causality, which would imply that low HDL-C levels merely represent an epiphenomenon of cancer-related inflammation and cancer cell renewal. Accordingly, the pharmacological increase of plasma HDL-C levels in large lipid modifying trials has not resulted in an amelioration of cancer-related outcomes. In such an intricate scenario, we conducted a comprehensive review of the literature with the aim to provide a wide perspective on the association between HDLs, mild and extreme changes in plasma HDL-C levels and cancer incidence and mortality, touching upon the certainties, the failures and the open issues in this intriguing area of research.

Background Aberrant attributional styles are counted to a set of circumscribed cognitive biases that are implicated in the pathogenesis of (paranoid) psychosis. However, evidence for a specific profile (e.g., an exaggerated self-serving bias, other-blaming bias) has become equivocal over the years. More recently, one-sided (monocausal) attributions have been reported in patients with psychosis. Methods We compared a large sample of patients with diagnosed schizophrenia ( n = 145) to nonclinical controls ( n = 30) on a revised version of the Internal, Personal and Situational Attributions Questionnaire (IPSAQ-R). In this task, participants have to assign probability estimates to each of three potential causes (i.e., myself, others, circumstances) for a specific (negative or positive) event. Results Participants with schizophrenia displayed an abolished self-serving bias and showed a significant preference for one-sided/monocausal attributions, which was neither correlated with jumping to conclusions nor overconfidence in errors. School education correlated with less monocausal attributions. We did not find any congruence between attributional styles with core delusional ideas. Conclusions: Our study corroborates earlier investigations showing that monocausal attributions may play a role in the pathogenesis of psychosis; this bias unlikely represents an epiphenomenon of established biases. Unexpectedly, attributional styles (e.g., external-blaming) did not shape delusional contents. The true prevalence of monocausal attributions in psychosis is perhaps underestimated in the study, as groups were equated on school education, which was correlated with monocausal attributions.

Liver dysfunction and jaundice are traditionally viewed as late features of sepsis and other critical illnesses and are associated with a complicated ICU stay. However, study results suggest that cholestatic alterations occur early in the course of critical illnesses, perceived only as minor abnormalities in routinely used biochemical liver tests. Inflammation-induced alterations in the transport of bile acids (BAs) appear to drive BAs and bilirubin toward the systemic circulation. Ongoing BA synthesis with an, at least partial, loss of feedback inhibition further contributes to elevated circulating BAs and bilirubin. To what extent these changes reflect a biochemical epiphenomenon, true illness-induced liver dysfunction, or a beneficial and adaptive response to illness should be investigated further. Because of the lack of specificity of standard laboratory tests, especially in the context of a complex systemic condition such as critical illness, identifying true cholestatic liver dysfunction remains a great challenge. However, high levels of cholestatic markers that are sustained in patients with prolonged critical illness almost always indicate a complicated illness course and should be monitored closely. Preventing cholestatic liver dysfunction comprises minimizing inflammation and hypoxia in the liver and preventing hyperglycemia, avoiding early use of parenteral nutrition, and reducing the administration of avoidable drugs. Future research on the effects of BAs and on modulating underlying drivers of cholestasis induced by critical illness is warranted as this could open perspectives for a targeted diagnostic approach and ultimately for novel therapies to improve outcome.

Background/Objectives The epidemiology of exocrine pancreatic insufficiency (EPI) after acute pancreatitis (AP) is uncertain. We sought to determine the prevalence, progression, etiology and pancreatic enzyme replacement therapy (PERT) requirements for EPI during follow-up of AP by systematic review and meta-analysis. Methods Scopus, Medline and Embase were searched for prospective observational studies or randomized clinical trials (RCTs) of PERT reporting EPI during the first admission (between the start of oral refeeding and before discharge) or follow-up (≥ 1 month of discharge) for AP in adults. EPI was diagnosed by direct and/or indirect laboratory exocrine pancreatic function tests. Results Quantitative data were analyzed from 370 patients studied during admission (10 studies) and 1795 patients during follow-up (39 studies). The pooled prevalence of EPI during admission was 62% (95% confidence interval: 39–82%), decreasing significantly during follow-up to 35% (27–43%; risk difference: − 0.34, − 0.53 to − 0.14). There was a two-fold increase in the prevalence of EPI with severe compared with mild AP, and it was higher in patients with pancreatic necrosis and those with an alcohol etiology. The prevalence decreased during recovery, but persisted in a third of patients. There was no statistically significant difference between EPI and new-onset pre-diabetes/diabetes (risk difference: 0.8, 0.7–1.1, P = 0.33) in studies reporting both. Sensitivity analysis showed fecal elastase-1 assay detected significantly fewer patients with EPI than other tests. Conclusions The prevalence of EPI during admission and follow-up is substantial in patients with a first attack of AP. Unanswered questions remain about the way this is managed, and further RCTs are indicated. Electronic supplementary material The online version of this article (10.1007/s10620-019-05568-9) contains supplementary material, which is available to authorized users.

A recent generation of family studies has revealed that autism can be predicted from an array of neurobehavioural susceptibilities that are appreciable before the syndrome is diagnosed, and that each may be traceable to partially-independent sets of genetic variation. Some of these liabilities are not necessarily specific to ASD—those that are non-specific could account for a significant share of the ‘missing heritability’ of autism, would (by definition) contribute to pleiotropy, and relate to so-called ‘co-morbidities’, which are inappropriately named if they actually contribute to (or exacerbate) the severity of autism itself. Linking genetic variants to these underlying traits rather than to a diagnosis of ‘autism’ may be more productive in devising personalized approaches to developmental intervention, especially if autism represents an epiphenomenon of earlier-interacting susceptibilities. In this article, the implications of conceptualizing autism as a syndrome of neurobehavioural degeneration is considered, predicated on the notion that it can arise from a critical co-aggregation of earlier-interacting neuropsychiatric liabilities, the phenotypic expression of which—importantly—can be moderated by sex.

In this discussion paper, I review a number of common misconceptions about the phonological deficit theory (PDH) of dyslexia. These include the common but mistaken idea that the PDH is simply about phonemic awareness (PA), and, consequently, is a circular “pseudo”-explanation or epiphenomenon of reading difficulties. I argue that PA is only the “tip of the phonological iceberg” and that “deeper” spoken-language phonological impairments among dyslexics appear well before the onset of reading and even at birth. Furthermore, not even reading-specific expressions of phonological deficits—PA or pseudoword naming, can be considered circular if we clearly distinguish between reading proper—real meaning-bearing words, or real text, and the mechanisms (subskills) of reading development (such as phonological recoding). I also explain why an understanding of what constitutes an efficient writing system explains why phonology is necessarily a major source of variability in reading ability and hence a core deficit (or at least one core deficit) among struggling readers whether dyslexic or non-dyslexic. I also address the misguided notion that the PDH has now fallen out of favor because most dyslexia researchers have (largely) ceased studying phonological processing. I emphasize that acceptance of the PDH does not imply repudiation of other non-phonological hypotheses because the PDH does not claim to account for all the variance in reading ability/disability. Finally, I ask where neurobiology enters the picture and suggest that researchers need to exercise more caution in drawing their conclusions.

INTRODUCTION: Idiopathic neutropenia (IN) of childhood is a benign, self-limiting disorder usually occurring in the first 3 years of life that differs from primary autoimmune neutropenia (AIN) because anti neutrophil antibodies are not detected on repeated indirect testing over time(1). Chronic idiopathic neutropenia (CIN) is a well characterized disorder of elderly with a peculiar immunological pattern(2). Pediatric AIN patients, with atypical features represented by longer disease duration (Long Lasting) or diagnosed later (Late Onset), were recently shown by our group to display a different immune-hematological profile vs typical primary AIN(3). Atypical pediatric IN subjects, i.e. diagnosed later or with longer disease duration, though occasionally reported, were never systematically investigated. In the present study we analyzed a cohort of young patients with atypical IN and AIN, diagnosed after the age of 3 years or with longer disease duration, aiming to identify an immunological signature that might predict their different outcome from classical AIN and IN of infancy. PURPOSE OF THE STUDY: to analyze a cohort of patients affected with AIN and IN rising > 3 years of age and with duration >12 months or rising MATERIALS AND METHODS: Clinical, immunological and genetic data (NGS panel of 160 immunodeficiency/disimmunity genes) of eligible patients were collected from the database of the Italian Neutropenia Registry. RESULTS: From 2005 to 2020, data from 46 patients (24F, 24 autoimmune and 22 Idiopathic Neutropenia) were retrieved. Median age at onset was 11.2 years (IQR13.2-16.7), median follow-up was 4.3 years (IQR 3.2-6.8). Neither autoimmunity nor additional cytopenias to neutropenia were present at onset. Cumulative incidence at 5 years of autoimmune manifestations (thyroiditis, arthritis, vitiligo, recurrent skin rash) was 11.8% (CI 95% 4.3-30). Throughout the follow up, infections occurred in 32/46 (70%) subjects and in only 16% were severe (meningitis, recurrent pneumonia, sepsis and pericarditis). Infections sites were upper respiratory (in 84% of subjects mouth and gums (47%), and skin (40%) ear (25%), lung (19%) and urinary tract (12%). Fever of unknown origin was detected in 40% of patients. Recurrent infections (more than 3/y) involved mouth (85%) and ear (88%). White Blood Cell, Absolute Neutrophil and Lymphocyte counts retrieved at the beginning of the study, in the middle and at the end of follow up are shown in Table 1. Leucocytes and Lymphocytes at the end of follow up were significantly lower than values seen at diagnosis (p < 0.001) whereas neutrophil count remained stable (p=ns). One third of the cohort had lower values than normal of CD19+ and CD3-CD56+CD16+ cells. B switched memory CD27+/IgD-/IgM- (in 94%) were lower, while marginal zone B lymphocytes CD27+/IgD+/IgM+ (62%) and Tγδ cells (70%) were increased than the normal population according to a pattern comparable to that described in chronic idiopathic neutropenia (CIN). Immunoglobulin serum levels (IgA, IgG and IgM) were below the normal value in 7.5% of the population, but specularly a small subset (7.5%) of IN showed an increase of IgM was seen, similar to what already descibed in adult CIN. The genetic study carried out in 32 patients showed in 5 (16%) pathogenic variants: of immunodeficit/dysregulation (2 TACI, 1 TINF2, 1 CARD11) and in 9 cases (28%) VUS in genes of the same groups (1CARD11, 4CASP10,1DDX41/SOCS1, 1TSR2/DCLRE1c, 1PIK3D, 1TERT/TACI). CONCLUSIONS: Atypical IN and AIN (of longer duration or occurring in advanced pediatric age) are different from those appearing in early infancy. They seem to display dysimmune/autoimmune features that is some case is proven to rely on a genetic dysimmune background. They might represent an anticipation of more complex autoimmune disorders which may fully manifest later in life. Interstingly these patients seem to share some features with CIN of adults. Definitive conclusions will be drawn by applying more comprehensive genetic nalysis (WES and WGS) on larger group of subjects. References: 1. Farruggia et al, Am J Hematol. 2019, 94:216-222 2. Mavroudi I et al, Clin Immunol. 2017 Oct;183:75-84 3. Fioredda F et al, Blood Adv 2020 Nov 24;4:5644-5649 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Supplemental Digital Content is available in the text., Background: Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity–induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. Methods: We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. Results: Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose–fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. Conclusions: Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

Headache is one of the most common ailments; migraine is one of the most prevalent and disabling neurological disorders and cluster headache presents as one of the most excruciating pain disorders. Both are complex disorder characterized by recurrent episodes of headache. A key feature is that various triggers can set off an attack providing the opportunity to explore disease mechanisms by experimentally inducing attacks. This review summarizes neuroimaging and hemodynamic studies in human in provoked and spontaneous attacks of migraine and cluster headache. Cerebral hemodynamics during different phases of the migraine attack demonstrate alterations in cerebral blood flow and perfusion, vessel caliber, cortical and sub-cortical function, underscoring that migraine pathophysiology is highly complex. Migraine attacks might begin in diencephalic and brainstem areas, whereas migraine aura is a cortical phenomenon. In cluster headache pathophysiology, the hypothalamus might also play a pivotal role, whereas the pattern of cerebral blood flood differs from migraine. For both disorders, alterations of arterial blood vessel diameter might be more an epiphenomenon of the attack than a causative trigger. Studying cerebral hemodynamics in provocation models are important in the search for specific biomarkers in the hope to discover future targets for more specific and effective mechanism-based anti-headache treatment.

Leukostasis in the retinal microvasculature in animal model studies of diabetes is associated with the development of diabetes-like retinopathy. Therefore, it is generally assumed that adhesion of leukocytes is a central event inciting a chronic, low-grade form of inflammation that causes the vascular abnormalities that are specific for the early stages of diabetic retinopathy (DR), which culminate in diabetic macular edema, proliferative DR, and vision loss in humans. Here, we review the literature critically with respect to leukostasis and assess its pathologic consequences in the human diabetic retina. First, we review the pathologic processes that are known to be involved in the development of human DR. Then, we summarize experimental evidence for the role of leukostasis in the development of DR and the mechanisms involved in leukostasis in the retina. Based on our critical review, we conclude that leukostasis may be an epiphenomenon of the diabetic retinal milieu, rather than a crucial, specific step in the development of human DR.

The role of autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in the development of secondary pulmonary alveolar proteinosis (PAP) in patients exposed to occupational and environmental dust remains unclear. Herein, we describe two cases of secondary PAP who had GM-CSF antibodies and absence of STAT5 phosphorylation index, suggestive of a potential relationship between the appearance of GM-CSF antibodies and environmental dust exposure. However, whether the presence of GM-CSF antibodies is a part of the pathological process or represents an epiphenomenon is currently unknown. In this report, we would like to present two cases supporting these new data and briefly discuss the possible role of autoimmune mechanisms in the development of secondary PAP. Am. J. Ind. Med. 60:591-597, 2017. © 2017 Wiley Periodicals, Inc.