Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19.

BACKGROUND & AIMS: Mechanisms and clinical impact of portal microthrombosis featuring severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesized that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19. METHODS: Ninety-three patients who died from COVID-19, were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-ß) markers, tissue factor (TF), viral spike-protein and nucleoprotein (SP, NP), fibrinogen, platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy (TEM). Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells (HPMEC) was assessed upon vWF treatment. RESULTS: IPVD was present in 16/66 COVID-19 patients with both liver and lung histology, with a younger age (62 vs 78yo), longer illness (25 vs 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and more ventilatory support (63 vs 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, were confirmed by chest-CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-ß+/ SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In-vitro SARS-CoV-2 infection of pericytes up-regulated TF and induced endothelial cells to overexpress vWF, which expanded HPMEC tubules. CONCLUSIONS: SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19. IMPACT AND IMPLICATIONS: Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a pro-coagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterized at the clinical level by development of hypoxemia and at the histological level, by phlebosclerosis and reduced caliber of the portal vein branches in the absence of cirrhosis. Moreover, our findings bring light to an as yet overlooked player of thrombosis pathophysiology, i.e. pericytes, which may provide novel therapeutic tools to halt prothrombotic mechanisms.

The bidirectional connection between family functioning and psychopathology: A network analysis in a large sample of adolescents with anorexia nervosa and their parents.

Family functioning is a risk and maintaining factor for anorexia nervosa (AN). This study aims to identify specific areas of family functioning according to adolescents and parental perspectives associated with eating and general psychological symptoms in people with AN. Four-hundred-forty-five adolescents with AN or atypical AN and their parents were enrolled. Adolescents completed the Eating Disorder Inventory-3, the Youth Self-Report questionnaire, and the Family Assessment Device (FAD). Their parents filled in the FAD. A network analysis was conducted including all subscales. The bridge function analysis was applied to identify the bridge nodes connecting each community constituted of family functioning perception with the communities of adolescents' eating and general psychological symptoms. Family communication was the node most strongly connecting fathers and mothers' perception of family functioning and adolescents' eating symptoms. Problem solving was the node with the highest bridge expected influence between mothers' family functioning and adolescents' general psychopathology. General functioning and problem solving were the bridge nodes between adolescents' view of family functioning and eating and general psychopathology. Maturity fear, interpersonal insecurity, and interpersonal alienation were the bridge nodes between adolescents' eating symptoms and mothers, fathers, and adolescents' family functioning communities respectively. Family members must be involved in the therapeutic process to improve family communication and problem solving diverting their attention toward emotional needs and interpersonal difficulties of adolescents with AN. Developing autonomy and independence from parents and building trustworthy relationships with peers may be favored by improving familiar dynamics and may contribute to prevent the maintenance of AN.

Mediation role of interpersonal problems between insecure attachment and eating disorder psychopathology.

PURPOSE: Although insecure attachment and interpersonal problems have been acknowledged as risk and maintaining factors of eating disorders (EDs), the mediating role of interpersonal problems between attachment style and ED psychopathology has been poorly explored. The purpose of this study was to investigate the mediating role of interpersonal problems between insecure attachment and ED psychopathology. METHODS: One-hundred-nine women with anorexia nervosa and 157 women with bulimia nervosa filled in the Eating Disorder Inventory-2 (EDI-2) and the Experiences in Close Relationships (ECR) revised scale to assess ED core symptoms and attachment styles, respectively. Interpersonal difficulties were evaluated by the Inventory of Interpersonal Problems (IIP-32). A mediator's path model was conducted with anxious and avoidant attachment subscores as independent variables, ED core symptoms as dependent variables and interpersonal difficulties as mediators. The diagnosis was entered in the model as a confounding factor. RESULTS: The socially inhibited/avoidant interpersonal dimension was a mediator between avoidant attachment and the drive to thinness as well as between avoidant attachment and body dissatisfaction. An indirect connection was found between attachment-related anxiety and bulimic symptoms through the mediation of intrusive/needy score. CONCLUSIONS: Social avoidance and intrusiveness mediate the relationships between avoidant and anxious attachment styles and ED psychopathology. These interpersonal problems may represent specific targets for psychotherapeutic treatments in individuals with EDs and insecure attachment. LEVEL OF EVIDENCE: Level III: Evidence obtained from well-designed cohort or case-control analytic studies.

Association between childhood maltreatment and cortical folding in women with eating disorders.

Childhood maltreatment (CM) is associated with distinct clinical and biological characteristics in people with eating disorders (EDs). The measurement of local gyrification index (lGI) may help to better characterize the impact of CM on cortical structure. Thus, the present study investigated the association of CM with lGI in women with EDs. Twenty-six women with anorexia nervosa (AN) and 24 with bulimia nervosa (BN) underwent a 3T MRI scan. All participants filled in the Childhood Trauma Questionnaire. All neuroimaging data were processed by FreeSurfer. LGI maps underwent a general linear model to evaluate differences between groups with or without CM. People with AN and BN were merged together. Based on the Childhood Trauma Questionnaire cutoff scores, 24 participants were identified as maltreated and 26 as non-maltreated. Maltreated people with EDs showed a significantly lower lGI in the left middle temporal gyrus compared with non-maltreated people, whereas no differences emerged in the right hemisphere between groups. The present study showed that in people with EDs, CM is associated with reduced cortical folding in the left middle temporal gyrus, an area that could be involved in ED psychopathology. This finding corroborates the hypothesis of a 'maltreated ecophenotype', which argues that CM may allow to biologically, other than clinically, distinguish individuals with the same psychiatric disorder.

Turn-Mimic Hydantoin-Based Loops Constructed by a Sequential Multicomponent Reaction.

A collection of peptidomimetics characterized by having an aspartic acid motif embedded in a rigid hydantoin heterocycle are synthesized through a sequential multicomponent domino process followed by standard regioselective deprotection/coupling reactions based on acid-base liquid/liquid purification protocols. 1H nuclear magnetic resonance experiments, molecular modeling, and X-ray analysis showed that the resulting hydantoin-based loops I (in particular) and II (to a lesser extent) can be considered novel ß-turn inducer motifs being able to project two peptide-like strands in a U-shaped conformation driven by the formation of intermolecular hydrogen bonds.

Childhood maltreatment is associated with cortical thinning in people with eating disorders.

Childhood maltreatment (CM) is a non-specific risk factor for eating disorders (ED) and is associated with a greater severity in their clinical presentation and poorer treatment outcome. These data suggest that maltreated people with ED may be biologically other than clinically different from non-maltreated people. The aim of the present study was to investigate cortical thickness (CT), a possible biomarker of neurodevelopment, in people with ED with or without history of CM and in healthy women. Twenty-four healthy women, 26 with anorexia nervosa and 24 with bulimia nervosa underwent a 3T MRI scan. All participants filled in the childhood trauma questionnaire. All neuroimaging data were processed by FreeSurfer. Twenty-four participants with ED were identified as maltreated and 26 participants with ED as non-maltreated. All healthy women were non-maltreated. Compared to healthy women, maltreated people with ED showed lower CT in the left rostral anterior cingulate gyrus, while compared to people with ED without history of CM showed lower CT values in the left superior frontal and in right caudal middle frontal and superior parietal gyri. No significant differences emerged in CT measures between healthy women and people with ED without history of CM. The present findings show for the first time that in adult people with ED childhood maltreatment is associated with cortical thinning in areas implicated in the modulation of brain processes that are acknowledged to play a role in the psychopathology of ED.

A network analysis in adolescent anorexia nervosa exploring the connection between both patient and carer reactions and outcome.

OBJECTIVE: This paper used network analysis to test the associations between eating disorder-related psychopathology and carers' responses to anorexia nervosa symptoms in adolescents. Additionally, the prognostic value of central and bridge network nodes was explored. METHOD: This is a secondary analysis of a three-armed randomised-controlled-trial of adolescents with anorexia nervosa (n = 149) and their primary carer (n = 149) who were allocated to either treatment as usual (TAU), or one of two versions of a carer skills intervention (ECHO) added to TAU. A network analysis was run in the full sample. The prognostic role of central and bridge nodes was tested through multiple regression analyses. RESULTS: Carers' depression and emotional over-involvement, as well as patients' depression showed the highest strength centrality. Patients' depression and carers' accommodation exhibited the highest bridge expected influence. Across the full sample, and in the ECHO group, carers' accommodation predicted patients' higher body mass index (BMI), while patients' depression predicted worse psychosocial functioning at 1-year follow-up. In the ECHO group, higher carers' depression also predicted lower BMI. CONCLUSIONS: Carers' accommodation and depression in both carers and patients were involved in the maintenance of psychopathology in adolescents with anorexia nervosa. Depression in both patients and carers is a potential treatment target for family interventions.

Pathways between childhood maltreatment and life satisfaction in adolescents with eating disorders: A network analysis.

OBJECTIVE: This study explored the association between Childhood maltreatment (CM) experiences and life satisfaction in adolescents with eating disorders (EDs). METHODS: Adolescent inpatients with EDs completed the Childhood Trauma Questionnaire, the Satisfaction With Life Scale, the Brief Symptom Inventory and the Eating Disorder Inventory-2 at admission (n = 361) and discharge (n = 354). A network analysis was conducted to identify the shortest pathways between different types of CM and life satisfaction at admission and discharge. RESULTS: General psychopathology, life satisfaction, and ED symptoms improved from admission to discharge. At admission, emotional abuse and emotional neglect were included in the pathway between sexual/physical abuse and life satisfaction. Emotional neglect was directly connected with life satisfaction while emotional abuse was connected through feeling disliked by others, feelings of inferiority and worthlessness. At discharge, only the direct negative connection between emotional neglect and perception of excellent conditions in the life persisted. CONCLUSIONS: Emotional maltreatment experiences and general psychopathology, but not disordered eating symptoms, are involved in the association between sexual/physical CM and life satisfaction in adolescents with EDs. Emotional neglect may affect life satisfaction regardless of symptoms severity. These findings inform clinicians for assessment and treatment of maltreated adolescents with EDs.

Emotional non-acceptance mediates the relationship between insecure attachment and specific psychopathology in women with eating disorders.

OBJECTIVE: Insecure attachment is considered a general risk factor for eating disorders (ED). Emotion dysregulation has been proposed as one of the possible mechanisms by which attachment insecurity may affect ED psychopathology. Aim of the present study was to investigate whether difficulties in acceptance of emotions or emotional clarity may mediate the connection between insecure attachment and ED psychopathology. METHOD: One hundred and twenty patients participated and completed the Italian version of Eating Disorder Inventory-2, Experience in Close Relationship questionnaire and Difficulties in Emotion Regulation Scale. A mediator path model was performed, in which insecure attachment dimensions were set as independent variables, ED specific psychopathology measures as dependent variables, and non-acceptance of emotion and lack of emotional clarity as mediators. RESULTS: The association between both attachment avoidance and anxiety and ED specific symptoms was mediated by emotional non-acceptance, but not by emotional clarity. CONCLUSIONS: This study showed the importance to address emotion regulation in individuals with ED, focussing on improving emotional acceptance. Exploring early developmental processes which lead to non-acceptance of emotions could improve this psychological trait in people with ED.

Clinical utility of circulating calprotectin to assist prediction and monitoring of COVID-19 severity: An Italian study.

BACKGROUND: Calprotectin (S100A8/A9) has been identified as a biomarker that can aid in predicting the severity of disease in COVID-19 patients. This study aims to evaluate the correlation between levels of circulating calprotectin (cCP) and the severity of COVID-19. METHODS: Sera from 245 COVID-19 patients and 110 apparently healthy individuals were tested for calprotectin levels using a chemiluminescent immunoassay (Inova Diagnostics). Intensive care unit (ICU) admission and type of respiratory support administered were used as indicators of disease severity, and their correlation with calprotectin levels was assessed. RESULTS: Samples from patients in the ICU had a median calprotectin concentration of 11.6 µg/ml as compared to 3.5 µg/ml from COVID-19 patients who were not in the ICU. The median calprotectin concentration in a cohort of healthy individuals collected before the COVID-19 pandemic was 3.0 µg/ml (95% CI: 2.820-2.969 µg/ml). Patients requiring a Venturi mask, continuous positive airway pressure, or orotracheal intubation all had significantly higher values of calprotectin than controls, with the increase of cCP levels proportional to the increasing need of respiratory support. CONCLUSION: Calprotectin levels in serum correlate well with disease severity and represent a promising serological biomarker for the risk assessment of COVID-19 patients.

Canakinumab in systemic juvenile idiopathic arthritis: real-world data from a retrospective Italian cohort.

OBJECTIVE: The objective of this study was to use real-world data to evaluate the effectiveness and safety of canakinumab in Italian patients with systemic JIA (sJIA). METHODS: A retrospective multicentre study of children with sJIA was performed. Clinical features, laboratory parameters and adverse events were collected at baseline, and 6 and 12 months after starting canakinumab. The primary outcome measure of effectiveness was clinically inactive disease (CID) off glucocorticoids (GCs) treatment at 6 months. RESULTS: A total of 80 children from 15 Italian centres were analysed. Of the 12 patients who started canakinumab in CID while receiving anakinra, all maintained CID. Of the 68 with active disease at baseline, 57.4% achieved CID off GCs at 6 months and 63.8% at 12 months. In univariate analysis, the variables significantly related to non-response were number of active joints (NAJs) ≥5, history of macrophage activation syndrome (MAS) and disease duration. Multivariate analysis confirmed the association between non-response and NAJs ≥5 [odds ratio (OR) 6.37 (95% CI: 1.69, 24.02), P = 0.006] and between non-response and history of MAS [OR 3.53 (95% CI: 1.06, 11.70), P = 0.039]. No serious adverse events were recorded in this series. There were two cases of MAS during canakinumab, leading to a rate of 2.9 episodes per 100 patient years. CONCLUSION: We have confirmed, using real-world data, the efficacy of canakinumab in sJIA in a multicentric cohort. History of MAS and higher NAJ were associated with lower probability of achieving CID.

Comparison of current methods for anti-dsDNA antibody detection and reshaping diagnostic strategies.

Anti-double-stranded DNA antibodies (anti-dsDNA) are considered a specific marker for systemic lupus erythematosus (SLE). Though the Farr technique was once the reference method for their detection, it has been almost entirely replaced by more recently developed assays. However, there is still no solid evidence of the commutability of these methods in terms of diagnostic accuracy and their correlation with the Crithidia luciliae immunofluorescence test (CLIFT). Anti-dsDNA antibody levels were measured in 80 subjects: 24 patients with SLE, 36 disease controls drawn from different autoimmune rheumatic diseases (14 systemic sclerosis, 10 Sjögren's syndrome, nine autoimmune myositis, three mixed connective tissue disease), 10 inflammatory arthritis and 10 apparently healthy blood donors by eight different methods: fluorescence enzyme immunoassay, microdot array, chemiluminescent immunoassay (two assays), multiplex flow immunoassay, particle multi-analyte technology immunoassay and two CLIFT. At the recommended manufacturer cut-off, the sensitivity varied from 67% to 92%, while the specificity ranged from 84% to 98%. Positive agreement among CLIFT and the other assays was higher than negative agreement. Mean agreement among methods assessed by the Cohen's kappa was 0.715, ranging from moderate (0.588) to almost perfect (0.888). Evaluation of the concordance among quantitative values by regression analysis showed a poor correlation index (mean r2, 0.66). The present study shows that current technologies for anti-dsDNA antibody detection are not fully comparable. In particular, their different correlation with CLIFT influences their positioning in the diagnostic algorithm for SLE (either in association or sequentially). Considering the high intermethod variability, harmonization and commutability of anti-dsDNA antibody testing remains an unachieved goal.

Metabolomics signatures of acutely ill and short-term weight recovered women with anorexia nervosa.

Although metabolomics studies are recently spreading and have allowed the characterization of putative biomarkers in many diseases, they are relatively scanty in anorexia nervosa (AN). In this explorative study we analyzed the fecal metabolomics profiles of women with AN in the underweight phase (n = 24) and after short-term weight restoration (n = 16) and compared them with 20 healthy women. An untargeted metabolomic procedure allowed the characterization of 224 metabolites involved in energy, lipid, and amino acid metabolism. A partial least square discriminant analysis identified 14 metabolites with a variable importance in projection score >1.5 that clearly differentiated underweight from weight-restored patients from healthy women. Compared with healthy women, fecal concentrations of valeric acid and 3-methyl,2-ketobutyric acid were increased in both underweight and weight-restored patients; fecal concentrations of propionic acid, stearic acid, linolenic acid, methyl-galactoside, coprosterol, cycloserine, and lauric acid were increased while fecal levels of xylose, fucose, and rhamnose were decreased in underweight patients and normalized after weight-restoration; fecal concentrations of piperine, phenylalanine, butyric acid, and meso-erythritol-1 were decreased while fecal levels of hydroxystearic acid were increased in weight-restored but normal in underweight AN patients. All these changes point to peculiar fecal metabolomics profiles of acute and short-term weight restored AN patients. The value of these changes to improve our understanding of the pathophysiology of AN and to characterize potential biomarker targets for developing new treatment strategies needs further studies to be clarified.

Psychopathology predicts mental but not physical bariatric surgery outcome at 3-year follow-up: a network analysis study.

PURPOSE: This study aimed to explore the psychopathological variables that may predict bariatric surgery outcomes after 3 years. METHODS: One hundred ninety-six candidates for bariatric surgery completed self-report questionnaires to assess eating attitudes, eating disorder (ED)-related psychopathology, affective symptoms, interpersonal and psycho-social functioning. One-hundred patients repeated this assessment 3 years after bariatric surgery. A network analysis was run including the pre-surgical measurements in the network. A composite score derived from the combination of the most central network nodes, as well as clinical and socio-demographical variables, was included in a multivariate regression analysis with weight loss, ED psychopathology and psycho-social functioning as outcomes. RESULTS: Depression, stress, and shape concerns were the most central network nodes. The composite network score predicted higher ED psychopathology and worse psycho-social functioning at 3-year follow-up, but not weight loss. Higher age, restricting type of bariatric surgery and higher pre-operative BMI were further predictors of reduced weight loss and greater ED psychopathology. CONCLUSIONS: Affective symptoms and shape concern play a central role in the psychopathology of candidates to bariatric surgery and predict post-surgery ED psychopathology and psycho-social functioning. These variables may allow to identify patients with higher pre-operative risk and in need of further psycho-social interventions. LEVEL OF EVIDENCE: III, evidence obtained from well-designed cohort study.

The connection between childhood maltreatment and eating disorder psychopathology: a network analysis study in people with bulimia nervosa and with binge eating disorder.

PURPOSE: Childhood maltreatment (CM) experiences are associated with heightened risk of Eating disorders (EDs). The psychopathological pathways promoting this association in people with Bulimia nervosa (BN) and in those with Binge eating disorder (BED) are under-investigated. METHODS: One hundred and eighty-one people with BN and 144 with BED filled in the Eating Disorder Inventory-2, to measure ED psychopathology, and the Childhood Trauma Questionnaire, to assess their early traumatic experiences. Network analysis was conducted to investigate the interplay between those variables. The shortest pathways function was employed to investigate the shortest out of all routes conveying the association between CM and ED-specific symptoms. RESULTS: In both people with BN and with BED, all CM types were connected to the ED psychopathology through the emotional abuse node. The association between emotional abuse and ED-specific symptoms (bulimia and body dissatisfaction) differed in the two groups: in people with BN, it included ineffectiveness, while in people with BED, it involved impulsivity. Interoceptive awareness, an indirect measure of emotion regulation, was included in these pathways in both groups. CONCLUSION: In the light of literature showing that emotional abuse has a connecting role between CM and ED psychopathology also in anorexia nervosa, the present findings support the idea that emotional abuse conveys such association in all the main ED diagnoses. Ineffectiveness and impulsivity may represent the specific psychopathological dimensions connected to emotional abuse and promoting the maintenance of ED-specific symptoms in BN and in BED, respectively. These findings are worth of attention by clinicians. LEVEL OF EVIDENCE: Level III: evidence obtained from well-designed cohort or case-control analytic studies.

Non-verbal social communication in individuals with eating disorders: an ethological analysis in experimental setting.

PURPOSE: Evidence that social difficulties promote the development and the maintenance of eating disorders (EDs) derive from self-reported data and only partially from experimental tasks. This study objectively assessed non-verbal behaviors of individuals with EDs in a psycho-social stress scenario. METHODS: Thirty-one women suffering from EDs (13 with anorexia nervosa and 18 with bulimia nervosa) and 15 healthy women underwent the Trier Social Stress Test (TSST), the paradigm of psycho-social stress, and were videotaped. Throughout the procedure, anxiety feelings were measured by the State-Trait Anxiety Inventory state subscale and saliva samples were collected to evaluate cortisol levels. Non-verbal behaviors were analyzed through the Ethological Coding System for Interviews and were compared between study samples through multivariate analysis of variance. Multivariate regression analyses were performed to assess the association between anxiety, cortisol and behavioral responses to TSST. RESULTS: Women with EDs showed reduced submissiveness, flight (cutoff from social stimuli) and gesture compared to healthy peers during TSST. Submissiveness and flight behaviors were negatively associated with stress-induced anxiety, while TSST-induced anxiety and cortisol increases were positively associated with looking at the other's face behavior in participants with EDs. In this population, cortisol reactivity was also positively associated with submissiveness and negatively with gesture. CONCLUSION: Women with EDs showed a hostile and freezing response to acute psycho-social stress: reduced submissiveness and flight may represent strategies to manage social anxiety. These findings confirm that the non-verbal behavior assessment provides complementary information to those derived from traditional measurements and suggests research and clinical implications. LEVEL OF EVIDENCE I: Evidence obtained from experimental study.

What do Italian healthcare professionals think about orthorexia nervosa? Results from a multicenter survey.

PURPOSE: Orthorexia nervosa (ON) is an obsession for healthy and proper nutrition. Diagnostic criteria for ON are lacking and the psychopathology of ON is still a matter of debate in the clinical and scientific community. Our aim was to better understand the Italian clinical and scientific community's opinion about ON. METHODS: Anonymous online survey for Italian healthcare professionals, implemented with the REDCap platform and spread through a multicenter collaboration. Information was gathered about socio-demographic, educational and occupational features, as well as about experience in the diagnosis and treatment of EDs. The main part of the survey focused on ON and its features, classification and sociocultural correlates. RESULTS: The survey was completed by 343 participants. Most responders (68.2%) considered ON as a variant of Eating Disorders (EDs), and 58.6% a possible prodromal phase or evolution of Anorexia Nervosa (AN). Most participants (68.5%) thought the next DSM should include a specific diagnostic category for ON, preferably in the EDs macro-category (82.1%). Moreover, 77.3% of responders thought that ON deserves more attention on behalf of researchers and clinicians, and that its treatment should be similar to that for EDs (60.9%). Participants thinking that ON should have its own diagnostic category in the next DSM edition had greater odds of being younger (p = 0.004) and of considering ON a prodromic phase of another ED, such as AN (p = 0.039). DISCUSSION: Our survey suggests that the scientific community still seems split between those who consider ON as a separate disorder and those who do not. More research is still needed to better understand the construct of ON and its relationship with EDs; disadvantages and advantages of giving ON its own diagnosis should be balanced. LEVEL OF EVIDENCE: V (descriptive cohort study).

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

BACKGROUND AND AIMS: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. METHODS: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. RESULTS: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. CONCLUSION: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. LAY SUMMARY: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.

COVID-19 Pandemic and Eating Disorders: What Can We Learn About Psychopathology and Treatment? A Systematic Review.

PURPOSE OF REVIEW: This systematic review aims to collect evidence regarding the impact of the SarsCov-2 pandemic on people affected by eating disorders (EDs) targeting the following variables: psychopathology changes, mechanisms of vulnerability or resilience, and perception of treatment modifications during the pandemic. RECENT FINDINGS: Since the beginning of the pandemic, a mental health deterioration has been detected in the general population and especially in people affected by pre-existing psychiatric conditions. Furthermore, mental healthcare has moved toward online treatment. ED people showed a trend toward worsening of ED-specific psychopathology and impairment in general psychopathology. The most common vulnerability mechanisms were social isolation and feelings of uncertainty, while heightened self-care and reduced social pressure were resilience factors. The online treatment, although raising many concerns related to its quality, was considered the best alternative to the face-to-face approach. These findings may support the idea that stressful events contribute to the exacerbation of ED psychopathology and highlight the relevance of internalizing symptoms in EDs. The identification of putative risk and resilience variables as well as of subjective factors affecting online treatment perception may inform healthcare professionals and may promote more personalized approaches.

Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: A series of 43 cases.

AIM: Coronavirus disease (COVID-19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID-19 patients. The aim of this study is to identify pathological microthrombi in COVID-19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation. METHODS: Forty-three post-mortem liver biopsy samples from COVID-19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated. RESULTS: We found liver sinusoidal microthrombosis in 23 COVID-19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10-fold, p = 0.04; AST: 11-fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p < 0.01), whereas SEA was not (p = 0.73). In COVID-19 livers, strong vWF staining in liver sinusoidal endothelial cells was associated with significantly increased platelet adhesion (1.7-fold, p = 0.0016), compared to those with weak sinusoidal vWF (2-fold, p < 0.0001). Sinusoidal erythrocyte aggregation in 19 (83%) liver samples was mainly seen in zone 2. Livers with SEA had significantly higher fibrinogen (1.6-fold, p = 0.031) compared to those without SEA in COVID-19 patients. CONCLUSIONS: Liver PMT is a pathologically important thrombosis associated with liver injury in COVID-19, while SEA is a unique morphological feature of COVID-19 patient livers. Sinusoidal vWF and hyperfibrinogenemia could contribute to PMT and SEA formation.